Radiation dosimetry of [11C]TZ1964B as determined by whole-body PET imaging of nonhuman primates.

Background: Phosphodiesterase 10A (PDE10A) is a postsynaptic, membrane bound cyclic nucleotide phosphodiesterase that is highly enriched in the striatal medium spiny neurons and regulates dopaminergic neurotransmission. The objective of this study is to determine the absorbed radiation dosimetry of a novel radiotracer for PDE10A: 3-(Methoxy-¹¹C)-2-((4-(1-methyl-4-(pyridine-4yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinolone ([¹¹C]TZ1964B) based on whole body PET imaging in nonhuman primates, a critical step before translating this radiotracer to imaging studies in humans. [¹¹C]TZ1964B may contribute to the clinical investigation of multiple neuropsychiatric conditions including Parkinson disease, Huntington disease and schizophrenia. For absorbed radiation measures, two males and one female cynomolgus monkeys (Macaca fascicularis) had intravenous injections of 302.3-384.4 MBq of [¹¹C]TZ1964B followed by sequential whole body PET imaging in a MicroPET-Focus220 scanner. Volumes of interest (VOIs) that either encompassed the entire organ or sampled regions of highest activity within larger organs were defined. Time-activity curves were derived from the PET data for each VOI, and analytical integration of its multi-exponential fit yielded the organ time-integrated activity. We generated human radiation dose estimates based on the scaled organ residence using OLINDA/EXM2.2.

Results: Highest retention was observed in the liver with total time-integrated activity of ~ 0.23 h. Absorbed organ dosimetry was highest in the liver (53.3 μGy/MBq), making it the critical organ. Gallbladder (35.9 μGy/MBq) and spleen (35.4 μGy/MBq) were the next highest organs for absorbed radiation dose. Effective doses were estimated to be 5.02 and 5.84 μSv/MBq for males and females, respectively.

Conclusions: This nonhuman primate dosimetry study suggests intravenous doses up to 938 MBq of [¹¹C]TZ1964B can be safely administered to human subjects for PET measurements of PDE10A activity. The tracer kinetic data is consistent with a hepatobiliary clearance pathway for the radiotracer.