Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A

Introduction: Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey. Methods: Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey. Results: T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC₅₀ value in an enzyme inhibitory assay was 0.77 nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [³H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [³H]T-773 bound to a single high affinity site of PDE10A with K_d values of 12.2 ± 2.2 and 4.7 ± 1.2 nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [¹¹C]T-773 showed good brain penetration and striatum-selective accumulation. Conclusion: These results suggest that [¹¹C]T-773 is a potential PET radioligand for PDE10A