Development of a [18F]-labeled positive allosteric modulator of the metabotropic glutamate receptor 2 (mGluR2) as a potential PET tracer

Objectives Preclinical and clinical studies provide evidence that mGluR2 agonists may provide an alternative approach for the treatment of anxiety disorders and schizophrenia. Relative distribution of mGluR2 is high in cerebellum, several limbic areas including the cortex, hippocampus, amygdala. Thus, non-invasive imaging of mGluR2 by PET may facilitate development of new drug candidates targeting mGluR2. This study describes the radiosynthesis of [18F]FE-JNJ42491293, a fluoroethyl analogue of a mGluR2 PAM ligand as a potential PET radiotracer for imaging mGluR2.

Methods Fluoroethyl analogue of JNJ42491293 was synthesized from the corresponding desmethyl precursor by treatment with 1-bromo-2-fluoroethane in the presence of sodium hydride in DMF. The radiosynthesis was achieved in 2-steps from the desmethyl precursor. [18F]fluoroethyltosylate was generated from 1,2-diethyltosylate which was then treated with the desmethyl precursor in the presence of cesium carbonate in DMF at 105 C for 20 min.

Results The synthesis of fluoroethyl analogue of JNJ42491293 proceeded in 53% yield from the corresponding desmethyl precursor. The synthesis of desmethyl- JNJ42491293 has been achieved in 8 steps from commercial 2,3-dichloro-4-iodopyridine and 2-bromo-1,4-difluoro-3-methoxybenzene in an overall yield of 10%. The 2-step radiosynthesis of FE-JNJ42491293 from the desmethyl precursor and previously generated [18F]fluoroethyltosylate proceeded in an overall yield of 20+5% for 2-steps.

Conclusions FE-JNJ42491293, a high affinity mGluR2 PAM amenable to radiolabeling with [18F] has been identified, synthesized and radiolabeled. The details of synthesis, radiosynthesis and in vitro evaluation of the radioligand will be presented.