Radiosynthesis and initial characterization of a PDE10A specific PET tracer [¹⁸F]AMG 580 in non-human primates

Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [¹⁸F]AMG 580 and in vitro and in vivo characterization results. Methods: The potency and selectivity were determined by in vitro assay using [³H]AMG 580 and baboon brain tissues. [¹⁸F]AMG 580 was prepared by a 1-step [¹⁸F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. K_D was estimated by Scatchard analysis of high and low affinity PET scans. Results: AMG 580 has an in vitro K_D of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121±18MBq was used in PET studies. In Rhesus, the baseline BP_ND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BP_ND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24mg/kg dose of AMG 580 resulted in about 70% decrease of BP_ND. The in vivo K_D of [¹⁸F]AMG 580 was estimated to be around 0.44 nM in baboons. Conclusion: [¹⁸F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.