Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A

Introduction: In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.

Materials & Methods: [C-11]MP10, [C-11]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice.

Results: Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [C-11](1) under bar (C-11-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [C-11](5) under bar ([C-11]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [C-11](4) under bar, [(18) F](3) under bar and [F-18](6) under bar was too low to visualize PDE10A using microPET. [C-11](2) under bar showed a specific binding, while kinetics of [C-11](1) under bar were too slow. [C-11](5) under bar reached equilibrium after 10 min (uptake index = 1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [C-11](5) under bar to PDE10A.

Conclusions: We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [C-11](1) under bar had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [C-11](5) under bar has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative. (C) 2014 Elsevier Inc. All rights reserved.