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We have developed 8‐amino‐3‐(2S,5R‐dimethyl‐1‐piperidyl)‐[1,2,4]triazolo[4,3‐a]pyrazine‐5‐[11C]carbonitrile ([11C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11C]MTP38 using [11C]hydrogen cyanide ([11C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11C]MTP38 was performed using an automated 11C‐labeling synthesizer developed in‐house within 40 min after the end of irradiation. [11C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11C]CO2 at the end of irradiation, decay‐corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [11C]MTP38 injection complied with our in‐house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11C]MTP38 for clinical applications using an 11C‐labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11C]MTP38 suitable for clinical applications. [ABSTRACT FROM AUTHOR]

Recently, we produced 11C‐labeled 2‐((1E,3E)‐4‐(6‐(methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[d]thiazol‐6‐ol ([11C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half‐life) of [11C]PBB3, we further synthesized 18F‐labeled 1‐fluoro‐3‐((2‐((1E,3E)‐4‐(6‐(methylamino)pyridine‐3‐yl)buta‐1,3‐dien‐1‐yl)benzo[d]thiazol‐6‐yl)oxy)propan‐2‐ol ([18F]PM‐PBB3). [18F]PM‐PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [18F]PM‐PBB3 for clinical applications. [18F]PM‐PBB3 was synthesized by direct 18F‐fluorination of the tosylated derivative, followed by removal of the protecting group. [18F]PM‐PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay‐corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [18F]PM‐PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV‐cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [18F]PM‐PBB3 injection complied with our in‐house quality control and quality assurance specifications. We have accomplished >200 production runs of [18F]PM‐PBB3 in our facility for various research purposes. [ABSTRACT FROM AUTHOR]

Among proteins utilized as sweeteners, neoculin and miraculin are taste-modifying proteins that exhibit pH-dependent sweetness. Several experiments on neoculin have shown that His11 of neoculin is responsible for pH dependence. We investigated the molecular mechanism of the pH dependence of neoculin by molecular dynamics (MD) calculations. The MD calculations for the dimeric structures of neoculin and His11 mutants showed no significant structural changes for each monomer at neutral and acidic pH levels. The dimeric structure of neoculin dissociated to form isolated monomers under acidic conditions but was maintained at neutral pH. The dimeric structure of the His11Ala mutant, which is sweet at both neutral and acidic pH, showed dissociation at both pH 3 and 7. The His11 residue is located at the interface of the dimer in close proximity to the Asp91 residue of the other monomer. The MD calculations for His11Phe and His11Tyr mutants demonstrated the stability of the dimeric structures at neutral pH and the dissociation of the dimers to isolated monomers. The dissociation of the dimer caused a flexible backbone at the surface that was different from the dimeric interface at the point where the other monomer interacts to form an oligomeric structure. Further MD calculations on the tetrameric structure of neoculin suggested that the flexible backbone contributed to further dissociation of other monomers under acidic conditions. These results suggest that His11 plays a role in the formation of oligomeric structures at pH 7 and that the isolated monomer of neoculin at acidic pH is responsible for sweetness. [ABSTRACT FROM AUTHOR]

Background: Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl receptor (NPY Y1-R) is the most widely studied NPY receptor, and is involved in many of these processes. BMS-193885 (1) was previously developed as a potent and selective NPY Y1-R antagonist, which has good systemic bioavailability and brain penetration. To evaluate the characteristics of 1 in vivo, we developed 11C-labeled BMS-193885 ([11C]1) and its desmethyl analog ([11C]2) for potential use as two new positron emission tomography (PET) tracers.Results: [11C]1 was synthesized from [11C]methyl iodide using 2. [11C]2 was synthesized from [11C]phosgene using its aniline and amine derivatives. The mean ± S.D. decay-corrected radiochemical yields of [11C]1 and [11C]2 from 11CO2 at the end of radionuclide production were 23 ± 3.2% (n = 6) and 24 ± 1.5% (n = 4), respectively. In biodistribution on mice, radioactivity levels for both tracers were relatively high in the kidney, small intestine, and liver at 60 min post-injection. The radioactivity levels in the kidney, lung, and spleen of mice at 30 min post-injection with [11C]1 were significantly reduced by pretreatment with 1 (10 mg/kg), and levels of [11C]1 in the brain of mice were significantly increased by pretreatment with the P-glycoprotein and breast cancer resistance protein inhibitor elacridar (10 mg/kg). In metabolite analysis using mouse plasma, [11C]1 and [11C]2 were rapidly metabolized within 30 min post-injection, and [11C]1 was mainly metabolized into unlabeled 2 and radiolabeled components.Conclusion: [11C]1 and [11C]2 were successfully synthesized with sufficient amount of radioactivity and high quality for use in vivo. Our study of [11C]1 and its desmethyl analog [11C]2 was useful in that it helped to elucidate the in vivo characteristics of 1. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1 + human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, 211 At-AITM. A single dose of 211 At-AITM (2.96 MBq) in mGluR1 + cancers exhibits long-lasting in vivo antitumor efficacy across seven subtypes of four of the most common tumors, namely, breast cancer, pancreatic cancer, melanoma, and colon cancers, with little toxicity. Moreover, complete regression of mGluR1 + breast cancer and pancreatic cancer is observed in approximate 50% of tumor-bearing mice. Mechanistically, the functions of 211 At-AITM are uncovered in downregulating mGluR1 oncoprotein and inducing senescence of tumor cells with a reprogrammed senescence-associated secretory phenotype. Our findings suggest α-radiopharmaceutical therapy with 211 At-AITM can be a useful strategy for mGluR1 + pan-cancers, regardless of their tissue of origin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The scandium triflate-catalyzed N -[ 18 F]fluoroalkylation of aryl- or heteroaryl-amines with [ 18 F]epifluorohydrin ([ 18 F] 2 ) was investigated. This reaction is mild and provides one-step access to N -[ 18 F]fluoroalkylated aryl- or heteroaryl-amines, which are used for positron emission tomography imaging. The use of 2,2,2-trifluoroethanol as a cosolvent improved the reaction efficiency. The use of ( S )- and ( R )-[ 18 F] 2 produced the corresponding enantiomeric N -[ 18 F]fluoroalkylated anilines.

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[ 11 C]carbonitrile ([ 11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [ 11 C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [ 11 C]MTP38 using [ 11 C]hydrogen cyanide ([ 11 C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [ 11 C]MTP38 was performed using an automated 11 C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [ 11 C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [ 11 C]CO 2 at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [ 11 C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [ 11 C]MTP38 for clinical applications using an 11 C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [ 11 C]MTP38 suitable for clinical applications., (© 2022 John Wiley & Sons, Ltd.)

Recently, we produced 11 C-labeled 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([ 11 C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half-life) of [ 11 C]PBB3, we further synthesized 18 F-labeled 1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([ 18 F]PM-PBB3). [ 18 F]PM-PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [ 18 F]PM-PBB3 for clinical applications. [ 18 F]PM-PBB3 was synthesized by direct 18 F-fluorination of the tosylated derivative, followed by removal of the protecting group. [ 18 F]PM-PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay-corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [ 18 F]PM-PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV-cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [ 18 F]PM-PBB3 injection complied with our in-house quality control and quality assurance specifications. We have accomplished >200 production runs of [ 18 F]PM-PBB3 in our facility for various research purposes., (© 2020 John Wiley & Sons, Ltd.)

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central-nervous-system disorders. 2-(2-(3-(4-([ 18 F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([ 18 F]MNI-659, [ 18 F]5) is a useful positron-emission-tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [ 18 F]5 can accumulate in the brain. In this study, using [ 18 F]5 as a lead compound, we designed four new 18 F-labeled ligands ([ 18 F]6-9) to find one more suitable than [ 18 F]5. Of these, 2-(2-(3-(4-([ 18 F]fluoromethoxy- d 2 )phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([ 18 F]9) exhibited high in vitro binding affinity ( K i = 2.9 nM) to PDE10A and suitable lipophilicity (log D = 2.2). In PET studies, the binding potential (BP ND ) of [ 18 F]9 (5.8) to PDE10A in the striatum of rat brains was significantly higher than that of [ 18 F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites in the brains of rats given [ 18 F]9 than in those given [ 18 F]5. In conclusion, [ 18 F]9 is a useful PET ligand for PDE10A imaging in brain.

Two novel radiotracers, namely, N-(4-[18F]fluorobenzyl)-N-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([18F]5) and 2-(5-(4-[18F]fluorophenyl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide ([18F]6), were developed for positron emission tomography (PET) imaging of translocator protein (18 kDa) (TSPO) in ischemic brain in this study. The two radiotracers with a [18F]fluorobenzene ring were derived from the corresponding [18F]fluoroethyl tracers [18F]7 and [18F]8 which underwent [18F]defluoroethylation in vivo easily. [18F]5 or [18F]6 was synthesized by the radiofluorination of the spirocyclic iodonium ylide precursor 10 or 17 with [18F]F- in 23 ± 10% (n = 7) or 56 ± 9% (n = 7) radiochemical yields (decay-corrected, based on [18F]F-). [18F]5 and [18F]6 showed high in vitro binding affinities (Ki = 0.70 nM and 5.9 nM) for TSPO and moderate lipophilicities (log D = 2.9 and 3.4). Low uptake of radioactivity for both radiotracers was observed in mouse bones. Metabolite analysis showed that the in vivo stability of [18F]5 and [18F]6 was improved in comparison to the parent radiotracers [18F]7 and [18F]8. In particular, no radiolabelled metabolite of [18F]5 was found in the mouse brains at 60 min after the radiotracer injection. PET studies with [18F]5 on ischemic rat brains revealed a higher binding potential (BPND = 3.42) and maximum uptake ratio (4.49) between the ipsilateral and contralateral sides. Thus, [18F]5 was shown to be a useful PET radiotracer for visualizing TSPO in neuroinflammation models.

To introduce the 3-[ 18 F]fluoro-2-hydroxypropyl moiety into positron emission tomography (PET) radiotracers, we performed automated synthesis of (rac)-, (R)-, and (S)-[ 18 F]epifluorohydrin ([ 18 F]1) by nucleophilic displacement of (rac)-, (R)-, or (S)-glycidyl tosylate with 18 F - and purification by distillation. The ring-opening reaction of (R)- or (S)-[ 18 F]1 with phenol precursors gave enantioenriched [ 18 F]fluoroalkylated products without racemisation. We then synthesised (rac)-, (R)-, and (S)- 2-{5-[4-(3-[ 18 F]fluoro-2-hydroxypropoxy)phenyl]-2-oxobenzo[d]oxazol-3(2H)-yl}-N-methyl-N-phenylacetamide ([ 18 F]6) as novel radiotracers for the PET imaging of translocator protein (18 kDa) and showed that (R)- and (S)-[ 18 F]6 had different radioactivity uptake in mouse bone and liver. Thus, (rac)-, (R)-, and (S)-[ 18 F]1 are effective radiolabelling reagents and can be used to develop PET radiotracers by examining the effects of chirality on their in vitro binding affinities and in vivo behaviour., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)