Development and preliminary evaluation of an aryl 18F-labeled PET tracer for imaging PDE10A

1040 Objectives: Modulation of phosphodiesterase 10A (PDE10A) has shown potential application in the treatment of neurodegenerative and neuropsychiatric disorders such as schizophrenia and Huntington’s disease. A PET tracer for PDE10A would offer non-invasive quantification of its density and distribution in vivo, which could enable target engagement studies for drug discovery. In this study, we aim to identify an aryl 18F-labeled PDE10A PET tracer ([18F]P10A-1910) with facile labeling procedures, high brain uptake, excellent in vivo stability and specificity. Methods: The PDE10A inhibitor P10A-1910 (2-(2-(3-(4-fluorophenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione) and its labeling precursor were prepared in house. [18F]P10A-1910 was labeled by Cu-mediated radiofluorination. Lipophilicity was tested by the shake-flask method. The stability and biodistribution studies were evaluated on CD-1 mice. Dynamic PET scans (0-90 min) were performed in the brain of mature cynomolgus. Results: P10A-1910 and its corresponding precursor were synthesized as colorless solids, with overall yields of 11% and 9%, respectively. [18F]P10A-1910 was produced in 28 ± 3% non-decay-corrected radiochemical yields, with high radiochemical purity (>99%) and high molar activity (>1 Ci/μmol). The LogD value was determined as 3.50, which is appropriate for brain permeability. Ex vivo biodistribution revealed high radioactivity levels in small intestine and liver (>50 %ID/g at 5 min), indicating possible enterohepatic circulation. Radiometabolism analysis showed that [18F]P10A-1910 maintained 80% of parent fraction in mice brain at 30 min post-injection. PET imaging in cynomolgus showed rapid brain uptake and heterogeneous distribution. Specifically, the uptake in the striatum was increased to 1.6 SUV at 3 min, and then slowly decreased to 0.9 SUV at the end of scan, which was consistent with the expression of PDE10A in brain, indicating good specific binding. Conclusions: We have successfully synthesized a new PDE10A PET tracer [18F]P10A-1910 in good radiochemical yields and high molar activities. The biodistribution study, stability testing and preliminary NHP PET imaging data indicated that [18F]P10A-1910 is promising for further evaluation.