Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates.

INTRODUCTION: Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [11 C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [11 C]T-773.

METHODS: [18 F]FM-T-773-d2 and [18 F]FE-T-773-d4 were synthesized from the same precursor used for11 C-labeling of T-773 in a two-step approach via18 F-fluoromethylation and18 F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [18 F]FM-T-773-d2 and [18 F]FE-T-773-d4 ; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [18 F]FM-T-773-d2 including arterial blood sampling with radiometabolite analysis in four NHPs.

RESULTS: Both [18 F]FM-T-773-d2 and [18 F]FE-T-773-d4 were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n=8) for [18 F]FM-T-773-d2 and 209 ± 26 GBq/μmol (n=4) for [18 F]FE-T-773-d4 , and a radiochemical yield of 10% (EOB, n=12, range 3%-16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [18 F]FM-T-773-d2 and ~3.5% for [18 F]FE-T-773-d4 at the peak) and a fast washout. Specific binding reached maximum within 30 min for [18 F]FM-T-773-d2 and after approximately 45 min for [18 F]FE-T-773-d4 . [18 F]FM-T-773-d2 data fitted well with kinetic compartment models. BPND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BPND calculated with SRTM was 1.0-1.7 in the putamen. The occupancy with 1.8 mg/kg of MP-10 was approximately 60%.

CONCLUSIONS: [18 F]FM-T-773-d2 and [18 F]FE-T-773-d4 were developed as fluorine-18 PET radioligands for PDE10A, with the [18 F]FM-T-773-d2 being the more promising PET radioligand warranting further evaluation.