Synthesis and Characterization of [F]JNJ-46356479 as the First F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Purpose: Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [C]7 as a PET radioligand for imaging mGluR2. Herein, [F]JNJ-46356479 ([F]8) was synthesized and characterized as the first F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.

Procedures: JNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.

Results: JNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [F]8 in rodents. In the non-human primate, [F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (V) results derived from 2T4k model showed enhanced V from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.

Conclusions: [F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [F]8 on its binding specificity would warrant translational study in human.