Characterization of [C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

Purpose: [C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [C]Lu AE92686 has high affinity for PDE10A (IC  = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.

Methods: A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.

Results: Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V ) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V values in target regions remained stable. Both pretreatment drugs significantly decreased [C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis.

Conclusions: The method proposed for quantification of [C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.