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Measured pKa values for selected BCAA/FBCAA pairs. pKa acid 5 carboxylic acid; pKa base 5 protonated amine.
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The large, neutral L-type amino acid transporters (LAT1-LAT4) are sodium-independent transporters that are widely distributed throughout the body. LAT expression levels are increased in many types of cancer, and their expression increases as cancers progress, leading to high expression levels in high-grade tumors and metastases. Because of the key...
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... of the arginine/ agmatine transporter AdiC from Escherichia coli displays crucial substrate binding via hydrogen bonds at the acid oxygens and amino group (27). To shed light on the effect of fluorination on the BCAAs, we measured the pKa of 3 BCAA/FBCAA couples: (S)-HL/(S)-5-fluorohomoleucine (FHL), pregabalin/5-FPregab, and (S)-aMHL/(S)-5-FaMHL (Fig. 4). In all cases, fluorination lowered the pKa values of the acid and base slightly. Although the effect of fluorination on ammonium pKa was relatively constant among the compounds analyzed (DpKa ; 20.40), fluorination decreased the pKa of the carboxylic acid function by about 0.1 for pregabalin and (S)-aMHL but had almost no effect (DpKa ...
Context 2
... of the arginine/ agmatine transporter AdiC from Escherichia coli displays crucial substrate binding via hydrogen bonds at the acid oxygens and amino group (27). To shed light on the effect of fluorination on the BCAAs, we measured the pKa of 3 BCAA/FBCAA couples: (S)-HL/(S)-5-fluorohomoleucine (FHL), pregabalin/5-FPregab, and (S)-aMHL/(S)-5-FaMHL (Fig. 4). In all cases, fluorination lowered the pKa values of the acid and base slightly. Although the effect of fluorination on ammonium pKa was relatively constant among the compounds analyzed (DpKa ; 20.40), fluorination decreased the pKa of the carboxylic acid function by about 0.1 for pregabalin and (S)-aMHL but had almost no effect (DpKa ...
Citations
... Most commonly, a synthetic precursor bearing a leaving group is required to enable an S N Ar [65,[165][166][167][168][169][170] or S N 2 reaction [171][172][173][174][175][176][177][178][179][180][181] to take place to install the 18 F substituent (e.g., 48-49). Some other reaction manifolds have also been exploited for radiofluorination of amino acid side chains or precursors thereof, including direct C-H fluorination (50) [182][183][184] and organocatalytic electrophilic fluorination (51) [76]. More complex structures have also been created in which the 18 F-radiolabel is attached to an amino acid side chain within a peptide or protein architecture. ...
Side chain-fluorinated amino acids are useful tools in medicinal chemistry and protein science. In this review, we outline some general strategies for incorporating fluorine atom(s) into amino acid side chains and for elaborating such building blocks into more complex fluorinated peptides and proteins. We then describe the diverse benefits that fluorine can offer when located within amino acid side chains, including enabling 19F NMR and 18F PET imaging applications, enhancing pharmacokinetic properties, controlling molecular conformation, and optimizing target-binding.
... The considerable achievements described above, along with others, [1,2,12] facilitate difluoromethylation as a strategy for both medicinal and radiopharmaceutical chemistry but are largely limited to radical and nucleophilic reaction manifolds. Considering this and our interest in both CÀ H fluorination [40,41] and radiofluorination, [42,43] we sought to design a reagent that would enable a formal electrophilic difluoromethylation of CÀ H, NÀ H and OÀ H bonds, and a fluorination protocol that would be sufficiently rapid to support production of [ 18 F]difluoromethylcontaining radiotracers (t 1/2 18 F~110 min). Schoenebeck [44,45] and others, [46,47] including ourselves, [48] have reported AgF-promoted desulfurative fluorination reactions (Figure 1 C) and we sought to advance this strategy to include the production of the difluoromethyl group. ...
The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O−H, N−H and C−H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5,6‐dimethoxy‐1,3‐benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support ¹⁸F‐difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag¹⁸F is demonstrated in the production of ¹⁸F‐labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol⁻¹, respectively. We expect that the DMBDT group and this ¹⁸F/¹⁹F‐difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production.
... For PET imaging applications, homology modeling has been combined with other methods, such as docking and MD, to design and optimize radiotracers for diverse receptors, such as Translocator Protein (TSPO) [73], L-type amino acid transporter (LAT) [74], and the GABA transporter [75]. ...
There has been impressive growth in the use of radiopharmaceuticals for therapy, selective toxic payload delivery, and noninvasive diagnostic imaging of disease. The increasing timeframes and costs involved in the discovery and development of new radiopharmaceuticals have driven the development of more efficient strategies for this process. Computer-aided drug design (CADD) methods and machine learning (ML) have become more effective over the last two decades for drug and materials discovery and optimization They are now fast, flexible, and sufficiently accurate to accelerate the discovery of new molecules and materials. Radiopharmaceuticals have also started to benefit from rapid developments in computational methods. Here we review the types of computational molecular design techniques that have been used for radiopharmaceuticals design. We also provide a thorough examination of success stories in the design of radiopharmaceuticals, and the strengths and weaknesses of the computational methods. We begin by providing a brief overview of therapeutic and diagnostic radiopharmaceuticals and the steps involved in radiopharmaceuticals design and development. We then review the computational design methods used in radiopharmaceutical studies – molecular mechanics, quantum mechanics, molecular dynamics, molecular docking, pharmacophore modelling, and data-driven ML. Finally, the difficulties and opportunities presented by radiopharmaceutical modelling are highlighted. The review emphasizes the potential of computational design methods to accelerate the production of these very useful clinical radiopharmaceutical agents and aims to raise awareness among radiopharmaceutical researchers about computational modelling and simulation methods that can be of benefit to this field.
... This approach creates a framework for the development of AA radiopharmaceuticals that are analogous to their canonical counterparts ( Figure 3). Furthermore, Britton and coworkers developed a method for the electrophilic radiofluorination of unactivated C-H bonds in hydrophobic amino acids ( Figure 3) to produce 18 Flabeled AAs that can visualize glioblastoma and prostate adenocarcinoma xenografts [121,122]. F]FLT has been used to predict response to chemotherapy or radiotherapy in lung, breast, and prostate cancer. [ 11 C]Choline is another radiopharmaceutical that is readily taken up by cancers during proliferation. ...
While the development of positron emission tomography (PET) radiopharmaceuticals closely follows that of traditional drug development, there are several key considerations in the chemical and radiochemical synthesis, preclinical assessment, and clinical translation of PET radiotracers. As such, we outline the fundamentals of radiotracer design, with respect to the selection of an appropriate pharmacophore. These concepts will be reinforced by exemplary cases of PET radiotracer development, both with respect to their preclinical and clinical evaluation. We also provide a guideline for the proper selection of a radionuclide and the appropriate labeling strategy to access a tracer with optimal imaging qualities. Finally, we summarize the methodology of their evaluation in in vitro and animal models and the road to clinical translation. This review is intended to be a primer for newcomers to the field and give insight into the workflow of developing radiopharmaceuticals.
Herein we report the automation and scale-up of a photofluorination process key to the production of branched-chain aliphatic radiotracers such as (S)-5-[18F]fluorohomoleucine ((S)-5-[18F]]FHL). (S)-5-[18F]FHL is a leucine analogue that is primarily taken up by the L-type amino acid transporter (LAT or System L). LAT1 expression levels correlate closely with tumor proliferation, angiogenesis, and treatment outcomes, making it an attractive target for molecular imaging of cancer. We have previously synthesized (S)-5-[18F]FHL and tested this tracer in mice bearing PC3 (prostate) or U87 (glioma) xenografts in order to establish its feasibility for detecting and monitoring treatment for a broad range of cancers. In this study, the radiosynthesis of 5-[18F]FHL is demonstrated on an automated DT-PhotoFluor module with a radiochemical yield of 20.1 ± 4.8% (n = 3), radiochemical purity of 94.5 ± 4.9% (n = 3), and a synthesis time of ~ 75 min. The reported DT-PhotoFluor module will allow for higher molar activity, better reproducibility, and reduced radiation exposure for upcoming first-in-human studies.
Over the past few decades, photocatalytic C–H functionalization reactions have received increasing attention due to the often mild reaction conditions and complementary selectivities to conventional functionalization processes. Now, photocatalytic C–H functionalization is a widely employed tool, supporting activities ranging from complex molecule synthesis to late-stage structure–activity relationship studies. In this perspective, we will discuss our efforts in developing a photocatalytic decatungstate catalyzed C–H fluorination reaction as well as its practical application realized through collaborations with industry partners at Hoffmann–La Roche and Merck, and extension to radiofluorination with radiopharmaceutical chemists and imaging experts at TRIUMF and the BC Cancer Agency. Importantly, we feel that our efforts address a question of utility posed by Professor Tobias Ritter in “Late-Stage Fluorination: Fancy Novelty or Useful Tool?” (ACIE, 2015, 54, 3216). In addition, we will discuss decatungstate catalyzed C–H fluoroalkylation and the interesting electrostatic effects observed in decatungstate-catalyzed C–H functionalization. We hope this perspective will inspire other researchers to explore the use of decatungstate for the purposes of photocatalytic C–H functionalization and further advance the exploitation of electrostatic effects for both rate acceleration and directing effects in these reactions.
To meet the increasing demand for environmentally benign and sustainable chemical processes, the use of light in organic synthesis is blossoming. Over the past decades, luminescent transition metal complexes have been extensively studied as photosensitizers due to their excellent photophysical properties and flexibility in structure modification. The visible‐light photo‐catalysis has been developed rapidly, from “proof of concept” to “a useful strategy,” in a broad range of organic transformation reactions that can be used in practical organic synthesis. Compared with the extensive literatures on ruthenium and iridium complexes used in visible‐light catalysis, the summaries on gold, platinum tungsten (except polyoxotungstates), and osmium complexes catalyzed photochemical reactions are scarce. In this article, the recent developments in photochemical reactions catalyzed by gold (Au), platinum (Pt), tungsten (W), and osmium (Os) complexes, as well as the mechanistic studies and their applications in organic synthesis are summarized. The photochemical reactions discussed herein mainly refer to the ones with transition metal complexes that absorb light in the UV–visible spectral region and which serve as a photo‐redox catalyst or a photosensitizer.
Positron emission tomography (PET) uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or chemical absorption. Depending on the targeted processes within the living organism, different tracers are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, and bone lesions, where the most commonly used tracers are radiolabeled with 18F (e.g., [18F]-FDG and NA [18F]). Oxygen-15 isotope is mostly involved in blood flow measurements, whereas a wide array of 11C-based compounds have also been developed for neuronal disorders according to the affected neuroreceptors, prostate cancer, and lung carcinomas. In contrast, the single-photon emission computed tomography (SPECT) technique uses gamma-emitting radioisotopes and can be used to diagnose strokes, seizures, bone illnesses, and infections by gauging the blood flow and radio distribution within tissues and organs. The radioisotopes typically used in SPECT imaging are iodine-123, technetium-99m, xenon-133, thallium-201, and indium-111. This systematic review article aims to clarify and disseminate the available scientific literature focused on PET/SPECT radiotracers and to provide an overview of the conducted research within the past decade, with an additional focus on the novel radiopharmaceuticals developed for medical imaging.
