ArticlePDF AvailableLiterature Review

Gallium-68: A systematic review of its nononcological applications

June 2013
Nuclear Medicine Communications 34(9)

June 2013
34(9)

DOI:10.1097/MNM.0b013e32836341e5

Source
PubMed

Authors:

Mariza Vorster

University of KwaZulu-Natal

Mike Machaba Sathekge

University of Pretoria

The increased availability of PET facilities worldwide has sparked renewed interest in the use of generator-produced tracers such as gallium-68 (Ga). Imaging with Ga provides exciting opportunities in terms of new ligand-labelling possibilities and the exploration of novel clinical applications. The aim of the study was to summarize and appraise what has been published on the clinical applications of Ga outside oncology practice. This systematic review was based on the PRISMA guidelines. Databases searched include PubMed, Medline, Scopus, Web of Science and Google Scholar. The following search strategy was used: 'Ga' OR 'Gallium' (all fields) NOT the following (title and abstract): Oncology/NET/neuroendocrine tumour/tumor/DOTATOC, DOTATATE, DOTANOC. These results were further limited to English publications, which resulted in 205 publications on PubMed. After duplicates and irrelevant articles were removed, 72 publications remained for inclusion. Only those studies in which compounds were labelled with Ga for applications other than in oncology-related indications were included. Publications in which the focus was on oncology-related applications of Ga imaging or in which the emphasis was on aspects relating to generators, radiochemistry or physics were excluded. Although a multitude of tracers have been labelled with Ga over several decades, it has not been established in routine clinical practice yet. In addition, neuroendocrine and other oncological applications have dominated the field until relatively recently following reports of applications in infection and inflammation. The majority of publications to date involve small numbers of subjects in mainly preclinical settings. Differences in methodology preclude grouping of studies to reach a clear conclusion. There is wide scope for Ga tracer application outside oncological practice, which remains greatly underutilized. Larger clinical trials are needed to validate these applications.

Summary of studies for central nervous system indications with 68 Ga-labelled PET probes

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Gallium-68: a systematic review of its nononcological

applications

Mariza Vorster

, Alex Maes

a,b,c

, Christophe Van deWiele

a,d

and Mike Sathekge

The increased availability of PET facilities worldwide has

sparked renewed interest in the use of generator-produced

tracers such as gallium-68 (

Ga). Imaging with

provides exciting opportunities in terms of new

ligand-labelling possibilities and the exploration of novel

clinical applications. The aim of the study was to

summarize and appraise what has been published on the

clinical applications of

Ga outside oncology practice.

This systematic review was based on the PRISMA

guidelines. Databases searched include PubMed, Medline,

Scopus, Web of Science and Google Scholar. The following

search strategy was used: ‘

Ga’ OR ‘

Gallium’ (all fields)

NOT the following (title and abstract): Oncology/NET/

neuroendocrine tumour/tumor/DOTATOC, DOTATATE,

DOTANOC. These results were further limited to English

publications, which resulted in 205 publications on

PubMed. After duplicates and irrelevant articles were

removed, 72 publications remained for inclusion. Only

those studies in which compounds were labelled with

for applications other than in oncology-related indications

were included. Publications in which the focus was on

oncology-related applications of

Ga imaging or in which

the emphasis was on aspects relating to generators,

radiochemistry or physics were excluded. Although a

multitude of tracers have been labelled with

Ga over

several decades, it has not been established in routine

clinical practice yet. In addition, neuroendocrine and other

oncological applications have dominated the field until

relatively recently following reports of applications in

infection and inflammation. The majority of publications to

date involve small numbers of subjects in mainly preclinical

settings. Differences in methodology preclude grouping of

studies to reach a clear conclusion. There is wide scope for

Ga tracer application outside oncological practice, which

remains greatly underutilized. Larger clinical trials are

needed to validate these applications. Nucl Med Commun

34:834–854 c2013 Wolters Kluwer Health | Lippincott

Williams & Wilkins.

Nuclear Medicine Communications 2013, 34:834–854

Keywords: clinical applications,

Ga tracer, generator-based PET,

infection imaging, nononcology review

Department of Nuclear Medicine, Steve Biko Academic Hospital, University of

Pretoria, Pretoria, South Africa,

Department of Nuclear Medicine, AZ Groeninge,

Kortrijk,

Department of Morphology and Medical Imaging, University Hospital

Leuven, Leuven and

Department of Nuclear Medicine, University Hospital Ghent,

Ghent, Belgium

Correspondence to Mike Sathekge, MD, PhD, Department of Nuclear Medicine,

Steve Biko Academic Hospital, University of Pretoria, Private Bag X169,

Pretoria 0001, South Africa

Tel: +27 123 541 794; fax: + 27 123 541 219; e-mail: mike.sathekge@up.ac.za

Received 16 February 2013 Revised 9 May 2013 Accepted 15 May 2013

Introduction

An increase in the availability of and accessibility to

PET/computed tomography (CT) facilities has sparked

renewed interest in generator-based PET radiopharma-

ceuticals. Gallium-68 (

Ga) in particular has received a

lot of attention as an alternative positron emitter as it

offers several important advantages when compared with

F-FDG.

Gallium (as

Ga-citrate) has long provided nuclear

physicians with a versatile tool for use over a broad

spectrum of clinical applications. The mechanism of

action, although incompletely explained, is generally

accepted to be the result of various specific and

nonspecific factors, which play a role in both infective/

inflammatory and malignant processes. It stands to reason

that

Ga would be as useful as

Ga with the added

advantage of improved image resolution gained from

PET/CT.

Compared with

F-FDG,

Ga provides shorter imaging

times and on-demand, year-round tracer availability that

negates the need for an onsite or nearby cyclotron. This

could have significant financial implications, which may

lead to a more cost-effective way of imaging. In addition,

the short half-life of 68 min provides attractive peptide-

labelling options for novel diagnostic and therapeutic

applications [1].

The majority of published work, however, has focussed on

the application of

Ga in oncology imaging and especially

in the setting of neuroendocrine tumours. This review

focusses on the application of

Ga-labelled tracers in

settings other than those that are oncology related. As

such, the role of

Ga tracers in oncology and neuro-

endocrine tumours will not be addressed again here,

and readers are directed to a number of publications

(including a recent meta-analysis by Treglia and collea-

gues) on this topic [2–4].

Aim

The aim of the study was to summarize and appraise what

has been published on the clinical applications of

outside oncology practice.

Review article

0143-3636 c2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MNM.0b013e32836341e5

Methodology

The selection of appropriate publications and writing of

this review was based on the guidelines contained in the

PRISMA statement [5].

We performed an extensive literature search using the

following databases: PubMed, Medline, Highwire Press,

Scopus, Web of Science and Google Scholar.

The following search strategy was used in PubMed: the

terms ‘Ga-68’ OR ‘Gallium 68’ was used to search all

fields. This resulted in a total of 508 publications, which

were then further limited to English publications,

resulting in 481 publications. Excluding the following

terms from both the title and the abstract (by adding

‘NOT’) resulted in the following numbers of publications

in parentheses: ‘Oncology’ (470), ‘NET’ (443), ‘neuro-

endocrine tumour’ (222), ‘DOTATOC’, ‘DOTATATE’

and ‘DOTANOC’, the results were finally limited to 205

papers.

Similar searches were conducted in Medline (142

publications), Google scholar (217 results), Highwire,

Scopus and Web of Science (121 results), which yielded

an additional 480 publications. Removal of duplicates

resulted in 255 papers, which were assessed for relevance

and quality by screening the titles and abstracts.

Inclusion criteria: Studies or reports in which compounds

were labelled with

Ga for applications other than in

oncology-related indications were included.

Every effort was made to include both the earliest and

the most recent publications relating to a particular

application, as well as any study with a significant new

contribution. The decision to include or exclude an

article was made by consensus.

Exclusion criteria: Publications in which the focus was on

oncology-related applications of

Ga imaging or in which

the emphasis was on aspects relating to generators,

radiochemistry or physics were excluded.

The scope of the literature search was broadened on the

basis of the reference lists of all retrieved articles.

Publications that were selected for this review were from

peer-reviewed indexed journals. Original manuscripts,

case reports, case series, abstracts, poster presentations,

review articles, editorials, conference proceedings and

poster presentations were also included.

After duplicates and irrelevant articles were removed,

72 publications remained for inclusion, of which 63 was

included in the qualitative synthesis. The nine excluded

publications included reviews and editorials, which were

referred to but not analysed as such.

The last literature search was performed on 15 January

2013 Fig. 1.

Clinical applications

During the literature search and article assessment

process, it became clear that publications could easily

be grouped under the various physiological systems to

which they apply. Hence, the selected literature has been

organized under the following system headings: Musculo-

skeletal, Respiratory, Cardiovascular, Central nervous

system, Genitourinary, Gastrointestinal and Miscella-

neous applications. For the most part, studies under each

heading have been discussed in chronological order.

Musculoskeletal system

Perhaps one of the better-known nononcological applica-

tions involves the use of

Ga in the imaging of

musculoskeletal infections.

Despite the fact that

F-FDG has a well-established role

in musculoskeletal infection imaging, imaging with

F-

FDG-PET cannot always clearly differentiate normal

healing processes from postsurgical and infective pro-

cesses.

The following groups have investigated this further

between 2005 and 2012

In 2005, a group from Finland (Ma

¨kinen and colleagues)

used a rat model (in a two-part study) to compare the

performances of

F-FDG and

Ga-chloride (

Ga-Cl)

PET in the differentiation of experimental osteomyelitis

from normal bone healing [6].

During the first part of the study, 50 rats underwent

surgery to the left tibia, with the right tibia serving as the

intact control.

During the second part of the study, osteomyelitis was

induced with Staphylococcus aureus in eight rats and

compared with normal bone healing in eight controls.

Imaging took place 2 weeks after surgery on consecutive

days using both

Ga-Cl and

F-FDG.

Osteomyelitis was confirmed with quantitative bacteriol-

ogy, and PET imaging was followed by both peripheral

quantitative computed tomography (pQCT) and radio-

graphy.

The following observations were made:

(1) Both tracers demonstrated statistically significantly

increased uptake in the tibias affected with osteo-

myelitis compared with the tibias in nonoperated

controls. The mean standardized uptake value (SUV)

ratio for

F-FDG was 1.74 (±0.37) and that for

Ga-Cl was 1.62 (±0.28).

(2)

F-FDG demonstrated increased uptake in control

animals (SUV ratio: 1.16) with healing bone, whereas

Ga-Cl did not accumulate significantly in these

lesions (SUV ratio: 1.02).

(3) This difference between

F-FDG and

Ga-Cl was

found to be statistically significant.

Nononcology applications of

Ga Vorster et al. 835

(4)

Ga-Cl accumulation correlated closely with changes

in bone density and area as measured by pQCT,

whereas

F-FDG did not [6,7].

These findings suggest that imaging with

Ga-Cl may

result in fewer false-positive findings due to normal

postsurgical inflammatory changes.

In two publications by Lankinen and colleagues, the use

Ga-DOTAVAP-P1 was evaluated in trying to

distinguish inflammation in healing bones from osteo-

myelitis. The rationale behind the use of this tracer is

that vascular adhesion protein-1 (VAP-1) is an endothelial

glycoprotein, which plays an important role in the

recruitment of CD8 T lymphocytes during inflammatory

conditions. As it is basically absent from normal

endothelial surfaces and only induced during inflamma-

tory conditions, it should provide a favourable target for

imaging of inflammatory processes in vivo [8].

In the first study, the above-mentioned investigators

compared two groups of rats using a standardized animal

model. The first group represented the infection group

and consisted of 34 rats with S. aureus-induced

osteomyelitis in the left tibia (with the right tibia serving

as the control). In the second group, each of the

34 rats had a healing cortical defect of the left tibia

(representing inflammation), with the right tibia used as

the control. SUV ratios were used to quantify the PET

findings, which were then compared with morphological

changes noted on pQCT and radiographs (parameters

used included cortical bone area and cortical bone

density).

The following observations were made:

(1) Both groups (infection and inflammation) demon-

strated increased

Ga-DOTAVAP-P1 accumulation

for up to 3 h.

Fig. 1

Records identified through PubMed

searching

(n=205)

Identification

Records after duplicates removed

(n=255)

Records screened

(n=255)

Full-text articles assessed for

eligibility

(n=100)

72 publications included in qualitative

synthesis

[(n=63) experimental studies and 9 other

(reviews, editorials)]

Full-text articles excluded

based on

radiochemistry/physics focus

(n=32)

Records excluded based on

oncology focus

(n=155)

Additional records identified

through Medline, Highwire, Scopus,

Google scholar (n=480)

ScreeningEligibilityIncluded

PRISMA 2009 flow diagram

Study selection process.

836 Nuclear Medicine Communications 2013, Vol 34 No 9

(2) After 36 h, only the infection group demonstrated

increased tracer accumulation.

(3) Statistically significant differences in SUV ratios

allowed for differentiation between infection and

inflammation at 7 days after intervention.

(4) Immunohistological evaluation of VAP-P1 allowed for

differentiation between normal healing and infection

as early as 24 h after surgery, whereas cortical bone

area and density could reliably discriminate between

the two at 7 days after surgical intervention [8].

These findings suggest that

Ga-DOTAVAP-P1 may be

able to differentiate bone infection with S. aureus from

normal bone healing as early as 7 days after surgery. It may

also be useful in determining the phase and rate of

infectious and inflammatory processes and as such is

anticipated to play a role in monitoring treatment

response. Limitations of this study included the use of

a clinical PET scanner rather than a micro-PET scanner,

which may have had an impact on the image resolution.

In a follow-up study in 2009 from the same group, Ujula

and colleagues further evaluated the labelling and

biodistribution of

Ga-DOTAVAP-P1. The authors noted

that

Ga-DOTAVAP-P1 binds to VAP-P1-infected cells

more efficiently than to normal cells.

Ga-DOTAVAP-P1

is cleared quickly from the blood pool to be excreted

into the urine and has an in-vivo half-life of around 26 min

in rats. They concluded that infection-induced VAP-P1

can be targeted successfully with

Ga-DOTAVAP-P1

and suggest that this novel tracer could be the first in a

series of similar VAP-P1-specifific imaging agents for the

diagnosis of osteomyelitis [9].

A recent study by Kumar and colleagues investigated the

potential use of

Ga-apo-transferrin (

Ga-TF) in the

detection of S. aureus infection. They injected five rats

with S. aureus and found that the site of infection could

be imaged within an hour after injection using a dose of

10–15 MBq. Infected lesions could be visualized as early

as 20 min after injection for up to 4 h with improving

target-to-background ratios (TBRs). This was in contrast

to the results obtained with the use of

Ga-Cl, which did

not demonstrate any remarkable uptake for up to 2 h after

injection. This study suggests that

Ga-apo-TF may be

valuable in the imaging of S. aureus (and possibly other

anaerobic bacterial infections) and also supports the

hypothesis that gallium uptake depends more on

transferrin binding than on vasodilatory changes [7,10].

In the authors’ experience with

Ga imaging, the image

quality deteriorates significantly after 2 h, which casts

some doubt over the repeatability of these results in the

clinical setting.

Nanni and colleagues in 2010 assessed the accuracy of

Ga-citrate in the evaluation of skeletal infections. A

total of 31 patients (with 40 scans in total) were enrolled

with either acute (n= 18) or chronic osteomyelitis

(n= 4) or diskitis (n= 9), and findings were validated

with the results of combinations of MRI, CT, radiographs,

white blood cell scintigraphy, biochemistry, biopsy results

and follow-up data (up to 1 year) [11].

All patients underwent biopsy, but only 11 turned out to

be diagnostic.

An average dose of 4.5 MBq was injected and images were

taken after an uptake period of 60 min. Tracer biodis-

tribution revealed relatively high vascular activity (mean

SUV

max

: 1.5) with mild hepatic and bone marrow uptake

and absence of bowel activity. All patients with proven

infection demonstrated increased tracer accumulation at

the infection site with a mean SUV

max

of 4.4 (±1.8).

The following observations were made:

(1) The diagnostic accuracy of

Ga-citrate for musculo-

skeletal infection (90% overall) imaging is similar to

that of other modalities currently in use.

(2) Sensitivity was 100%, specificity was 76%, positive

predictive value was 85% and negative predictive

value was 100%.

(3) Imaging with

Ga-citrate has a very high negative

predictive value and no false positives occurred as a

result of implants.

(4) It may be used to evaluate treatment response.

(5) Added value includes being a simple and fast imaging

procedure with low dosimetry and no contraindica-

tions to scanning [11].

To the best of the authors’ knowledge, this is the first

study of its kind to involve the imaging of patients.

Possible limitations of this study include the small

number of patients and no inclusion of patients who

had sustained recent trauma or who had undergone

recent surgery.

Mitterhauser and colleagues sought to develop a simple

preparation method for

Ga-EDTMP as a PET bone-

imaging agent. This was done in anticipation of making

use of the superior resolution of PET imaging together

with the convenience of a generator-based tracer. They

demonstrated that a simple kit preparation was plausible

and that binding of

Ga-EDTMP to bone mineral was

irreversible. However, the uptake and image quality

were inferior to that of

F-fluoride, and therefore the

advantages of this tracer were not clear [10].

Suzuki and colleagues investigated the use of

Ga-

NOTA-Bisphosphonate (

Ga-NOTA-BP) as an alterna-

tive to imaging with

99m

Tc-MDP in a rat model. Although

their study involved the use of this novel

Ga tracer in

the setting of metastatic bone disease evaluation, its

application could easily be extended to include the

nononcological indications for conventional bone imaging

and therefore deserves a brief mention here. The authors

Nononcology applications of

Ga Vorster et al.837

compared

Ga-NOTA-BP with

99m

Tc-MDP and

F-NaF

and found that

Ga-NOTA-BP cleared faster from the

blood, had higher bone-to-blood ratios and allowed

imaging as early as 1 h after injection. This study was

conducted primarily to overcome some of the limitations

experienced with

F-NaF imaging (such as the higher

costs of a cyclotron-produced tracer) and to find a

generator-based alternative in light of the molybdenum

shortage. Other tracers evaluated by various groups before

Ga-NOTA-BP included

Ga-citrate,

Ga-tripoly-

phosphate and

Ga-EDTMP, which did not demonstrate

sufficient efficacy for clinical application [12].

Riss and colleagues in 2008 developed two NODAPA-

glucosamine derivatives for

Ga-labelling for another

novel musculoskeletal application. Glucosamine forms

part of the normal cartilage and synovial fluid and

therefore may be useful in the imaging of osteoarthritis.

To the authors’ best knowledge, no clinical data on this

application are available to date [13].

Summary

(1) The limitations of imaging with

F-FDG in the

setting of musculoskeletal infections are well known.

Of greatest significance clinically is the difficulty to

differentiate normal bone healing or inflammation

from infected bone using this tracer.

(2) Imaging with

Ga may provide attractive alternatives

such as

Ga-Cl,

Ga-DOTAVAP-P1,

Ga-apo-trans-

ferrin,

Ga-citrate and

Ga-NOTA-BP.

(3) A simple kit formulation was plausible with

Ga-

EDTMP, although the tracer did not provide any

advantages over those already in existence.

The majority of publications relating to this application

involve limited numbers of patients and relate to

preclinical settings. They also focus mainly on infection

with S. aureus only.

The outcomes of preclinical studies are as follows:

(1) Bone infection imaging with

Ga-Cl appears to yield

fewer false positives due to postsurgical inflammatory

changes.

(2) Differentiation between infection and inflammation

is possible as early as 7 days after intervention with

Ga-DOTAVAP-P1.

(3)

Ga-apo-transferrin imaging allows the detection of

infection with S. aureus and other anaerobic infections

as early as 1 h after injection.

(4) Work on

Ga-NODAPA-glucosamine derivatives for

possible osteoarthritis imaging is still in a preclinical

phase.

The only study that involved humans suggested a

diagnostic accuracy for

Ga-citrate similar to that of

currently used gold standards with additional practical

advantages such as shorter imaging times and lower

dosimetry.

Many exciting opportunities for tracer development exist

with the emergence of novel applications such as in

osteoarthritis imaging.

More studies in clinical settings involving larger numbers

of patients are clearly needed. Please see Table 1 for a

summary on the musculoskeletal system.

Respiratory system

In the preclinical setting of lung pathology,

Ga has been

labelled mostly to albumin microspheres, to macroaggre-

gates of albumin (MAA) or to transferrin. These have

been applied in various studies to evaluate pulmonary

blood flow, calculate lung water compartments and assess

pulmonary capillary permeability (PTCER). In the

clinical setting,

Ga has been labelled successfully to

siderophores and microspheres. In addition, several

studies have made use of ‘Galligas’, wherein

Ga-Cl is

labelled to carbon particles in a manner similar to

technegas production.

Many lung conditions result in an increase in pulmonary

capillary permeability and extravascular lung water. PET

imaging allows for the quantification of the rate at which

intravenously injected radiolabelled proteins escape into

the extravascular space, which is then expressed as the

pulmonary transcapillary escape rate (PTCER). This

provides an estimate of the severity of lung injury. It

could potentially be used to differentiate cardiogenic

from noncardiogenic causes of pulmonary oedema

and may find clinical application in such conditions

as acute respiratory distress syndrome (ARDS), pneumo-

nia, acute interstitial lung disease, reimplantation re-

sponse and acute ejection after lung transplantation.

Accurate quantification of lung function, however,

remains difficult for several reasons. Tracer activity is

typically expressed per millilitre of tissue (SUV) and

as such changes in values may result from differences in

regional lung volumes, rather than from any real change

in tracer concentration. Other drawbacks include the high

pulmonary blood flow, which results in high background

activity and movement during breathing, which may

result in various artifacts. Therefore, the use of a SUV

alone in the setting of lung disease appears inade-

quate [14].

As early as 1987, Mintun and colleagues measured

pulmonary vascular permeability using

Ga-transferrin.

They imaged six dogs injected with oleic acid to induce

lung injury, as well as two patients with ARDS and two

healthy volunteers.

Ga-citrate was injected intra-

venously and was followed by sequential 1–5-min PET

scans taken over 1 h using a two-compartment model for

analysis. They found that the PTCER was increased 10-

fold in the lungs affected by oleic acid injury and four-fold

838 Nuclear Medicine Communications 2013, Vol 34 No 9

in patients with ARDS (compared with normal lung

values) [15].

Mintun’s study provides proof-of-concept for the use of

Ga-citrate PET in the measurement of pulmonary

vascular permeability. Further generalizations or applica-

tions are not really possible in light of the small size of

the samples and because of the discrepancies between

the protocols used in animals and humans.

Schuster and colleagues in 1998 compared PTCER values

obtained with

Ga-transferrin (370–555 MBq) and

C-

methylalbumin (185 MBq) in the evaluation of lung injury.

The authors imaged two groups of dogs (seven in total):

one group with normal lungs (n= 3) and the other group

with lung injury induced by injection of oleic acid (n= 4).

Imaging and plasma samples were obtained 2 min after

tracer injection for up to 45 min. Blood and tissue samples

were used in a two-compartment analysis to calculate the

PTCER. They concluded that the two tracers correlated

strongly over a wide range of values and that either tracer

could be used to evaluate the severity of lung injury.

Labelled transferrin, however, provided significant prac-

tical advantages, such as availability from a generator [16].

In a follow-up study by the same group published in 2002,

Schuster and colleagues evaluated the use of

Ga-transferrin

PET and

99m

Tc-albumin single-photon emission computed

tomography (SPECT) in the detection of acute lung injury

in a group of patients. They imaged 38 patients in total, of

whom 21 patients had noncardiogenic pulmonary oedema,

seven had hydrostatic forms of pulmonary oedema and 10

were healthy volunteers. All patients were selected on the

basis of radiological criteria and imaged within 24 h of

symptom onset. Their aim was to compare the values of

PTCER obtained with gamma imaging (

99m

Tc-albumin

SPECT) with the values obtained with PET imaging

(222 MBq of

Ga-transferrin) [17].

They made the following observations:

(1) PTCER could not reliably distinguish noncardiogenic

pulmonary oedema from hydrostatic pulmonary

oedema.

(2) PTCER and the normalized slope index are strongly

correlated.

(3) Gamma-obtained PTCER correlated better with

PET PTCER and PaO

/FIO

than with normalized

slope index.

They concluded that, on the basis of the (limited) available

data, gamma camera methods should probably not be used as

a screening tool in acute lung injury trials [17].

In 2010, Kotzerke and colleagues evaluated the use of

Ga-microspheres and Galligas for PET imaging of lung

function. This was done in an attempt to deal with the

Table 1 Summary of the studies for musculoskeletal indications with

Ga-labelled PET probes

Target Tracer/probe Dose (MBq) Uptake time (min)

Experimental setting

(number of subjects) Tracer comparison Quantification type (value) Validation References

Infection vs. inflammation

Ga 28.54±3.74 70 Rat model

Tibia-OM Staphylococcus aureus

(n= 50)

F-FDG SUV ratio (1.62) Microbiol histology

and pQCT

¨kinen et al. [6]

Ga-DOTA-VAP-P1 25.21±5.37 40 Rat model

Tibia-OM S. aureus (n= 34)

NA SUV ratio (1.87 vs.

1.09 at 7days)

Microbiol histology

and pQCT

Lankinen et al. [8]

Skeletal imaging

Ga-DOTA-VAP-P1 22±4 15, 30, 60, 120 Rat model

Tibia-OM S. aureus (n=6)

F-FDG Peptide: 2.3 vs.

F-FDG: 3.1

Microbiol histo-

logy, immuno-

histochemistry

Ujula et al. [9]

Ga-apo-transferrin

(in-vitro labelling)

167 60 Humans with skeletal infections

(n= 31)

NA Mean SUV

max

4.4±1.8

Histology,

combinations of

imaging,

biochemistry and

follow-up

Nanni et al. [11]

Ga-EDTMP 0.31±2.0 – Mouse model (n=2)

F-Fluoride Mean SUV

max

Femur <2

– Mitterhauser et al.

[10]

Ga-NOTA-BP – – Mouse model (n=6)

99m

Tc-MDP

F-fluoride – – Suzuki et al. [12]

NA, not available; OM, osteomyelitis; pQCT, peripheral quantitative computed tomography; SUV

max

, maximum standardized uptake value.

Nononcology applications of

Ga Vorster et al. 839

worldwide shortage of molybdenum by finding a suitable

alternative. Galligas could be produced in a relatively

simple manner, similar to the procedure used for

technegas production. The greater than 3.5 h in-vivo

stability allowed for PET imaging with a dose of

5–10 MBq of

Ga. They found that

Ga-DOTA micro-

spheres were rapidly filtered from venous blood in rats

and accumulated in the lungs in a manner that allows for

quantification [18].

In 2011, Borges and colleagues compared the PET

acquisition of ventilation images using ‘Galligas’ with

those acquired using conventional techniques (consisting

of technegas and SPECT imaging). They made use of a

porcine model and imaged 12 piglets in total, all of which

underwent sequential SPECT and PET imaging. The

animals were divided into three groups: those with lobar

obstruction (a balloon catheter was used to occlude the

lower main bronchus), those with diffuse airway obstruc-

tion (continuous metacholine infusion used to cause

bronchoconstriction) and those with normal lung func-

tion. ‘Galligas’ was prepared using the same technique

and equipment as those used for the production of

technegas, with the substitution of technetium-99m with

GaCl

solution that was inhaled within 10 min of

preparation. Image analysis revealed similar tracer dis-

tribution in both studies for the normal group as well as

for those with lobar obstruction. With diffuse ventilation

involvement, however, nonuniformity on PET images

appeared more pronounced and was confirmed by a

statistically significant difference in tracer count varia-

bility [19]. (The authors implemented correcting mea-

sures to overcome the limitation of differences in

acquisition times.)

The rationale for imaging with a positron emitter includes

better resolution and the possibility of rapid, repeated

studies if needed. In this study, the authors concluded that

PET imaging provides a more accurate picture of ventilation

distribution in the setting of diffuse bronchoconstriction and

that ‘Galligas’ is a ‘promising new diagnostic tool for the

assessment of ventilation distribution’ [19].

Hofman and colleagues in 2011 investigated the use of

Ga PET as a high-resolution alternative to ventilation

perfusion imaging with SPECT. In this prospective pilot

study, they imaged 10 patients suspected of having

pulmonary embolism using both SPECT and PET.

‘Galligas’ was used for PET ventilation, and

Ga-MAA

was injected before PET perfusion image acquisition.

Five out of the 10 patients underwent SPECT and PET

imaging on the same day, with the rest of the patients

undergoing both studies within a period of 1–8 days apart.

Interpreting physicians were blinded to the results of

other investigations and had to make use of a scoring

system in their image evaluation. Image quality was then

rated on a scale of 1 (poor) to 10 (very high) judged on

the uniformity of tracer distribution. The number of

matched and mismatched defects in each lobe was

counted and characterized as segmental, subsegmental

or nonsegmental. In conclusion, a remark of testing

positive or negative for pulmonary embolism was made.

The following observations were made:

(1) PET images demonstrated a more homogeneous

tracer distribution compared with SPECT images

and were judged to be of superior quality compared

with SPECT in all patients (P< 0.01).

(2) Matched and mismatched defects were similar (in

terms of number and localization) in eight out of 10

studies.

(3) Advantages of PET over SPECT imaging included

higher resolution, the possibility of better regional

lung function quantification, greater flexibility in

image acquisition protocols and less time (3–6 min/

study) with a similar effective radiation dose of

3–5 mSv.

(4) The authors concluded that

Ga PET imaging of

ventilation and perfusion is clinically feasible [20].

An important limitation of this study is the fact that half

of the participants underwent the comparative studies

several days apart (1–8 days), during which time the

pathology may have changed.

Ament and colleagues recently confirmed the clinical

feasibility of

Ga-PET ventilation perfusion imaging in a

2012 publication. They concluded that imaging with

aerosol (Galligas) and

Ga-MAA provides an interesting

alternative with high accuracy to

99m

Tc-labelled tracers.

This is relevant especially in times of molybdenum

shortage and in light of the increasing availability and use

of PET/CT scanners and

Ga generators [21].

In 2010, Ambrosini and colleagues investigated the novel

use of

Ga-DOTA-NOC PET/CT in the imaging of

idiopathic pulmonary fibrosis (IPF). This condition

remains difficult to diagnose and has rapid progression

with poor prognosis. The diagnosis is based on radio-

logical and clinical criteria with a pathophysiologic

hallmark of fibroblast foci. These fibroblast aggregates

express somatostatin receptors that can be imaged with

Ga-DOTA-NOC because of the tracer’s affinity for

somatostatin receptors 2, 3 and 5. Because healthy lungs

demonstrate no

Ga-DOTA-NOC, any tracer accumula-

tion may be regarded as abnormal [22].

The authors imaged 14 patients in total, half with a

diagnosis of IPF and the other half with nonspecific

interstitial pneumonia (NSIP). All patients were imaged

with

Ga-DOTA-NOC PET/CT (185 MBq, 60 min

uptake time) and high-resolution CT (HRCT) within a

3-week time frame. The severity of the lung involvement

on CT was scored visually according to a five-point scale.

840 Nuclear Medicine Communications 2013, Vol 34 No 9

The sites and extent of the abnormal tracer accumulation

on PET/CT were then compared with the areas of

pathology on HRCT. All of the study participants (with

the exception of one) were undergoing treatment at the

time of the investigations. Treatment included adminis-

tration of steroids, cyclophosphamide, azathioprine,

methotrexate and various combinations thereof.

Their findings were as follows:

(1) In patients with IPF, abnormal

Ga-DOTA-NOC

correlated with areas of reticular fibrosis and honey-

combing noted on HRCT and was typically located in

the subpleural and peripheral regions.

(2) A linear correlation was found between SUV

max

and

the extent of disease noted on CT.

(3) Patients with NSIP demonstrated less intense

uptake in the areas of ground-glass opacification.

The authors concluded that somatostatin overexpression

in IPF could be imaged with

Ga-DOTA-NOC with the

potential for future treatment response evaluation [22].

In a series of publications between 2010 and 2012, Petrik

and colleagues investigated both the in-vitro and in-vivo

potential of

Ga siderophores to diagnose invasive

pulmonary aspergillosis.

Aspergillus fumigatus is one the most common airborne

fungi and, although easily eliminated in the immuno-

competent host, infection with this pathogen in the

immunocompromised individual remains potentially fatal.

Diagnosis of this increasingly prevalent serious condition

using conventional investigations remains suboptimal.

Iron plays an essential role in the nutrition and survival of

the causative pathogen A. fumigatus and is crucial to its

virulence. Many of its siderophores (which function as

iron transporters in most bacteria and fungi) demonstrate

an affinity for

Ga similar to that for iron [22].

The above-mentioned group from Innsbruck labelled two

different siderophores from A. fumigatus (desferri-triace-

tylfusarinine C/TAFC and desferriferricrocin/FC) with

Ga. They injected it into a group of immunosuppressed

mice as well as into a healthy group and found the

following:

(1) Both

Ga siderophores demonstrated high

affinity, stability, specific activity and hydrophilic

properties.

(2) Tracer uptake in the lungs depended on the severity

of the infection, with no uptake noted in the lungs of

the control group and rapid accumulation noted in

mice with severe infection. This was observed in

particular with

Ga-TAFC.

(3) Tracer accumulation was highly dependent on the

iron load, which could be blocked by administering

high amounts of siderophores or NaN

. This suggests

the presence of a specific energy-dependent uptake

mechanism [23].

In a 2012 publication, the same group (Petrik and

colleagues) compared various siderophores in the PET

imaging of A. fumigatus infections.

They found significant differences in the stability and

labelling efficiencies and discovered that uptake in A.

fumigatus cultures was dependent on both the iron load

and the siderophore type.

Normal, uninfected mice were injected with around

2 MBq of

Ga and evaluated at 30 and 90 min after

injection. Biodistribution varied according to the sidero-

phore type, with

Ga-TAFC and

Ga-ferrioxamine

(FOXE) demonstrating low plasma values early after

injection with rapid renal excretion.

Ga-ferricrocin and

Ga-ferrichrome showed high blood retention, and

Ga-

fusarinine demonstrated very high renal retention.

According to their experiments,

Ga-TAFC and

Ga-

FOXE showed the most promise as PET imaging tools

in invasive pulmonary aspergillosis with high, specific

uptake and favourable biodistribution [24].

In the latest publication by Petrik and colleagues, the two

tracers mentioned above were further evaluated both

in vitro and in vivo using rat models.

In-vitro studies were used to evaluate the uptake of

siderophores using A. fumigatus in iron-sufficient medium

(30 mmol/l FeSO

added) compared with iron-deficient

medium (no iron added) after 45 min of incubation at

room temperature [24].

In-vivo biodistribution was evaluated in two groups of rats –

a group of neutropenic rats infected with A. fumigatus and a

normal comparison group. Imaging was carried out with

Ga-TAFC in 20 rats and with

Ga-FOXE in 19 rats. The

acquisition of dynamic PET/CT images started with

intravenous injection and continued for up to 60 min,

whereas static images were acquired after 30 min for 30 min.

The following observations were made:

(1) The uptake of both

Ga-TAFC and

Ga-FOXE was

increased in iron-deficient cultures and could be

blocked with excess ferrisiderophore and sodium azide.

(2) The intensity of the tracer accumulation correlated

with the severity of the infection (and abnormal CT

findings) and was not significantly decreased by iron

preloading.

(3) Both tracers demonstrated early (10–20 min after

injection for up to 60 min) selective uptake in infective

lung lesions with rapid renal elimination [25].

Summary

The following trends were observed:

(1) The PTCER can be determined using

Ga-citrate or

Ga-MAA and appears valuable in the assessment of

various types of lung injury.

Nononcology applications of

Ga Vorster et al. 841

(2) Unfortunately, the use of PTCER does not help to

differentiate cardiogenic pulmonary oedema from

cardiogenic oedema.

(3) Imaging with

Ga-transferrin PET/CT appears to be

of value in distinguishing sterile induced lung injury

from ARDS with higher tracer accumulation indicat-

ing a more severe injury.

(4) With regard to imaging parameters, a dose of

185–370 MBq with an uptake time of 45–60 min

and a two-compartment model for analysis appear

sufficient for accurate image interpretation.

(5) Promising results have been found with

Ga-DOTA-

NOC imaging of IPF, which may find clinical

application especially in the evaluation of treatment

response.

(6) For lung infection imaging, promising results have

been found with

Ga-TAFC and

Ga-FOXE in

Aspergillosis imaging. These tracers have been shown

to accumulate selectively in infective lung lesions in

animal models, with a correlation noted between

tracer intensity and severity of infection.

(7) ‘Galligas’ and

Ga-MAA provide an attractive,

clinically feasible alternative for lung ventilation

and perfusion imaging that offers advantages such

as improved resolution with faster, more flexible

imaging protocols.

Readers are also referred to a review published in 2011 by

Bomanji and colleagues on the use of PET/CT in imaging

pulmonary infections and inflammation [26]. Please

see Table 2 for a summary on the respiratory system.

Cardiovascular system

Publications focussing on the cardiovascular applications

Ga began to appear during the early 1980s. These

papers focussed mainly on the search for suitable ligands,

on kit development and refinements and on clinical

application of

Ga-labelled tracers as perfusion or blood

pool agents. More recently, however, interest has been

rekindled with a new focus on the application of

Ga-

labelled tracers as atherosclerotic plaque agents and on its

emerging role in interventional cardiology.

The search for an appropriate ligand, as well as kit

development and refinements

The development of cardiac PET tracers was pursued

with the aim of improving the resolution and quantifica-

tion of myocardial imaging and started with the search for

appropriate ligands.

In 1993, Green and colleagues evaluated four novel

gallium complexes as potential PET myocardial perfusion

tracers. The four ligands (n-BuO–, iso-BuO, sec-BuO–

and n-PrO) were labelled to

Ga and then used to image

rat hearts. From these initial experiments,

Ga-[(sal)

3tame-O-iso-Bu] was selected as the most promising

complex for further evaluation in PET studies and was

Table 2 Summary of the studies for respiratory indications with

Ga-labelled PET probes

Target Tracer/probe Dose (MBq)

Uptake time

(min)

Experimental setting

(number of subjects) Tracer comparison Quantification type (value) Validation References

Pulmonary vascular permeability

Ga-citrate 296 60

Dogs with oleic acid-induced

lung injury (n=6)

Human comparison (n=4)

NA PTCER two-compartment

model. Normal: 49±18;

injured: 485±114

Arterial blood

samples

Mintun et al. [15]

Ga-transferrin 370–555 45

Dogs with oleic acid-induced

lung injury (n=4)

Controls with normal lungs

(n=3)

C-Methylalbumin PTCER two-compartment

model

Blood and tissue

samples

Schuster [14]

Ga-transferrin 222 Human patients with

pulmonary oedema (n= 28)

vs. healthy volunteers

(n= 10)

99m

Tc-Albumin PTCER Clinical criteria

PaO

/FiO

Schuster et al. [17]

Pulmonary embolism

GaCl

(Galligas) 5–10 NA Piglets (n= 14) Technegas Peptide: 2.3 vs.

F-FDG: 3.1 Clinical criteria

PaO

/FiO

Borges et al. [19]

GaCl

and

Ga-MAA

10 and 39 NA Human (n= 10) Technegas

99m

Tc-MAA

Normal/abnormal/

nondiagnostic quality scale

Number of defects

PET vs. SPECT Hofman et al. [20]

Infection/inflammation

Ga-DOTA-NOC 120–185 60 Humans with pulmonary

fibrosis (n= 14)

NA PE + or PE– HR-CT

Lung function tests

Ambrosini et al. [22]

Ga-siderophores

Ga-TAFC

Ga-FOXE

Ga-FC

2 30 and 90 Rodent model

Aspergillus fumigatus vs.

healthy controls (n= 12)

NA Healthy: 0.04%ID/g

Mild infection: 0.04; severe

infection: 0.95%ID/g

Petrik et al. [23–25]

NA, not available; PE, pulmonary embolism.

Dynamic imaging.

842 Nuclear Medicine Communications 2013, Vol 34 No 9

used on a healthy dog. This study was conducted to

improve upon previous poor results obtained with

uncharged

Ga complexes that tend to resist ligand

exchange with transferrin. Previous work carried out

with

Ga [(5-MeOsal)3tame] demonstrated a flow-

dependent extraction fraction and clearance that re-

quired correction for tracer activity remaining in the

ventricle [27].

The following observations were made:

(1) The

Ga complexes demonstrated rapid plasma

clearance with good myocardial accumulation, sig-

nificant (unwanted) liver accumulation and, despite

the lipophilic nature, no penetration of the blood–

brain barrier.

(2) The suboptimal pharmacokinetics of all these com-

plexes were still considered to be superior to those of

Ga-[(5-MeOsal)3tame], which was previously re-

garded as the most promising tracer.

(3) PET images of a healthy dog using

Ga-[(sal)3tame-

O-iso-Bu] were of high quality as early as 2–10 min

after injection [27].

Good results had been found with

Ga-BAPEN as a

myocardial imaging agent in terms of stability and

biodistribution [28]. However, its complicated and

time-consuming preparation prompted Yang and collea-

gues in 2010 to develop a simple, two-step labelling kit

for

Ga with this ligand. This involves adding eluted

Ga to the BAPEN kit, followed by a filtering step.

Labelling is carried out at room temperature and this kit

provides a relatively quick and simple way of labelling

salicylaldimine ligands to

Ga with a high labelling

efficiency and radiochemical purity. Imaging with

Ga-

BAPEN provides high myocardial uptake, which de-

creases slowly over time [29].

Hoffend and colleagues investigated the use of

Ga-

DOTA-RSA (rat serum albumin) as an alternative PET

blood pool tracer. They made use of a rat model and

analysed the biodistribution, making use of volumes of

interest and time–activity curves at 10 and 60 min after

injection.

Ga-DOTA-RSA demonstrated long plasma

retention; it remained stable and was considered

a suitable alternative to

O-H

O in centres without an

onsite cyclotron. The authors evaluated the use of

Ga-DOTA-RSA in the setting of tumour angiogenesis,

but broader applications should also be considered [30].

Plo

¨ssl and colleagues developed a new gallium compound

for myocardial perfusion imaging. They made use of an

chelating core to which they added three cyclohexyl

rings. Again, the rationale was to improve resolution and

quantification and provide a generator-based PET tracer

with

Ga should labelling with

Ga prove successful.

These studies followed on previous work conducted with

and NS

-based compounds. The added cyclohexyl

rings lead to added stability and an increase in both

lipophilicity and first-pass extraction. The radiochemical

purity achieved was greater than 92%. Biodistribution was

determined using a rat model, which demonstrated high

cardiac tracer accumulation with retention of 2.1% and

0.9% of the initial dose (10–100 mCi) at 2 and 60 min after

injection, respectively. Autoradiography was then used to

evaluate the feasibility of gallium-bisamino-isthiolate

as a myocardial perfusion tracer in two groups of rats,

and comparisons were made with equal doses of

99m

Tc -

sestamibi. The first group consisted of healthy rats

(n= 3) and the second had undergone surgical ligation

of the LAD (n= 3). Imaging demonstrated even uptake

in the heart, which was retained at 30 min in the healthy

group and showed a marked decrease in the areas affected

by LAD ligation. Limitations of this tracer included the

high liver uptake as well as the kinetics that showed that

the tracer was neither trapped nor feely diffusible.

Despite the limitations, this compound could potentially

be used as an alternative generator-based PET myocardial

perfusion imaging agent [31].

Tarkia and colleagues recently evaluated the use of

several

Ga tracers as alternatives to currently used PET

perfusion tracers. These consist of nitrogen-13-ammonia,

rubidium-82 chloride and

O-H

O. Despite the fact that

these current PET tracers have been validated for the

quantification of myocardial perfusion, widespread appli-

cation thereof has been limited by the short physical

half-lives and the need for an onsite cyclotron. The

investigators selected four hexadentate salicylaldimine

ligands derived from bis(3-aminopropyl)ethylenediamine

(BAPEN), which has shown promise in previous rat

experiments, to be compared with

O-H

Oin14healthy

pigs. Dynamic PET images were acquired for 90min and

analysed in combination with the results from serial arterial

blood collections. The authors found that myocardial uptake

with all four

Ga tracers was too slow for clinical application.

Ga[Ga-(sal)2BAPDMEN] demonstrated the highest myo-

cardial uptake but did not correlate with myocardial

perfusion as quantified by

O-H

O. They thus concluded

that none of the tested

Ga tracers would be suitable for

clinical application [32].

The vulnerable plaque

The vulnerable plaque presents an exciting target for

research and is generally accepted to be a plaque with a

lipid-rich core, a thin fibrous cap and inflammatory

infiltrates. Macrophages have clearly been implicated in

culprit lesions leading to cardiac events and tend to

express somatostatin receptors (subtypes 1 and 2), which

may be detected with

Ga-DOTA-TATE as a marker

of plaque vulnerability. Increased expression of certain

integrins such as anb

/anb

have also been demonstrated,

which has generated novel imaging possibilities for both

the diagnosis and treatment of atherosclerosis.

Nononcology applications of

Ga Vorster et al. 843

Currently, there is no generally accepted accurate, non-

invasive way to identify vulnerable plaques, and it seems

that markers of inflammation or remodelling would be ideal.

Early identification of vulnerable plaques with such tracers

may lead to early intervention with improved outcomes.

In a 2009 publication, Haukkala and colleagues investi-

gated the feasibility of occlusive atherosclerotic imaging

with the use of

Ga-DOTA-RGD peptide. Atherosclero-

tic lesions are associated with increased microvessel

formation within the vessel walls with migration of

activated endothelial cells, which is regulated partly

by the anb

/anb

integrin. The expression of the afore-

mentioned integrin is also increased in CD-68-positive

macrophages, in the necrotic core of atherosclerotic lesions

and in the shoulder of advanced plaques, which makes it an

attractive target in cardiovascular disease.

The authors evaluated the uptake of intravenously

administered

Ga-DOTA-RGD peptide in vivo in excised

tissue samples and aortic sections of LDLR

–/–

ApoB

100/

100

atherosclerotic mice (n= 12).

Ga-DOTA-RGD peptide is known to bind to anb

/anb

integrin with high affinity and showed rapid plasma

clearance with renal excretion and high uptake in the

lungs, liver, spleen and bowel. Tracer biodistribution was

examined in vivo in mice with atherosclerotic plaques

(n= 6) combined with immunohistological analysis. Find-

ings were compared with those in control rats (n=6) and

expressed as a ratio of atherosclerotic to normal vessel

uptake. Results showed statistically significantly higher

tracer accumulation in atherosclerotic plaques compared

with normal vessels (mean ratio value of 1.4), suggesting

the feasibility of imaging with this tracer. Confirmatory

studies are needed to assess the clinical relevance [33].

Substitution of the –DOTA ligand with –NOTA has

resulted in some practical and imaging advantages. Initial

work, which involved PET imaging with

Ga-NOTA-

RGD, was done in the setting of oncology in which it has

been used as an angiogenesis imaging agent [34].

Recently, however, Caforio and colleagues in a 2012

review on myocarditis suggested its application in the

imaging of myocarditis on the basis of the promising

results published from studies conducted on animal

models of myocardial infarction imaging with

Ga-

DOTA-TATE and

Ga-NOTA-RGD [35].

More recently, Rominger and colleagues retrospectively

evaluated the use of

Ga-DOTA-TATE in imaging of the

coronary arteries in 70 consecutive oncology patients.

They assessed the tracer uptake in the LAD, which they

then correlated with coronary calcium burden and cardiac

risk factors [36].

Ga-DOTA-TATE uptake was quantified in the following

novel manner: fixed-sized regions of interest (ROIs) were

placed manually on the LAD of all patients, which was

chosen to match the lumen of the vessel. A mean blood

pool SUV was calculated from three ROIs placed in the

mid-lumen of the superior and inferior vena cava. The

SUV

max

from the LAD was subsequently divided by

the blood pool SUV

max

to yield a TBR. A TBR of at least

1.5 was considered as high uptake and a TBR less than

1.5 constituted low tracer accumulation.

Patients were divided into those with and without

calcified plaques based on the Hounsfield units obtained

from the CT part of each study.

The authors found a significant correlation between

increased tracer accumulation and the presence of vessel

wall calcifications. They also found a significant correla-

tion between increased

Ga-DOTA-TATE uptake in the

LAD and the presence of prior cardiovascular events.

They suggested that

Ga-DOTA-TATE might be useful

in the imaging of coronary artery plaques [36].

It is not clear from the methodology whether the authors

considered the effect of attenuation correction on the intensity

of the tracer accumulation. It is well known that areas of

calcification might falsely increase the SUV in such areas.

On the basis of the accepted inflammatory nature of

atherosclerosis and the increased number of activated

macrophages in rupture-prone plaques, Silvola and collea-

gues evaluated the uptake of

Ga-Cl in atherosclerotic

plaques. They used two groups of mice: nine with

LDLR

–/–

ApoB

100/100

and six normal mice as controls. All

the mice were injected with B17 MBq of

Ga-Cl and

killed 3 h after injection [37]. Blood and tissue samples

were measured for radioactivity using a gamma counter,

and aortic tissue was evaluated with a combination of

digital autoradiography and hematoxylin and eosin staining.

Image analysis consisted of four ROIs, which were

analysed on each aorta as follows: (a) plaque excluding

media; (b) healthy vessel wall; (c) adventitia with adjacent

fat; and (d) muscle for internal control tissue. Tissue

staining with Mac-3 was used to grade plaques into the

following categories: (a) no inflammation = no macro-

phages; (b) mild inflammation = occasional macrophages;

macrophages; and (d) abundant macrophage infiltrations.

They imaged an additional three LDLR

–/–

ApoB

100/100

mice with a micro-PET scanner. These were injected

with a mean dose of 16 MBq of

Ga-Cl, which was

followed by acquisition of a contrasted CT angiography.

PET findings were quantified by drawing same-sized

ROIs over the following areas: the left ventricle, the

aortic arch and the brachiocephalic artery (as identified

on CT angiography).

Their results were as follows:

(1) Autoradiography demonstrated significantly increased

Ga activity (1.8±0.2) in areas of (especially

844 Nuclear Medicine Communications 2013, Vol 34 No 9

macrophage rich) atherosclerotic plaques compared

with healthy vessels (P= 0.0002).

(2) PET/CT imaging demonstrated high tracer accumu-

lation in the heart and the aorta.

(3) The high plasma activity and slow blood clearance,

combined with the short half-life, may limit the

clinical applicability of

Ga as an atherosclerotic

plaque-imaging agent [37].

Interventional cardiology

Unfortunately, restenosis follows angioplasty all too often

because of factors such as elastic recoil, proliferation and

migration of smooth muscle, synthesis of extracellular matrix

and late constrictive remodelling, among others.

Various investigators have tried to combat this by means of

medicated stents and brachytherapy. In the early 2000s,

intracoronary radiation therapy was considered a promising

novel approach in the prevention of restenosis. Initial

commercial systems made use of solid sources emitting b-

radiation or g-radiation. This has the advantage of avoiding

any radioactive spill in case of damage but poses the

problem of proper centring within the coronary arteries

and ensuring a uniform field of radiation.

Stoll et al. [38] proposed the use of

Ga (with its

convenient 68 min half-life) for intracoronary radiation

therapy with liquid-filled balloons in restenosis prevention.

They made use of in-vitro studies on bovine aortic smooth

muscle cells to ascertain the antiproliferative efficacy of

positrons emitted by

Ga. They found that cellular

proliferation rates were inversely proportional to the

radiation dose in cultures irradiated with both gamma

and positron radiation and that they were equally effective

as reflected by the similar ED

and ED

values.

Phantom studies were performed with standard angio-

plasty balloon catheters, which were inflated with various

liquid positron emitters and used to quantify the radiation

tissue penetration. Modelling of balloon rupture and spills

was also performed. The rationale behind this study was

that balloon catheters with short-lived liquid radioisotopes

would provide a homogeneous, readily available dose that

would be safer than the conventionally used

186

Re and

188

Re in case of rupture or spillage.

The authors concluded that under a worst-case scenario a

balloon rupture with

Ga would result in a maximal

whole-body dose of 50 mSv and that

Ga could therefore

be considered a safe alternative for coronary radiation

therapy [35,36].

Platelet and thrombus imaging

Imaging of platelet behaviour in thrombosis in the

presence or absence of atherosclerosis provides an

interesting target for understanding the pathophysiology

of cardiovascular disease. Platelets play an important role

in the development of atherosclerosis and tend to

accumulate only in active thrombi; incorporation of

thrombi into the vessel wall represents a potentially fatal

complication of atherosclerosis. Imaging of platelets

provides the location of thrombi and also provides a

noninvasive functional assessment of thrombotic activity.

Karanikas and colleagues set out to identify the best

chelate for the radiolabelling of platelets with gallium as

this could prove to be a useful probe in the imaging of

platelet behaviour both in thrombosis and atherosclerosis.

Blood for platelet labelling was obtained from 172 healthy

volunteers without any cardiovascular risk factors. The

platelet-labelling characteristics of

Ga was evaluated

with oxine, tropolone and MPO, and

Ga-MPO of

autologous platelets was finally selected as the most

appropriate agent to substitute for platelet imaging. This

could easily be substituted with

Ga, resulting in

Ga-

MPO platelets for PET imaging [39].

Jalilian and colleagues evaluated the early detection of

thrombi through imaging by labelling streptokinase with

Ga for possible application in stroke management.

Streptokinase imaging acts as a probe for plasminogen

detection in thrombi or emboli. A rat thrombosis model was

used and B50 mCi of

Ga-DTPA-streptokinase was injected

into the tail vein, followed by SPECT imaging. The best

time to image was determined as 1–2 h after injection, as

enzymatic degradation of the protein starts after 80 min.

The authors suggested that, in light of the promising imaging

results with

Ga,

Ga-streptokinase could also be consid-

ered a potentially useful tracer for thrombus detection,

providing better resolution and amoresuitablehalf-life[40].

Summary

(1) Several interesting tracer possibilities with

for cardiovascular imaging exist. In particular,

Ga-[(sal)3tame-O-iso-Bu],

Ga-BAPEN and

Ga-

bisamino-isthiolate appear promising for myocardial

imaging and

Ga-DOTA-RSA seems to be a reliable

alternative PET blood pool tracer. Refinements

of tracers with development of kits should accelerate

once clinical applications and demand increase.

(2) Many novel and exciting applications for

Ga-

labelled tracers have emerged, which are not limited

to diagnosis only. Imaging of the ‘vulnerable plaque’ and

the processes of atherosclerosis and thrombus formation

provide insight into the pathophysiology of these

processes, which may find broader clinical application.

(3) For the imaging of vulnerable plaques and athero-

sclerosis the following tracers have shown the most

promise:

Ga-DOTA-TATE and

Ga-DOTA-RGD.

With regard to thrombus imaging (for possible applica-

tion in stroke management)

Ga-MPO platelets/

Ga-streptokinase shows some promise.

(4) Interventional cardiology provides a whole new field for

Ga tracer applications. Intracoronary balloon cathe-

ters filled with short-lived radioisotopes such as

Nononcology applications of

Ga Vorster et al. 845

Ga have been proven to be safe and effective in

preventing restenosis following vascular intervention.

Please see Table 3 for a summary on the cardiovascular

system.

Central nervous system

Various disease processes (such as brain tumours and

dementia) affect the functioning of the blood–brain

barrier.

Ga-EDTA is an ideal tracer for the evaluation

and quantification of these changes as its permeability of

the blood–brain barrier under normal circumstances is

low.

Ga-EDTA has also been applied in the evaluation

of cerebrospinal fluid flow as early as 1970 [42].

In 1984, Hawkins and colleagues used

Ga-EDTA to

estimate the permeability of the blood–brain barrier and

the local cerebral blood volume in 12 patients with

primary or metastatic brain tumours. They made use of a

two-compartment model and arterial blood samples to

calculate values for the forward (k

) and reverse (k

)

transverse constants, and patients were imaged for up to

2 h after injection [43].

Friedland and colleagues in 1985 evaluated the perme-

ability of the blood–brain barrier in Alzheimer’s disease

(AD) using dynamic PET imaging with both

Rb and

Ga-EDTA making use of a two-compartment model.

Imaging was performed on a group of patients diagnosed

with AD and the results were compared with those of a

group of healthy participants. A total of 17 patients were

imaged. The k

values calculated using both tracers did not

deviate significantly from zero and the affected areas in

AD did not demonstrate any increase in permeability [44].

Pozzilli and colleagues sought to quantify the increase in

blood–brain barrier permeability in patients with multiple

sclerosis(MS),whichwasnotedinpreviousstudies

conducted with contrasted CT scans. To do so, they injected

15 patients having confirmed MS with 6–8 mCi of

Ga-EDTA, followed by PET/CT imaging. Quantification

was performed using multiple-time graphical analysis, which

allowed for simultaneous calculation of the blood to brain

influx (K

) and plasma volume (V

) [45].

The following observations were made:

(1) Four patients with clinical exacerbation of disease

demonstrated focal areas of increased

Ga-EDTA,

which corresponded to the areas of enhancement

noted on CT (both in terms of localization and

extent).

(2) A moderate increase in the K

value was found in the

areas of pathology, with no corresponding increase in

values [45].

Although this study suffers from several limitations, with

many questions remaining, it does provide some insight

Table 3 Summary of studies for cardiovascular system indications with

Ga-labelled PET probes

Target Tracer/probe

Dose

(MBq)

Uptake time

(min)

Experimental

setting (number

of subjects)

Tracer

comparison

Quantification

type (value) Validation References

CAD perfusion/blood

pool imaging

Ga-[(sal)3tame-O-iso-

Bu]

370 45 Animal model (n=1)

O-H

O Counts/pixel/min Green et al. [27]

Ga-DOTA-RSA 3–6 10,60 Rat model (n=3)

O-H

OVOI

TAC

Hoffend et al. [30]

Ga-bisamino-isthiolate 10–100 mCi 2,30,60

120

Rat model (n=6)

99m

Tc-sestamibi %dose/g Organ tissue

Autoradiography

Plo

¨ssl et al. [31]

Ga-BAPEN-derivatives 68–249 90 Healthy pigs (n= 14)

O-H

O Myocardium to blood/lung/liver

ratio

Serial arterial blood

samples

Tarkia et al. [32]

Atherosclerosis/plaque

imaging

Ga-DOTA-RGD

peptide

167 60 Atherosclerosis mouse

model (n=6)

NA Atherosclerotic to normal

vessel ratio

Organ tissue

Autoradiography

Haukkala

et al. [33]

Ga-DOTA-TATE 211 60 Human oncology patients

(n=70)

NA TBR Plaques assessed

on CT

Rominger

et al. [36]

Ga-chloride 16 180 Mouse model (n=3) NA %dose/g

Plaque: wall

Organ tissue

Autoradiography

Silvola

et al. [37,41]

CAD, coronary artery disease; CT, computed tomography; NA, not available; TBR, tumour-background ratio; TAC, time–activity curve; VOI, volume of interest.

846 Nuclear Medicine Communications 2013, Vol 34 No 9

into the function of the blood–brain barrier in patients

with MS. Further studies would be of value. To the

authors’ knowledge no similar studies have been

attempted with

Ga-based compounds.

In 1999, Cutler and colleagues investigated the potential

Ga-S

N as a possible cerebral blood flow tracer. This

amine complexed to

Ga demonstrates ideal properties

for blood–brain penetration, as it is small, neutral,

lipophilic and kinetically stable. Biodistribution studies

demonstrated significant brain, cardiac and liver uptake,

and the authors concluded that

Ga-S

N could be

promising in terms of cerebral blood flow imaging [46].

In 2002, McCarthy and colleagues labelled leptin to

GA-DTPA to assess whether intrathecal administration

of leptin could achieve therapeutic levels at the site of

action in the hypothalamus. They injected the tracer into

the intrathecal space of the lumbar spine of three

baboons and compared it with unconjugated

Ga-DTPA.

They found that the

Ga-labelled leptin compound

reached the arcuate nucleus between 90 and 140 min

after injection at levels 40 times higher than normal

levels, whereas the unconjugated

Ga-DTPA was re-

sorbed back into the blood. These findings could have

important implications for the management of obesity, as

it has long been accepted that leptin plays a major role in

weight control. Finding a suitable route of administration,

however, is problematic, primarily because of the satur-

ability of the transport system over the blood–brain

barrier. The authors suggest that the intrathecal method

of administration may potentially overcome this pro-

blem [47].

Summary

(1) The blood–brain barrier remains an important

imaging target in the evaluation of central nervous

system disorders. A few investigators have made use

Ga-EDTA in this setting for possible application

in Alzheimer’s dementia and MS. Studies have been

small (involving 12–17 patients) and have centred

around the period 1984–1988, after which it seems

that these applications were abandoned.

(2)

Ga-S

N demonstrated promise as a cerebral perfu-

sion agent.

(3) Other unusual applications such as

Ga-DTPA-

leptin in the investigation of obesity management

appear to be limited to a single study only with the

most recent publication seen in 2002. Please see

Table 4 for a summary on the central nervous system.

Genitourinary system

Renal imaging has been performed with the use of

since the late 1960s. The first

Ga/

Ga generator was

eluted with an EDTA solution, which resulted in

Ga-

EDTA for application in glomerular filtration rate (GFR)

determination mostly. It is only recently that the

attention has shifted away from renal function quantifica-

tion towards infection imaging.

One of the first publications on the use of

Ga in renal

imaging reported on renal imaging with

Ga in the form

Ga-polymetaphosphate. The authors concluded that

the high kidney accumulation and the short half-life

would make

Ga-polymetaphosphate a useful tracer in

renal imaging [48].

In 1988, Yamashita and colleagues evaluated renal

function with the use of

Ga-EDTA in six healthy male

volunteers. Organ activity was corrected for blood content

with the use of

C-O gas. They found the blood volume

to be around 12 ml/100 g kidney and the GFR to be

around 30 ml/min/100 g kidney. As these values corre-

sponded well to those published in standard physiology

textbooks, the authors concluded that PET studies could

find a valuable clinical application in the measurement of

GFR [49].

In a 2006 publication, Szabo and colleagues discussed the

future direction of renal PET and attributed the slow

development thereof to the success of planar and SPECT

renal imaging and to the usefulness of other noninvasive

imaging modalities such as ultrasound, CT and MRI.

Despite the infrequent use of

Ga, its value in the

determination of GFR was again emphasized. When

labelled to EDTA, its kinetics are described by a

Table 4 Summary of studies for central nervous system indications with

Ga-labelled PET probes

Target

Tracer/

probe

Dose

(MBq)

Uptake time

(min)

Experimental setting (number of

subjects)

Tracer

comparison

Quantification type

(value) Validation References

BBB

permeability

Ga-ETDA – 120 Human patients with brain tumours

(n= 12)

–k

and k

Arterial blood

samples

Hawkins

et al. [43]

Ga-EDTA – – Human patients with AD and healthy

controls (n=17)

Rb k

and k

– Friedland

et al. [44]

Ga-EDTA 222–296 – Human patients with MS (n= 15)

F-FDG K

and V

– Pozzilli

et al. [45]

Cerebral

blood flow

Ga-S

N 15–20 mCi Rats (n= 16) NA – – Cutl er

et al.[46]

Ga-DTPA-

leptin

– – Baboons (n=3)

Ga-DTPA – – McCarthy

et al.[47]

AD, Alzheimer’s disease; BBB, blood–brain barrier; MS, multiple sclerosis.

Nononcology applications of

Ga Vorster et al.847

noncompartmental impulse response function, which is

identical to that of

99m

Tc-DTPA (which has been studied

extensively) [50].

In a 2008 publication by the same authors, Szabo and

colleagues again mentioned the role of

Ga-EDTA in

renal imaging and the use of

Ga-labelled alizarin red S.

This radiopharmaceutical accumulates in the renal cortex

within 90 min after injection in a way similar to DMSA

but has a lower urinary excretion. It appears promising as

an imaging agent for acute pyelonephritis, for determina-

tion of anatomical kidney defects and for relative blood

flow assessment [51].

In a 2009 publication, Nanni and colleagues investigated

the use of

Ga-Cl in the imaging of genital infection.

The group sought to assess the feasibility of

Ga-Cl in an

animal model of genital infection induced with Chlamydia

muridarum. Eleven infected mice (as well as three

controls with inflammation and one healthy control)

were imaged on several occasions (with

Ga-Cl and

small animal PET) for up to 19 days after vaginal

inoculum with C. muridarum. The results from this study

demonstrated increased tracer accumulation in the

infected mice, which was not seen to the same extent

in controls. Cervical swabs and in-vivo analysis validated

the PET findings, and the authors concluded that

Ga-

Cl may be a suitable marker for genital infection

assessment in a mouse animal model. In the light of

the inability of

Ga-Cl to distinguish clearly between

infection and sterile inflammatory changes, the authors

suggested that

Ga-citrate may be a promising agent in

this setting because of the more stable nature of the

compound [52].

Summary

With regard to renal imaging,

Ga-based alternatives are

available for most of the commonly used

99m

Tc-based

tracers.

(1)

Ga-EDTA has been shown to be as accurate in the

assessment of GFR as

99m

Tc-DTPA.

(2)

Ga-alizarin red S can be used as an alternative to

99m

Tc-DMSA in the imaging of anatomical kidney

abnormalities, pyelonephritis imaging and split func-

tion assessment.

(3) Future developments may include the ability to

distinguish between genital infections and inflam-

matory changes with the use of

Ga-Cl or

Ga-citrate.

Despite the above-mentioned possibilities, imaging with

Ga in this setting remains underutilized for reasons

that are not quite clear. Possible explanations include

dosimetry considerations and lack of knowledge and/or

expertise. Please see Table 5 for a summary on the

genitourinary system.

Table 5 Summary of studies for genitourinary indications with

Ga-labelled PET probes

Target Tracer/probe

Dose

(MBq) Uptake time (min)

Experimental setting

(number of subjects)

Tracer

comparison

Quantification

type (value) Validation References

GFR

Ga-EDTA 37–185 – Healthy male volunteers (n= 6) GFR Known values Yamashita et al. [49]

Infection/

inflammation

Ga-Cl 20 60 Mice model of genital infection

induced

with Chlamydia muridarum (n= 15)

NA Pelvic TBR Cervical–vaginal

swabs,

microbiol histology

Nanni et al.[52]

RES

Ga-alizarin

red/

Ga-

alizarin red S

37 5, 10, 15, 30, 60 Rat model (n= 7) %dose/g organ/%dose/whole

organ

Organ tissue activity

measurements

Schuhmacher

et al. [53]

Hepatobiliary

function

Ga-BP-IDA 2.5, 6, 10, 15, 30,

Rat model (n= 7) %dose/g organ/ Organ tissue activity

measurements

Schuhmacher

et al.[54]

IBD

Ga-GSA 130 10, 60 Rat model

99m

Tc-GSA Haubner et al. [55]

Ga-citrate 15 90 Human NA Clinical data Rizzello et al. [56]

Ga-citrate 150 5, 30, 60 Rat model and human NA Kumar et al. [57]

GFR, glomerular filtration rate; IBD, inflammatory bowel disease; NA, not available; R ES, reticuloendothelial system; TBR, tumour–background ratio.

848 Nuclear Medicine Communications 2013, Vol 34 No 9

Liver and gastrointestinal applications

Alizarin and alizarin red S had been labelled with

Ga as

early as the late 1970s for visualization of the reticulo-

endothelial system (RES) and kidneys. Alizarin is known

to form stable compounds with gallium in neutral or

slightly acidic conditions, whereas alizarin red S stains

calcifying tissues a fluorescent red.

Schuhmacher and colleagues in 1980 investigated these

two substances coupled to

Ga. In their investigation, both

groups of animals (rats and dogs) and the single healthy

volunteer studied demonstrated high tracer accumulation

intheliverandspleenwithin5minofinjectionof

Ga-alizarin, whereas

Ga-alizarin red S demonstrated

high renal accumulation 2 h after injection. These features,

combined with the resolution advantages of PET/CT and

the simple and fast preparation, rendered them promising

imaging agents of the RES and kidneys [53].

In 1983, Schuhmacher and colleagues described the use of

Ga-BP-IDA for the evaluation of hepatobiliary function

using PET to try and overcome some of the inaccuracies

experienced with SPECT tracers when subtle changes in

hepatic excretion or comparisons among patients had to be

evaluated. The compound was tested in a rat model

(n= 7) and in two healthy human volunteers. It provided

good stability, favourable kinetics and biodistribution, and

competition from exogenous bilirubin was low. These

findings led the authors to conclude that the use of

Ga-

BP-IDA for quantitative evaluation of hepatobiliary func-

tion would be feasible [54].

In a 2009 publication by Rizzello and colleagues on the

synthesis and quality control of

Ga-citrate, the authors

included an image from a patient with inflammatory bowel

disease that demonstrated increased tracer accumulation in

the descending bowel. This suggests that an application for

the use of

Ga-labelled radiotracers also may exist in the

imaging of inflammatoryboweldisease[56].

Several studies involving

Ga compounds for application in

the liver or gastrointestinal system were published in 2011.

Haubner et al. [55] developed the

Ga compound for liver

function imaging based on receptor density determination

of a glycoprotein receptor (ASGP-R). They found that

Ga-GSA could be produced relatively easily with high

radiochemical purity and yield. Rat biodistribution studies

demonstrated a favourable biodistribution [58].

Zimny et al. [59] investigated the imaging of sulphonyl-

urea receptor 1 (SUR-1) for the purpose of imaging b-cell

masses. This could potentially play an important role in

the success of b-cell transplantation in type I diabetes

mellitus.

F-FDG-based tracers are limited by high liver

uptake that precludes adequate pancreas visualization,

which leads to the successful development of

Ga-

NODAPA-NCS-glibenclamide by this group [60].

Kumar and colleagues in a 2012 publication further

investigated the possibility of using

Ga in the imaging

of intra-abdominal infections. The authors induced

infection with S. aureus in rats and found increased tracer

accumulation as early as 5 min after injection, with

intense uptake noted between 30 min and 6 h at the site

of infection. Increased tracer accumulation was also

present in a patient with postoperative intra-abdominal

infection, highlighting the possible clinical role of this

tracer in infection imaging [57].

The use of

Ga-MAA in the assessment of extrahepatic

shunts before selective internal radiation therapy (SIRT)

has also been successfully evaluated [61].

Summary

(1) Many interesting

Ga-based imaging options exist

for application in routine liver and gastrointestinal

imaging. These include the use of

Ga-MAA for

extrahepatic shunt evaluation before SIRT and the

use of

Ga-alizarin red and alizarin red S for RES and

kidney function imaging.

(2) In the imaging of hepatic function,

Ga-PP-IDA may

overcome some of the limitations of

99m

Tc-IDA

agents and provide quantification options. Recent

advances include imaging of liver function with

Ga-

GSA based on ASGP receptor density.

(3) Recent publications have revealed novel imaging possibi-

lities such as the use of

Ga-citrate in the evaluation of

inflammatory bowel disease and postoperative abdominal

infections as well as the ability to image SUR-1 to

determine the b-cell mass of the pancreas with the use of

Ga-NODAPA-NCS-glibenclamide. These are mainly

case reports, which will require validation in larger studies

before routine clinical application.

Miscellaneous applications

The recent worldwide shortage of molybdenum has

sparked interest in the search for alternative generator-

based radiopharmaceuticals such as

Ga for a multitude

of routine clinical and novel indications. Various reports,

case studies and short communications have reported on

new

Ga compounds and applications, some of which are

mentioned here.

Folate receptors tend to be overexpressed in many malignant

processes as well as on activated macrophages. Often, these

activated macrophages either cause, or contribute signifi-

cantly to, various debilitating illnesses such as rheumatoid

arthritis, Crohn’s disease, atherosclerosis, lupus, inflammatory

osteoarthritis, diabetes, ischaemia–reperfusion injury, glomer-

ulonephritis, sarcoidosis, psoriasis, Sjogren’s disease and

vasculitis.

Ga-deferoxamine-folate has been developed

and tested in tumour-bearing animals, and thus far folate-

receptor PET imaging appears to be promising both as a

diagnostic and as a therapeutic target for potential application

in the nononcological indications mentioned above [62,63].

Nononcology applications of

Ga Vorster et al.849

Necrosis has also become an interesting target for the

diagnosis of, and for monitoring the therapeutic effect on,

several conditions in which excessive cell death plays a

role. This occurs, for example, in myocardial infarction,

chronic heart failure, transplant rejection, neurodegen-

erative conditions and stroke, among others. However,

molecular imaging of this process has proven troublesome

so far, because of the many substances that are released

following cell membrane integrity loss. Prinsen and

colleagues evaluated

Ga-bis-DTPA-PA as a potential

tracer for necrosis imaging. This compound demonstrated

significantly higher uptake in necrotic tissues compared

with viable tissue and was able to differentiate between

apoptosis and necrosis. Findings were validated in vitro,

ex vivo and in vivo [64].

Despite the well-established role of sentinel lymph node

imaging, no PET tracers had been developed until 2010

when a group from Seoul National University developed

Ga-mannosylated human serum albumin (MSA) for this

purpose. They successfully developed a PET sentinel

lymph node imaging tracer,

Ga-NOTA-MSA, with high

stability and labelling efficiency at room temperature.

The imaging target here is the mannose binding protein,

which is expressed by the RES. After subcutaneous

injection of 7.4 MBq into the footpads of mice, which

were imaged with micro-PET, persistent increased

activity was noted in the inguinal lymph nodes as early

as 1 min after injection. In addition, biodistribution

studies demonstrated high hepatic uptake with mild

splenic and bone marrow accumulation. The authors

concluded that sentinel lymph node imaging with

Ga-

NOTA-MSA would be feasible with rapid lymph node

migration and early imaging possibilities. A bprobe

(proven to be superior to gprobes) has also been

developed that can detect positron and bemissions from

lymph nodes intraoperatively [65].

Pichler and colleagues recently published an image of a

53-year-old woman with Graves’ orbitopathy. PET/CT

images with

Ga-DOTA-NOC showed increased uptake

in the right inferior rectus muscle, which corresponded to

morphological muscle changes noted on CT and MRI and

which represented active endocrine orbitopathy [66].

Infection/inflammation imaging

The field of infection and inflammation imaging is an

interesting and rapidly growing one, and therefore it was

felt that certain aspects needed to be highlighted despite

some overlap with various sections of this review.

Recently, Roivainen and colleagues published a compre-

hensive review on gallium-labelled peptides for inflam-

mation imaging, which readers are directed to [67].

Infection/inflammation imaging has always suffered from the

limitation of being unable to clearly distinguish between

these two processes, as so many aspects concerning their

pathophysiology overlap. There is a definite need for tracers

that target processes or cells, which are expressed exclusively

during infection or inflammation.

Thus far, one of the promising radiopharmaceuticals that has

emerged is

99m

Tc-ubiquicidin. This is a bacteria-specific

peptide that has been proposed as an infection-specific

agent [68]. The development of a new radiotracer based on

an antibiotic derivative, the assessment of its biodistribution

and binding to the target bacteria are also of interest to our

group and hence our work on

Ga-NOTA-UBI30-41 [69].

The biodistribution of

Ga-ubiquicidin in rabbits infected

with S. aureus demonstrates increased tracer uptake in

infectedmuscleswhencomparedwithhealthyandinflamed

muscles. This increased accumulation in infected muscles

therefore supports an argument for a mechanism that, at

least partly, involves bacteria-specific binding. This correlates

well with our in-vitro results, which demonstrated binding to

bacteria. Further, the results of our recent study (which

involved injecting

Ga-NOTA-UBI30-41 into healthy mon-

keys) revealed no activity in target organs, such as the lungs,

the musculoskeletal system or the abdomen, revealing

potential infection (e.g. TB). In-vivo results demonstrated

compound blood clearance within 60 min of injection

through renal excretion and transient liver metabolism [70].

Certain common potentially debilitating conditions have an

inherently inflammatory nature, such as atherosclerosis,

obesity and diabetes. These and other conditions such as

musculoskeletal infections and cardiovascular, lung and

abdominal inflammatory or infectious processes would

potentially benefit from infection and inflammation imaging.

Earlier discussions have highlighted that

Ga-labelled

siderophore desferri-triacetylfusarinine C can display

highly selective accumulation by A. fumigatus in vivo. This

is potentially useful for imaging invasive pulmonary

aspergillosis, which may benefit patients who are

immunosuppressed [25].

In the musculoskeletal section, Kumar and colleagues

demonstrated the potential use of

Ga-apo-transferrin

(

Ga-TF) in the detection of S. aureus infection and Gram-

negative Proteus mirabilis with highly promising results [7].

One tracer that appears particularly promising in this

regard is

Ga-DOTA-VAP-P1. This tracer targets VAP-1,

which is normally stored in intracellular granules within

the endothelial cells to be released to the endothelial

surface only when inflammation occurs. VAP-1 promotes

leucocyte adhesion, mediates various leucocyte interac-

tions and also has some mono-amine-oxidase activity.

These properties provide an imaging target for inflamma-

tion as well as for the monitoring of anti-inflammatory

treatment. Tumour expression of VAP-1 also occurs and

varies considerably among the different tumour types.

Therefore, knowledge of VAP-1 expression for the various

malignancies is required for accurate interpretation in the

oncology setting.

850 Nuclear Medicine Communications 2013, Vol 34 No 9

Ga-DOTA-VAP-P1 was the first tracer to be developed

for the imaging of VAP-1 and has since been applied in

the setting of musculoskeletal infections, with promising

results seen in the studies by Lankinen et al. [8] and

Silvola et al. [41] as discussed earlier.

Autio and colleagues investigated the use of

Ga-DOTA-

VAP-P1 to distinguish between inflammation and malignant

processes. They made use of an animal model with two

groups of rats. Human pancreatic adenocarcinoma cells were

implanted subcutaneously into a group of athymic rats,

whereas turpentine oil was used to induce sterile skin or

soft tissue inflammation in the other group. The biodis-

tribution of

Ga-DOTAVAP-P1,

F-F DG and

C-choline

was compared using an experimental rat model.

Their findings were as follows:

(1) Imaging with

Ga-DOTAVAP-P1 was ‘more inflam-

mation-selective’ than that with

F-FDG or

C-

choline.

(2)

Ga-DOTAVAP-P1 could differentiate inflammatory

foci from malignant ones with sensitivity similar to

that of

F-FDG.

(3)

C-Choline was found to be the most tumour-

selective tracer compared with

F-FDG and

Ga-

DOTAVAP-P1 [71].

Attempts to improve the biochemical properties of

Ga-

DOTAVAP-P1 have led to the development of

Ga-

DOTAVAP-PEG-P2. This compound has a significantly

longer metabolic half-life, with slower renal excretion and

a higher TBR. It has a radiochemical purity of more than

95% and has been shown to be stable in vitro for around

2 h in human plasma [41].

Ga-Siglec-9 is another new compound, which is based

on a granulocyte ligand for VAP-1 for the detection of

vascular inflammation and malignant tumours [67].

Another promising target for labelling with

Ga is anb

which is increased in malignant cells and tumour

neovasculature as well as in chronic inflammatory

conditions such as inflammatory bowel disease and

inflamed synovial tissues in rheumatoid arthritis. Integrin

anb

mediates intercellular adhesion of all proteins in

which arginine–glycine–aspartic acid (RGD) is exposed.

Ga-RGD peptides provide an imaging tool for the

above-mentioned processes, which are relatively fast and

simple to synthesize and image. Haukkala et al. [33]

evaluated the use of

Ga-DOTA-RGD in an animal

model of atherosclerosis with promising results.

Silvola et al. [37] evaluated inflammation imaging with

Ga in vulnerable atherosclerotic plaques with promising

results (as described earlier).

Ga-NODAGA-RGD is a new RGD peptide with a high

affinity for anb

integrin. This can be prepared relatively

fast and easily at room temperature and has improved

imaging characteristics when compared with

Ga-DOTA-

RGD on micro-PET [72].

Ambrosini et al. [22] have found

Ga-DOTA-NOC PET

imaging to be useful in the evaluation of IPF and NSIP as

described earlier.

Several authors have investigated the use of

Ga-citrate

in the evaluation of various infectious and inflammatory

conditions. So far, the most promising results have been

found in the imaging of musculoskeletal infections [6,11].

Summary

(1)

Ga-Transferrin appears to be capable of detecting

both Gram-positive S. aureus and Gram-negative P.

mirabilis, thus justifying further investigations.

(2)

Ga-DOTAVAP-P1, a peptide inhibitor of vascular

adhesion protein-1/semicarbazine sensitive amine

oxidase (VAP-1/SSAO), is a promising target molecule

for the assessment of inflammatory reaction, more so

in healing bones.

(3) Preliminary data confirm the possible role of

Ga-

citrate for the diagnosis of bone infections,

with reliable negative predictive value and overall

accuracy.

Inflammatory and infectious diseases are a heterogeneous

class of diseases that continue to be imaged with

nonspecific radiopharmaceuticals. Thus, accelerated re-

search and development with a

Ga-labelled tracer may

help address this poor record.

So, why are we not using it every day?

Clearly, many convincing and compelling reasons and

indications exist for the use of

Ga in various non-

oncological (and of course all of the better-known

oncological) settings. The convenient in-house supply,

the multitude of labelling possibilities and the prospects

of freeze-dried kits with

Ga makes it a very attractive

option for PET imaging.

Its advantages over both

Ga and

F-FDG are well

known and include improvements in resolution, labelling

possibilities, lower radiation burden and faster and more

cost-effective imaging. It may also overcome some of the

limitations of

F-FDG, such as false negatives in highly

differentiated tumours with low growth rates, the

inability to evaluate lesions located close to tissues with

high metabolic activity and limited ability to distinguish

malignant processes from inflammation or infection in

certain settings.

Why then has it failed to find widespread clinical

application despite publications as early as the 1950s

and despite constant improvements in generator design,

labelling techniques and options and a host of clinical

application possibilities?

Nononcology applications of

Ga Vorster et al. 851

Several authors have addressed the issues that have so far

prevented widespread clinical application.

In a 2007 editorial, Breeman and colleagues attributed

the lack of widespread clinical application of

Ga to

(among others) the following issues.

The requirements imposed by pharmaceutical legisla-

tions on the generator, the ligands and on the final

compound are very complex, entailing a lengthy process

in obtaining marketing authorization. In addition, there is

a perception of limited returns on investment by

investors.

The authors proposed some solutions to the above-

mentioned problems, including the need for manufacturers

of medicinal products to obtain marketing authorization for

Ga-labelling kits. This would, however, still be a lengthy

process involving extensive clinical trials. Alternatively,

physicians could be allowed the autonomy to take personal

responsibility for radiopharmaceuticals administered, which

in their opinion would potentially benefit the patient [73].

In a recent editorial, Ballinger and Solanki reflected on the

progress made in the preceding 4 years and the obstacles

that remain and concluded that the use of

Ga will never be

as simple as that of technetium-99m for the following

reasons:

(1)

Ga generators continue to be labelled as ‘not for

human use’ despite following good manufacturing

practices.

(2) The short half-life of

Ga may lead to the need for

several elutions per day.

(3) There are concerns over long-term generator sterility.

(4) It is the opinion of the above-mentioned authors that

manual labelling cannot be performed safely and that

automated or remote-controlled labelling procedures

are essential.

(5) The HCl needed for elution of the generator requires

pharmacological formulation.

(6) There is a lack of licensed kits and reagents for labelling

with

Ga and a need for chelators that can be labelled

rapidly at room temperature and at a neutral pH [74].

Dosimetry

Rizello et al. [56] in their landmark paper reported the

effective dose per unit of administered activity for

Ga-

citrate as 2.6 10

–2

mSv/MBq, compared with 1.1 10

–1

mSv/MBq for

Ga-citrate.This calculation was based on data

gathered from human subjects using a dynamic bladder

model with a 4.8-h voiding interval, and our initial

calculations have yielded comparable results.

Conclusion

Many exciting imaging opportunities exist for

Ga tracer

applications outside oncological practice, most of which

remain greatly underutilized. Larger clinical trials are

needed to validate these applications for future use in

routine clinical practice.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Uptake pattern of [68Ga]Ga-DOTA-NOC in tissues: implications for inflammatory diseases

Article

Dec 2019
Q J Nucl Med Mol Imag

Purpose: [68Ga]Ga-DOTA-NOC binds to somatostatin receptor (SSTR) subtypes 2 and 5, also expressed on lymphocytes and macrophages, but no information is available about uptake in tissues that might be affected by a chronic inflammatory process. Our aim was to obtain normal reference values for :[68Ga]Ga-DOTA-NOC uptake in tissues prone to chronic inflammation. Methods: Retrospective study in 81 patients who performed the scan for a suspicion of neuroendocrine tumor (NET). We analysed major joints, salivary glands, thyroid, aortic wall from images acquired after injection of 173,9±1 Mbq of :[68Ga]Ga-DOTA-NOC. We calculated the SUVmax and SUVtarget/SUVgluteus ratio or SUVtarget/SUVaorta ratio. Data are reported as mean±2 or ±3 standard deviations (SD). Results: SUVmax values appeared more reliable than other ratios. In thyroid we found a mean SUVmax of 1.36±0.45, with no values >3SD; in parotid glands 0.98±0.40, with 2 values>3SD; in submandibular glands 0.99±0.37, with 2 values >3SD; in aortic arch 1.71±0.50, with 1 value >3SD; in thoracic aorta 2.03±0.52, with 1 value >3SD; in abdominal aorta 2.19±0.49, with no value >3SD; in shoulders 0.92±0.31 and in hips 0.87±0.34, with 2 and 4 values >3SD, respectively. These 12 values with SUVmax >3SD, belong to 5 patients, 3 of which had signs of xerostomia and/or arthritis. A statistically significant correlation was observed between SUVmax and age in all examined tissues but in the aorta. Conclusions: Tissues in which lymphocytic infiltration may occur show that SUVmax is tissue-dependent. Within tissue variability, an SUVmax greater than the mean +3SD is rarely found amongst patients without a symptomatic chronic inflammatory process but, when found, may highlight a chronic inflammatory condition.

68-Gallium DOTATATE scanning in symptomatic patients with negative anatomic imaging but suspected neuroendocrine tumor

Article

Full-text available

Feb 2018

Aim The study's aim was to determine the utility of 68-Gallium DOTATATE positron emission tomography (PET)-CT scanning in patients with carcinoid-like symptoms and negative anatomical imaging. Methods Retrospective analysis of 22 of 196 patients with carcinoid-like symptoms and no evidence of primary neuroendocrine tumor (NET) based on anatomical imaging and endoscopy who underwent 68-Gallium DOTATATE PET-CT as part of a prospective clinical trial. Results Of the biochemically positive patients (n = 11), 18% (n = 2) had additional evidence of NETs based on 68-Gallium DOTATATE PET-CT. Of the patients identified by 68-Gallium DOTATATE PET-CT, 50% (n = 1) had a treatment change and 100% showed symptom improvement. Of the biochemically negative patients (n = 11), 68-Gallium DOTATATE PET-CT identified NETs in 64% (n = 7). Change in management occurred in 71% patients, and 57% of patients showed symptom improvement. Conclusion 68-Gallium DOTATATE PET-CT imaging is useful in detecting NETs in symptomatic patients with negative anatomical imaging and changes the treatments in these patients.

The Role of [68Ga]Ga-DOTA-SSTR PET Radiotracers in Brain Tumors: A Systematic Review of the Literature and Ongoing Clinical Trials

Article

Full-text available

Jun 2022

Background: The development of [68Ga]Ga-DOTA-SSTR PET tracers has garnered interest in neuro-oncology, to increase accuracy in diagnostic, radiation planning, and neurotheranostics protocols. We systematically reviewed the literature on the current uses of [68Ga]Ga-DOTA-SSTR PET in brain tumors. Methods: PubMed, Scopus, Web of Science, and Cochrane were searched in accordance with the PRISMA guidelines to include published studies and ongoing trials utilizing [68Ga]Ga-DOTA-SSTR PET in patients with brain tumors. Results: We included 63 published studies comprising 1030 patients with 1277 lesions, and 4 ongoing trials. [68Ga]Ga-DOTA-SSTR PET was mostly used for diagnostic purposes (62.5%), followed by treatment planning (32.7%), and neurotheranostics (4.8%). Most lesions were meningiomas (93.6%), followed by pituitary adenomas (2.8%), and the DOTATOC tracer (53.2%) was used more frequently than DOTATATE (39.1%) and DOTANOC (5.7%), except for diagnostic purposes (DOTATATE 51.1%). [68Ga]Ga-DOTA-SSTR PET studies were mostly required to confirm the diagnosis of meningiomas (owing to their high SSTR2 expression and tracer uptake) or evaluate their extent of bone invasion, and improve volume contouring for better radiotherapy planning. Some studies reported the uncommon occurrence of SSTR2-positive brain pathology challenging the diagnostic accuracy of [68Ga]Ga-DOTA-SSTR PET for meningiomas. Pre-treatment assessment of tracer uptake rates has been used to confirm patient eligibility (high somatostatin receptor-2 expression) for peptide receptor radionuclide therapy (PRRT) (i.e., neurotheranostics) for recurrent meningiomas and pituitary carcinomas. Conclusion: [68Ga]Ga-DOTA-SSTR PET studies may revolutionize the routine neuro-oncology practice, especially in meningiomas, by improving diagnostic accuracy, delineation of radiotherapy targets, and patient eligibility for radionuclide therapies.

A Comparative 68Ga-Citrate and 68Ga-Chloride PET/CT Imaging of Staphylococcus aureus Osteomyelitis in the Rat Tibia

Article

Full-text available

Feb 2018
CONTRAST MEDIA MOL I

There may be some differences in the in vivo behavior of 68Ga-chloride and 68Ga-citrate leading to different accumulation profiles. This study compared 68Ga-citrate and 68Ga-chloride PET/CT imaging under standardized experimental models. Methods. Diffuse Staphylococcus aureus tibial osteomyelitis and uncomplicated bone healing rat models were used (n = 32). Two weeks after surgery, PET/CT imaging was performed on consecutive days using 68Ga-citrate or 68Ga-chloride, and tissue accumulation was confirmed by ex vivo analysis. In addition, peripheral quantitative computed tomography and conventional radiography were performed. Osteomyelitis was verified by microbiological analysis and specimens were also processed for histomorphometry. Results. In PET/CT imaging, the SUVmax of 68Ga-chloride and 68Ga-citrate in the osteomyelitic tibias (3.6 ± 1.4 and 4.7 ± 1.5, resp.) were significantly higher (P = 0.0019 and P = 0.0020, resp.) than in the uncomplicated bone healing (2.7 ± 0.44 and 2.5 ± 0.49, resp.). In osteomyelitic tibias, the SUVmax of 68Ga-citrate was significantly higher than the uptake of 68Ga-chloride (P = 0.0017). In animals with uncomplicated bone healing, no difference in the SUVmax of 68Ga-chloride or 68Ga-citrate was seen in the operated tibias. Conclusions. This study further corroborates the use of 68Ga-citrate for PET imaging of osteomyelitis.

Using 68Ga-DOTATATE PET for Postoperative Radiosurgery and Radiotherapy Planning in Patients With Meningioma: A Case Series

Article

Feb 2023
NEUROSURGERY

Background: For patients with either an incompletely resected meningioma or recurrence after surgery, stereotactic radiosurgery is frequently used. MRI is typically used for stereotactic radiosurgery targeting, but differentiating tumor growth from postoperative change can be challenging. 68Ga-DOTATATE, a positron emission tomography (PET) radiotracer targeting the somatostatin receptor type 2, has been shown to be a reliable meningioma biomarker. Objective: To evaluate the impact of 68Ga-DOTATATE on treatment planning in patients who had previously undergone meningioma resection. Methods: We present a consecutive case series of 12 patients with pathology-proven meningioma who received a 68Ga-DOTATATE PET between April 2019 and April 2021. Treatment planning was performed first using MRI. DOTATATE-PET images were then used to assess accurate tumor identification. Results: Ten patients had WHO Grade 2 meningioma, and 2 patients had Grade 1 tumor. Eight patients had recurrent meningiomas, and 4 patients had newly diagnosed disease. Overall, 68Ga-DOTATATE PET scans altered previously formulated treatment plans in 5 of 12 patients. In addition, 9 of 12 patients had disease foci not appreciated on MRI. Conclusion: In this series, incorporating 68Ga-DOTATATE PET imaging had clinical utility for most patients in whom it was used. It proved particularly adept in demonstrating intraosseous meningiomas, differentiating recurrence from postoperative changes, and identifying subcentimeter disease foci. It is an imaging modality that our center will continue to use as a means of improving postoperative treatment plans after the surgical resection of meningiomas.

Gallium Imaging of Infection and Inflammation

Chapter

Jan 2022

Infection and inflammation are both important causes of morbidity and mortality and often co-exist not just with each other but also with other disease entities. In instances where a definite distinction between the two processes is required in order to best manage the patient, time may not be sufficient to wait for the results of time-consuming cultures. Imaging provides a noninvasive diagnostic tool, which, when applied as positron emission tomography/computed tomography (PET/CT), is able to image the whole body in one investigation and to provide detailed morphological information combined with molecular information on the pathophysiology in one convenient study. Application of gallium-68-based tracers provides further important advantages with regard to costs, availability, and versatility. These advancements developed from earlier infection and inflammation single-photon emission computed tomography (SPECT) imaging performed with [⁶⁷Ga]Ga-citrate, which has supplied physicians over many decades with a versatile diagnostic tool, commonly referred to as “the poor man’s alternative to PET.” In this chapter, inflammation and infection imaging will be discussed and further divided into preclinical developments, clinical applications, and possible future applications.

Regular production and supply of ready-to-use gallium-68 radiopharmaceuticals: centralized radiopharmacy concept with supply experience of 300 doses

Article

Aug 2021

The present work illustrates the feasibility of production and supply of ready-to-use gallium-68 (68Ga) radiopharmaceuticals, similar to [18F]FDG, through a centralized production facility. The supply logistic from centralized facility to various imaging centers situated within the radius of 50 km was investigated using germanium-68/gallium-68 generator system of fixed (1.85 GBq) capacity. However, the logistics discussed and conclusion drawn can be definitely extrapolated to many other 68Ga radiopharmaceuticals, where the 68Ga radioisotope used is produced via direct cyclotron route.

Should 68Ga-DOTATATE PET/CT be Performed Routinely in Patients with Neuroendocrine Tumors Before Surgical Resection?

Article

Oct 2019

Background The only potential cure for neuroendocrine tumors (NETs) is operative resection, which may also offer a survival benefit for advanced disease. We aimed to assess the role of ⁶⁸Ga-DOTATATE PET/CT in preoperative planning and compared its performance to CT with IV contrast and MRI with Eovist®, for abdominal NETs. Methods Records of patients who underwent ⁶⁸Ga-DOTATATE PET/CT in addition to MRI with Eovist® and/or CT with IV contrast were retrospectively evaluated. The effect of imaging findings on surgical management and characteristics of detected lesions were analyzed. Descriptive statistics were used. Results Of 21 patients who underwent ⁶⁸Ga-DOTATATE PET/CT prior to surgical resection, five (24%) had a change in surgical management due to findings. In three patients, ⁶⁸Ga-DOTATATE PET/CT identified the primary tumor. In two patients, ⁶⁸Ga-DOTATATE PET/CT helped clarify equivocal hepatic lesions seen on MRI with Eovist®. MRI with Eovist® had the highest number of lesions found (median 13, versus 9 on CT and 9.5 on ⁶⁸Ga-DOTATATE PET/CT). DOTATATE-avid lesions were on average larger than lesions seen only on MRI with Eovist® (1.6 cm versus 0.6 cm, p = 0.0002). The optimal cutoff point for detection by ⁶⁸Ga-DOTATATE PET/CT was a size of 0.95 cm, with a sensitivity of 56% and specificity of 98%. Conclusions Preoperative ⁶⁸Ga-DOTATATE PET/CT is useful only in a subset of patients undergoing surgical resection for NETs. MRI with Eovist® is superior at identifying liver metastases when compared to ⁶⁸Ga-DOTATATE PET/CT and should therefore be used routinely before hepatic cytoreduction of NETs.

Comparison between Gallium‐68 citrate PET‐CT and Gallium‐67 citrate scintigraphy for infection imaging

Article

Jan 2019

Background Preliminary studies have reported promising results for the utility of Ga‐68 citrate PET‐CT for infection imaging. This technique offers reduced radiation dose to patients, shorter time between injection and imaging and reduced time for image acquisition compared to the 'gold standard' nuclear imaging technique: Ga‐67 citrate scintigraphy. Aims To compare the two imaging modalities to ascertain whether Ga‐68 citrate PET‐CT is of equivalent diagnostic efficacy for bone and joint infection or pyrexia of unknown origin (PUO) and to assess image quality and reporter confidence. Methods Patients with PUO and suspected bone or joint infection underwent Ga‐67 citrate scintigraphy and Ga‐68 citrate PET‐CT. Participants were followed up for 3 months to record subsequent treatment, investigations and outcome. Results 60 patients were recruited to this multicentre prospective study: 32 for bone and joint infection, 28 for PUO. The results show a sensitivity of 81% for Ga‐67 citrate scintigraphy and 69% for Ga‐68 citrate PET‐CT, a specificity of 79% for Ga‐67 citrate and 67% for Ga‐68 citrate and were concordant for 76% of the participants. The reporting physician confidence was significantly lower for Ga‐68 citrate (p<0.05), frequently due to prominent physiologic blood pool activity adjacent to the site of infection. Conclusion The sensitivity and specificity of Ga‐68 citrate PET‐CT was found to be consistently lower than Ga‐67 citrate scintigraphy. Additionally, due to the insufficient level of confidence of the reporting physicians for the Ga‐68 citrate PET‐CT, this modality could not currently be recommended to replace Ga‐67 citrate scintigraphy for routine clinical use. This article is protected by copyright. All rights reserved.

Increased Activity Due to Fractures Does Not Significantly Affect the Accuracy of 68Ga-DOTATATE PET/CT in the Detection of Culprit Tumor in the Evaluation of Tumor-Induced Osteomalacia

Article

Sep 2018

Objective: Ga-DOTATATE PET/CT is currently the most common imaging modality in localizing culprit tumors, which can result in tumor-induced osteomalacia (TIO). Fracture, which is one of the most common consequences of the TIO, can also lead to increased Ga-DOTATATE activity and potentially affect the accuracy of Ga-DOTATATE PET/CT imaging. The aim of this investigation is to evaluate whether the increased Ga-DOTATATE activity at the sites of the fracture will cause interpretation difficulty in the localizing the culprit tumor causing TIO. Method: The images of Ga-DOTATATE PET/CT scan from a total of 54 patients who had multiple foci of increased Ga-DOTATATE PET/CT on PET/CT were retrospectively analyzed. Not only was the intensity of the activity on PET but also the appearance of the activity on CT taken into consideration when the interpretation of the images occurred. The results from imaging analysis were compared with the clinical chart record. All patients had tentative clinical diagnosis of TIO. Results: The causative tumors in 53 patients were eventually identified. In 1 patient, the causative tumor was not identified. Among the 53 patients with confirmed TIO, 52 tumors were accurately localized. Conclusions: Mild activity at the sites of fracture is not a major challenging factor in the interpretation of Ga-DOTATATE PET/CT in the evaluation of TIO when both intensity on PET and morphology on CT were assessed.

Synthesis of 68Ga-NOTA-UBI30-41 and in vivo biodistribution in vervet monkeys towards potential PET/CT imaging of infection

Article

Full-text available

Jan 2012

Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement

Article

Full-text available

Jan 2014

Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

Article

Full-text available

Jun 2002

Timothy J Mccarthy

Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcu-ate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with 68 Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with 68 Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation .

Development of 68Ga-labelled DTPA galactosyl human serum albumin for liver function imaging

Article

Full-text available

Apr 2013
EUR J NUCL MED MOL I

Purpose: The hepatic asialoglycoprotein receptor is responsible for degradation of desialylated glycoproteins through receptor-mediated endocytosis. It has been shown that imaging of the receptor density using [(99m)Tc]diethylenetriamine pentaacetic acid (DTPA) galactosyl human serum albumin ([(99m)Tc]GSA) allows non-invasive determination of functional hepatocellular mass. Here we present the synthesis and evaluation of [(68)Ga]GSA for the potential use with positron emission tomography (PET). Methods: Labelling of GSA with (68)Ga was carried out using a fractionated elution protocol. For quality control thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC) techniques were evaluated. Stability of [(68)Ga]GSA was studied in phosphate-buffered saline (PBS) and human serum. For in vivo evaluation [(68)Ga]GSA distribution in Lewis rats was compared with [(99m)Tc]GSA by using a dual isotope protocol. PET and planar imaging studies were performed using the same scaled molar dose of [(68)Ga]GSA and [(99m)Tc]GSA. Time-activity curves (TAC) for heart and liver were generated and corresponding parameters calculated (t50, t90). Results: [(68)Ga]GSA can be produced with high radiochemical purity. The best TLC methods for determining potential free (68)Ga include 0.1 M sodium citrate as eluent. None of the TLC methods tested were able to determine potential colloids. This can be achieved by SEC. HPLC confirmed high radiochemical purity (>98%). Stability after 120 min incubation at 37 °C was high in PBS (>95% intact tracer) and low in human serum (∼27% intact tracer). Biodistribution studies simultaneously injecting both tracers showed comparable liver uptake, whereas activity concentration in blood was higher for [(68)Ga]GSA compared to [(99m)Tc]GSA. The [(99m)Tc]GSA TACs exhibited a small degree of hepatic metabolism compared to the [(68)Ga]GSA curves. The mean [(68)Ga]GSA t90 was higher than the mean t90 for [(99m)Tc]GSA. The mean [(68)Ga]GSA t50 was not significantly different from the mean t50 for [(99m)Tc]GSA. Conclusion: This study provides a promising new (68)Ga-labelled compound based on a commercially used kit for imaging the functional hepatocellular mass.

Uptake of 68gallium in atherosclerotic plaques in LDLR-/-ApoB100/100 mice

Article

Jan 2011

Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice

Article

Jan 2008

Evaluation of 68Ga-labelled tracers for PET imaging of myocardial perfusion in pigs - comparison with 15O-water

Conference Paper

Apr 2011

Simultaneous estimations of blood brain barrier (BBB) permeability and local cerebral blood volume (CBV) in human brain tumors with positron tomography and Ga68 EDTA

Article

Jan 1984

Using Ga-68 EDTA and a two compartment model for diffusion across the BBB that includes a weighted subtraction term for determination of the relative CBV (compared to a normal region of brain with an intact BBB) or the absolute value of CBV (using measurements of Ga-68 concentrations in the blood: the input function), the authors determined values for the forward and reverse rate constants (k1 and k2) for diffusion across the BBB as well as values of CBV in 12 subjects with primary or metastatic brain tumors. Patients were studied on a NeuroECAT tomograph; imaging times were 1 to 10 minutes per scan for a total of about 2 hours. Measurements of Ga-68 concentrations were made on plasma arterial samples. Four direct measurements (in 3 subjects) of CBV using C(15-0) were also obtained. Values of k1 (the transfer constant which numerically approximates the capillary permeability surface area (PS) product) averaged 0.0030 (+- 0.0017) ml/min/gm while k2 averaged 0.0308 (+- 0.0157)/min. Linear regression analysis of the relative CBV in 7 tumor deposits in 4 paired Ga-68 EDTA/C(15-0) studies compared to normal brain tissues resulted in a correlation coefficient of 0.97 for the two methods. The estimates of k1 and k2 were insensitive to changes in the location of the control regions (although CBV estimates changed appropriately) as well as to substituting the input function for a normal brain region when determining the absolute CBV of the lesions.

In vitro evaluation of 68Ga-Schiff bases for myocardial imaging

Article

Aug 2010
NUCL MED BIOL

Dynamic PET studies of blood-brain barrier permeability in Alzheimer's disease

Conference Paper

May 1985

Alterations in blood-brain barrier (BBB) function may play an important role in Alzheimer's disease (AD), thus dynamic PET was used to quantitate the brain uptake of two radionuclides with low BBB permeability, Rb-82 and Ga-68 EDTA. Studies were performed on subjects meeting current research criteria for AD as well as healthy aged controls. Dynamic tomograhic data were collected using the Donner 280-crystal tomograph for 5 min with Rb-82 (N=10) and 30 min for Ga-68 EDTA (N=7), and analyzed using a two compartment model and a nonlinear least-squares fitting procedure for quantitation of the passage of isotope from blood to brain (k1). For both Rb-82 and Ga-68 EDTA studies kl values were not significantly different from zero. There were no significant differences between groups and the permeability of the barrier was not greater in temporal cortex, the region of neocortex most heavily involved in AD.

Gallium-68: A systematic review of its nononcological applications

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