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 [¹¹C]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [¹¹C]CH₃I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [¹¹C]1 and [ ¹¹C]2 had high striatal accumulation (at peak time) for [ ¹¹C]1 and [¹¹C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [ ¹¹C]1 and [¹¹C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [¹¹C]1 and [ ¹¹C]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 [¹¹C]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 [¹¹C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [ ¹¹C]1 is a promising candidate for quantification of PDE10A in vivo using PET.