Quantitative preclinical evaluation of a novel PDE10A PET tracer using MRI template-based volume-of-interest analysis

Objectives Inhibitors of PDE10A, a phosphodiesterase expressed in the GABAergic neurons of the striatum, are efficacious in rodent models of schizophrenia and have potential benefit in multiple neurological disorders. A novel PET tracer was used to determine target coverage and binding characteristics of a PDE10A inhibitor in the rat brain.

Methods SD rats were administered the PDE10A inhibitor MP-10 or vehicle 110 min prior to PDE10A tracer injection, followed by 120 min dynamic PET scans. T2-weighted MRI was performed on one animal to generate an anatomic brain template that was registered to the PDE10A tracer PET scan of the same animal. A volume of interest (VOI) set of brain regions was defined on the MRI template scan. Tracer uptake was quantified using template-based VOI analysis: the PDE10A PET scan of the template animal was affine-registered to individual PDE10A PET tracer scans, and the VOI set was mapped to FDG PET images to determine regional uptakes. Standardized uptake value (SUV) and binding potential (BP) were calculated for each region.

Results In vehicle-treated animals, pronounced tracer uptake was observed in the PDE10A-abundant striatum (SUV=3.0±0.4; BP=3.4±0.4) while uptake in the prefrontal cortex, hippocampus, and cerebellum was similar to background (SUV≈0.6; BP≈0). In animals treated with the PDE10A inhibitor MP-10, tracer uptake was significantly reduced in the striatum (SUV=1.9±0.1, 36% decrease; BP=1.4±0.1, 59% decrease) while SUV and BP in the prefrontal cortex, hippocampus, and cerebellum were comparable to vehicle-treated animals.

Conclusions The PDE10A PET tracer distributed to brain regions consistent with PDE10A expression and exhibited on-target binding as measured by competitive inhibition with MP-10. This novel PDE10A tracer provides a noninvasive method to measure target coverage and could provide utility in lead optimization and human dose selection.