Figure 2 - uploaded by Nicolas Lepareur
Content may be subject to copyright.
![Schematic representation of the signaling pathways induced by somatostatin receptors activation. Green arrows: activated pathways; red arrows: inhibited pathways. Adapted from [8].](profile/Nicolas-Lepareur/publication/344140606/figure/fig1/AS:933752536580099@1599635361678/Schematic-representation-of-the-signaling-pathways-induced-by-somatostatin-receptors.png)
Schematic representation of the signaling pathways induced by somatostatin receptors activation. Green arrows: activated pathways; red arrows: inhibited pathways. Adapted from [8].
Source publication
![Figure 11. [ 188 Re]-P2045. Figure 11. [ 188 Re]-P2045.](profile/Nicolas-Lepareur/publication/344140606/figure/fig2/AS:933752536571907@1599635361772/188-Re-P2045-188-Re-P2045_Q320.jpg)
Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling...
Contexts in source publication
Context 1
... effects of somatostatin are expressed through different signaling pathways [4,5]. After a cascade of reactions, this leads on the one hand to the inhibition of tumor growth (action on the secretion of hormones) and blocking proliferation via the activation of different tyrosine phosphatases (anti-proliferative and pro-apoptotic action), but also to the inhibition of the secretion of growth factors such as growth hormone or IGF-1 having a major role in the inhibition of tumor growth (anti-angiogenic) ( Figure 2) [6,7]. The effects of somatostatin are expressed through different signaling pathways [4,5]. ...
Context 2
... effects of somatostatin are expressed through different signaling pathways [4,5]. After a cascade of reactions, this leads on the one hand to the inhibition of tumor growth (action on the secretion of hormones) and blocking proliferation via the activation of different tyrosine phosphatases (anti-proliferative and pro-apoptotic action), but also to the inhibition of the secretion of growth factors such as growth hormone or IGF-1 having a major role in the inhibition of tumor growth (anti-angiogenic) ( Figure 2) [6,7]. Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 ...
Similar publications
Neuroendocrine neoplasms (NENs) encompass a diverse range of biologically and behaviorally distinct epithelial malignancies that derive from neuroendocrine cells. These neoplasms are able to secrete a variety of bioactive amines or peptide hormones. The majority of NENs are well-differentiated and are defined as neuroendocrine tumors (NETs). While...
Somatostatin receptors (SST), especially SST subtype 2 (SST2), are important targets for the management of patients with neuroendocrine tumours (NETs) or neuroendocrine neoplasias (NENs). Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷ Lu-labelled SST agonists, for example, ¹⁷⁷ Lu-DOTA-TOC or ¹⁷⁷ Lu-DOTA-TATE, is recommended by the European N...
Prostate cancer is one of the most common malignancies affecting elderly men worldwide and the fifth leading cause of cancer death in men. Prostate cancer includes many histological variants with the prostatic acinar adenocarcinoma variant accounting for the majority of the diagnosed cases. Other less common histological variants are broadly classi...
PET/CT molecular imaging has been imposed in clinical oncological practice over the past 20 years, driven by its two well-grounded foundations: quantification and radiolabeled molecular probe vectorization. From basic visual interpretation to more sophisticated full kinetic modeling, PET technology provides a unique opportunity to characterize vari...
This review article explores the dynamic field of radiopharmaceuticals, where innovative developments arise from combining radioisotopes and pharmaceuticals, opening up exciting therapeutic possibilities. The in-depth exploration covers targeted drug delivery, delving into passive targeting through enhanced permeability and retention, as well as ac...
Citations
... Ideal for therapeutic radiopharmaceuticals is to have a cellular target that is highly overexpressed on malignant cells and with limited or absent expression in healthy tissues. For NETs, two molecules were initially developed: metaiodobenzylguanidine (mIBG; norepinephrine analog) and octreotide (one of the SSAs) [7][8][9][10]. The role of mIBG in patients with GEP-NET has subsided over the years due to its less favorable tumor targeting, toxicity profile and pharmacokinetic behavior, as compared to PRRT [11]. ...
... DOTATOC and DOTATATE). These radiopharmaceuticals had high tumor affinity, limited accumulation in non-target organs, high stability of the complex in vivo, and flexibility to label either diagnostic or therapeutic nuclides to similar targeting molecules [7]. ...
Purpose of Review
To provide insights into the role of peptide receptor radionuclide therapy (PRRT) in patients with advanced neuroendocrine tumors (NET) and an overview of possible strategies to combine PRRT with locoregional and systemic anticancer treatments.
Recent Findings
Research on combining PRRT with other treatments encompasses a wide variety or treatments, both local (transarterial radioembolization) and systemic therapies, chemotherapy (i.e., capecitabine and temozolomide), targeted therapies (i.e., olaparib, everolimus, and sunitinib), and immunotherapies (e.g., nivolumab and pembrolizumab). Furthermore, PRRT shows promising first results as a treatment prior to surgery.
Summary
There is great demand to enhance the efficacy of PRRT through combination with other anticancer treatments. While research in this area is currently limited, the field is rapidly evolving with numerous ongoing clinical trials aiming to address this need and explore novel therapeutic combinations.
... This unique property, stemming from their high-affinity characteristics, enables the radiopeptide to be highly effective in early cancer detection and treatment initiation. With these advantages, the search and development of novel peptide compounds are on the rise. 2 One of the promising candidates is a radiopeptide designed to target the peptide receptor of somatostatin receptor 2 (SSTR2), 3,4 offering enhanced visualization for cancer imaging and targeted therapy. 5 Naturally occurring peptides with cytotoxic properties were predominantly developed as anticancer peptides (ACPs) due to their ability to traverse cell membranes and penetrate the cancer cell. ...
Radiolabeled peptides belong to a highly specific group of radiotracers used in oncology, particularly for diagnostics and cancer therapy. With the notable advantages of high binding affinity and selectivity to cancer cells, they have proven to be very useful in nuclear medicine. As a result, efforts have been focused on discovering new peptide sequences for radiopeptide preparation. Nocardiotide A, a cyclic hexapeptide comprising the amino acids cyclo-Trp-Ile-Trp-Leu-Val-Ala (cWIWLVA) isolated from Nocardiopsis sp., has shown significant cytotoxicity against cancer cells, rendering it a suitable candidate for the process. Therefore, the present study aimed to design a stable and effective radiopeptide by labeling nocardiotide A with iodine-131 (131 I), ensuring that its affinity to SSTR2 is not compromised. In silico study showed that structural modification of nocardiotide A labeled with 131 iodine exhibited good affinity value, forming hydrogen bonds with key residues, such as Q.102 and T.194, which are essential in SSTR2. Based on the results, cyclic hexapeptides of cWIWLYA were selected for further synthesis, and its peptide product was confirmed by the presence of an ionic molecule peak m/z [M + Na] + 855.4332 (yield, 25.60%). In vitro tests conducted on cWIWLYA showed that cWIWLYA can bind to HeLa cancer cells. Radiopeptide synthesis was initiated with radiolabeling of cWIWLYA by 131 I using the chloramine-T method that showed a radiochemical yield of 93.37%. Non-radioactive iodine labeling reaction showed that iodination was successful, which detected the presence of di-iodinated peptide (I 2-cWIWLYA) with m/z [M + Na] + 1107.1138. In summary, a radiopeptide derived from nocardiotide A showed great potential for further development as a diagnostic and therapeutic agent in cancer treatment.
... Whilst PRRT with somatostatin receptor (SSTR) agonists is a well-established treatment for the management of advanced NETs [3,[16][17][18], radiolabelled SSTR antagonists may further improve responses, with previous studies demonstrating higher uptake and longer retention in tumours compared with SSTR agonists [16,19,20] 177 Lu-DOTA-JR11), has recently shown a favourable pharmacokinetic and biodistribution profile, as well as high metabolic stability in patients with NETs [21,22]. In a preliminary clinical study of four patients with progressive NETs, [ 177 Lu]Lu-satoreotide tetraxetan administered at a single mean activity of 1.0 GBq demonstrated, on average, a three-fold higher tumour absorbed dose and a two-fold higher tumour-to-kidney absorbed dose ratio compared with [ 177 Lu]Lu-DOTA-TATE administered at a single mean activity of 1.1 GBq [22]. ...
... Whilst PRRT with somatostatin receptor (SSTR) agonists is a well-established treatment for the management of advanced NETs [3,[16][17][18], radiolabelled SSTR antagonists may further improve responses, with previous studies demonstrating higher uptake and longer retention in tumours compared with SSTR agonists [16,19,20] 177 Lu-DOTA-JR11), has recently shown a favourable pharmacokinetic and biodistribution profile, as well as high metabolic stability in patients with NETs [21,22]. In a preliminary clinical study of four patients with progressive NETs, [ 177 Lu]Lu-satoreotide tetraxetan administered at a single mean activity of 1.0 GBq demonstrated, on average, a three-fold higher tumour absorbed dose and a two-fold higher tumour-to-kidney absorbed dose ratio compared with [ 177 Lu]Lu-DOTA-TATE administered at a single mean activity of 1.1 GBq [22]. ...
Purpose
To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs).
Methods
This study was part of a phase I/II trial of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients.
Results
In all evaluated organs, maximum [¹⁷⁷Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57–66% within 48 h following the first treatment cycle. At the first treatment cycle, [¹⁷⁷Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [¹⁷⁷Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles.
Conclusion
[¹⁷⁷Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy.
Trial registration
NCT02592707. Registered October 30, 2015.
... SST is a cyclic neuropeptide consisting of 14 amino acids (Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys) that binds to SSTRs and regulates the secretion of endocrine and exocrine substances [60]. SSTRs (SSTR1-5) are found in various cell types [60]. ...
... SST is a cyclic neuropeptide consisting of 14 amino acids (Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys) that binds to SSTRs and regulates the secretion of endocrine and exocrine substances [60]. SSTRs (SSTR1-5) are found in various cell types [60]. Among them, SSTR2 is overexpressed in NETs, which makes SSTR2 an attractive target for tumor imaging and therapy [61]. ...
... However, native SST has a short circulating half-life, limiting its effectiveness. Many SST analogs, including octreotide (Sandostatin®), lanreotide (BIM 23014, Soma-tuline®), vapreotide (RC160, Sanvar®), and pasireotide (SOM-230, Signifor®) ( Figure 3), have been developed with modifications to increase their half-life [60]. Among them, octreotide (D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys) was the first FDA-approved agonist peptide analog. ...
Targeting receptors overexpressed on cancer cells with radiolabeled peptides has become a crucial aspect of molecular imaging in oncology. Small peptides offer favorable characteristics for tumor targeting with minimal side effects and toxicity owing to their small size and simple radiolabeling protocols. Among them, somatostatin analogs have received regulatory approval for the diagnosis and treatment of neuroendocrine tumors. Cyclic RGD (Arg‐Gly‐Asp) peptides, bombesin analogs, and glucagon‐like peptide‐1 analogs are currently under development and/or undergoing clinical trials. The most used radionuclides for tumor imaging include 99mTc and ¹¹¹In for single‐photon emission computed tomography, ⁶⁸Ga and ¹⁸F for positron emission tomography. This review highlights the clinical potential and future prospects of 99mTc‐labeled peptides for tumor imaging.
... NENs overexpress specific peptide receptors, particularly somatostatin receptors (SSTRs) (Fig. 3b) [61]. Radiolabeled somatostatin (SST) analogs targeting SSTRs are the most advanced radiopharmaceuticals for NENs (Table 2 and Fig. 3) [62,63]. There are two major categories of SST analogs: agonists and antagonists (Fig. 3b) [63]. ...
... Radiolabeled somatostatin (SST) analogs targeting SSTRs are the most advanced radiopharmaceuticals for NENs (Table 2 and Fig. 3) [62,63]. There are two major categories of SST analogs: agonists and antagonists (Fig. 3b) [63]. The agonist octreotide was the first synthesized SST analog, and was the starting point for the development of radiolabeled SST analogs (Fig. 3a) [64]. ...
... In addition, the phase III trial evaluating the efficacy and safety of 177 Lu-DOTA-TOC in patients with GEP-NETs is ongoing (NCT03049189), with estimated completion by June 2029. Furthermore, the introduction of SSTRs antagonists, such as LM3, and JR11, is an important advance in the field of SSTRs targeting [63]. Preclinical and clinical studies have shown that SSTR antagonists have better binding ability to SSTR, a higher tumor uptake rate, and can deliver a higher dose of radiation than agonists (Fig. 3c) [67][68][69]. ...
Radiopharmaceuticals play a vital role in cancer therapy. The carrier of radiopharmaceuticals can precisely locate and guide radionuclides to the target, where radionuclides kill surrounding tumor cells. Effective application of radiopharmaceuticals depends on the selection of an appropriate carrier. Herein, different types of carriers of radiopharmaceuticals and the characteristics are briefly described. Subsequently, we review radiolabeled monoclonal antibodies (mAbs) and their derivatives, and novel strategies of radiolabeled mAbs and their derivatives in the treatment of lymphoma and colorectal cancer. Furthermore, this review outlines radiolabeled peptides, and novel strategies of radiolabeled peptides in the treatment of neuroendocrine neoplasms, prostate cancer, and gliomas. The emphasis is given to heterodimers, bicyclic peptides, and peptide-modified nanoparticles. Last, the latest developments and applications of radiolabeled nucleic acids and small molecules in cancer therapy are discussed. Thus, this review will contribute to a better understanding of the carrier of radiopharmaceuticals and the application in cancer therapy.
... The potential advantages of treating GBM with 4'-F-CBD, compared to CBD, are, brie y, that 4'-F-CBD is reported to have increased potency in in vivo behavioural assays compared to CBD, suggesting potentially increased binding at the molecular level, or increased delivery to the brain 16,18-19 . There is also the opportunity that the uorine atom on 4'-F-CBD provides for imaging and potentially theranostic purposes [51][52] . ...
Background
Glioblastoma multiforme (GBM) is an aggressive cancer with poor prognosis, partly due to resistance to the standard chemotherapy treatment, temozolomide (TMZ). Phytocannabinoid cannabidiol (CBD) has exhibited anti-cancer effects against GBM, however, the ability of CBD to overcome common resistance mechanisms to TMZ have not yet been investigated. 4’-Fluoro-cannabidiol (4’-F-CBD, or HUF-101/PECS-101) is a derivative of CBD, that exhibits increased activity compared to CBD during in vivo behavioural studies.
Methods
This work investigated the anti-cancer activity of cannabinoids against GBM cells sensitive to and representing major resistance mechanisms to TMZ. The cannabinoids were also studied in combination with imidazotetrazine agents, and the OrbiSIMS technique was used to investigate the mechanism of action of CBD.
Results
CBD and 4’-F-CBD were found to overcome two major resistance mechanisms (methylguanine DNA-methyltransferase (MGMT) activity and DNA mismatch repair (MMR)-deficiency). Synergistic responses were observed when cells were exposed to cannabinoids and imidazotetrazine agents. Synergy was increased with T25 and 4’-F-CBD. OrbiSIMS analysis highlighted the presence of methylated-DNA, a previously unknown anti-cancer mechanism of action of CBD.
Conclusions
This work demonstrates the anti-cancer activity of 4’-F-CBD and the synergy of cannabinoids with imidazotetrazine agents for the first time and expands understanding of CBD mechanism of action.
... Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin receptor (SSTR) agonists has shown to be well tolerated and effective, thereby becoming integral in management of advanced neuroendocrine tumours (NETs) [1][2][3]. Radiolabelled SSTR antagonists may further improve responses, with data demonstrating higher uptake and longer retention in tumours compared with SSTR agonists, despite lack of internalisation of the ligand-receptor complex [2,4,5]. Their higher tumour uptake appears to reflect affinity for a greater number of receptor binding sites and slower dissociation, allowing for a longer accumulation of, and cellular exposure to, ionising beta radiation [2,6,7]. ...
... Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin receptor (SSTR) agonists has shown to be well tolerated and effective, thereby becoming integral in management of advanced neuroendocrine tumours (NETs) [1][2][3]. Radiolabelled SSTR antagonists may further improve responses, with data demonstrating higher uptake and longer retention in tumours compared with SSTR agonists, despite lack of internalisation of the ligand-receptor complex [2,4,5]. Their higher tumour uptake appears to reflect affinity for a greater number of receptor binding sites and slower dissociation, allowing for a longer accumulation of, and cellular exposure to, ionising beta radiation [2,6,7]. ...
... Radiolabelled SSTR antagonists may further improve responses, with data demonstrating higher uptake and longer retention in tumours compared with SSTR agonists, despite lack of internalisation of the ligand-receptor complex [2,4,5]. Their higher tumour uptake appears to reflect affinity for a greater number of receptor binding sites and slower dissociation, allowing for a longer accumulation of, and cellular exposure to, ionising beta radiation [2,6,7]. ...
Purpose
We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity.
Methods
This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow.
Results
Median cumulative administered activity of [¹⁷⁷Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3).
Conclusion
[¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing.
Trial registration
ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.
... Conversely, no significant change was observed in primary tumor sites or metastatic lesions. SSAs, as synthetic SSAs targeting SSTRs, have been widely applied in NETs imaging and therapy (34). The rationale is the tumor cell receptor-mediated internalization of the radio-or non-radiolabeled SSAs and their retention in the cytoplasm (21). ...
Background
The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients.
Methods
The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool.
Results
A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe¹-Tyr³-Thr⁸-octreotide (⁶⁸Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 vs. 7.62±2.12, P=0.001) and spleen (25.74±7.14 vs. 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique.
Conclusions
Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.
... 5 Radionuclides emitting γ or β+ (e.g., 111 In and 68 Ga) are exploited for imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET), respectively, while those emitting βor α (e.g., 177 Lu and 211 At) are used for therapeutic treatments. 6 In this last case, after the binding of a radiopharmaceutical to the given target and its subsequent internalization, a cytotoxic dose of radiation is delivered to the cancer cell. 7 In some cases, the radionuclide emits both β+ and β-( 64 Cu), or γ and β-( 177 Lu), making their use suitable for theranostics. ...
... 17 To date, eight peptide-based radiopharmaceutical compounds targeting somatostatin receptors have been approved by FDA, and are routinely used in clinics for different applications (Table 1). 6 Radiopharmaceuticals targeting SSTR2 share a similar three components structure made by (1) a biovector mimicking the structure of the endogenous ligand somatostatin, that is conjugated with (2) a chelator moiety carrying (3) a radionuclide ( Figure 1). 19 In the last year, different structures of SSTR2 in multiple conformational states have been published. ...
The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use (64Cu/68Ga-DOTATATE, 68Ga-DOTATOC, 64Cu-SARTATE) and some in clinical development (68Ga-DOTANOC, 64Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2.
... Although there was wide acceptance of Octreoscan for NEN imaging, the radiopharmaceutical had many limitations-less favorable tumor-to-background ratio, moderate affinity for receptors, and high gamma energy causing more background noise and high radiation absorbed dose to the patient. To a great extent, these limitations have been alleviated with the advent of the next generation of SSA labelled with positron emitter radiometal [ 68 Ga] to be used with PET-CT [13,14]. Recent advancements in the detection and mapping of SSTR expression in vivo has opened avenues for targeting the same for therapeutic benefits and personalized management. ...
Somatostatin receptor (SSTR) agonist-based Positron Emission Tomography-Computed Tomography (PET-CT) imaging is nowadays the mainstay for the assessment and diagnostic imaging of neuroendocrine neoplasms (NEN), especially in well-differentiated neuroendocrine tumors (NET) (World Health Organization (WHO) grade I and II). Major clinical indications for SSTR imaging are primary staging and metastatic workup, especially (a) before surgery, (b) detection of unknown primary in metastatic NET, (c) patient selection for theranostics and appropriate therapy, especially peptide receptor radionuclide therapy (PRRT), while less major indications include treatment response evaluation on and disease prognostication. Dual tracer PET-CT imaging using SSTR targeted PET tracers, viz. [68Ga]Ga-DOTA-Tyr3-Octreotate (DOTA-TATE) and [68Ga]Ga-DOTA-NaI3-Octreotide (DOTA-NOC), and fluorodeoxyglucose (FDG), have recently gained widespread acceptance for better assessment of whole-body tumor biology compared to single-site histopathology, in terms of being non-invasive and the ability to assess inter- and intra-tumoral heterogeneity on a global scale. FDG uptake has been identified as independent adverse risk factor in various studies. Recently, somatostatin receptor antagonists have been shown to be more sensitive and specific in detecting the disease. The aim of this review article is to summarize the clinical importance of SSTR-based imaging in the clinical management of neuroendocrine and related tumors.
