Characterization of [C]PXT012253 as a PET Radioligand for mGlu Allosteric Modulators in Nonhuman Primates.

Purpose: Modulation of presynaptic metabotropic glutamate receptor 4 (mGlu) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson's disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu, [C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu ligand in nonhuman primates.

Procedures: [C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu allosteric ligand PXT002331, currently in clinical trials for Parkinson's disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [C]PXT012253 for further clinical studies.

Results: [C]PXT012253 displayed binding in mGlu-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [C]PXT012253 was estimated to be 0.0042 mSv/MBq.

Conclusions: [C]PXT012253 was shown to be a promising PET radioligand for mGlu allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [C]PXT012253 in human subjects is warranted.