Abstract
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Objectives Preclinical and early clinical evaluation of the PDE10 occupancy and displacement by candidate drugs is an important part of in vivo characterization in the clinical development of potential new treatments for schizophrenia and other neuropsychiatric disorders. Such studies aid in prioritization among competing drug candidates and provide rational dosing strategies. The aim of this research is to validate in primates (non human and human) the two structurally related PDE10 (phosphodiesterase 10) tracers [18F]MNI654 and [18F]MNI659.
Methods Positron emission tomography (PET) studies were carried out in rhesus macaque (Macaca mulatta) and baboon (Papio anubis). Eleven PET studies (four baselines and seven blockade studies using MP10, a selective PDE10 inhibitor) were conducted with [18F]MNI654 (dose 4.9 ± 0.2 mCi) and five PET studies (three baselines and two blockade studies) were conducted with [18F]MNI659 (dose 4.5 ± 0.8 mCi). MP10 doses of 1.8, 0.6, 0.2 and 0.07 mg/kg were administered i.v. over 30 min prior to tracer injection.
Results [18F]MNI654 and [18F]MNI659 displayed regional brain uptakes in accordance with expected PDE10 distribution: highest in putamen and globus pallidus and lowest in cerebellum. Baseline and blockade studies were modeled with a two-tissue compartment model to estimate the distribution volume. The binding potential BPnd was derived using the cerebellum as a reference region. It was also estimated directly by non-invasive modeling with SRTM. The occupancy was estimated from BPnd at baseline and following blockade with MP10. [18F]MNI654 and [18F]MNI659 PET imaging estimated a dose-dependent occupancy of PDE10 by MP10 similar to published results with [11C]MP10.
Conclusions Preliminary data suggest both [18F]MNI654 and [18F]MNI659 may be useful for investigating PDE10, albeit with different pharmacokinetics, and non-invasive models may be appropriate for signal quantification. Human studies are currently ongoing