Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate

The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [C-11]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [C-11]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [11C] 1 and [C-11]2 had high striatal accumulation (at peak time) for [C-11]1 and [C-11]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [C-11]1 and [C-11]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [C-11]1 and [C-11]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [C-11]1 reached 1.8 at 30 min with a 3.5-fold striatum: cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [C-11]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [C-11]1 is a promising candidate for quantification of PDE10A in vivo using PET. (C) 2014 Elsevier Ltd. All rights reserved.