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

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.

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