Presentation Development of new radioprobes for PET imaging of metabotropic glutamate receptor subtype 2 in rat brain

Kumata, Katsushi  ,  Yamasaki, Tomoteru  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Mori, Wakana  ,  Fujinaga, Masayuki  ,  Ming-Rong, Zhang

OBJECTIVES: Metabotropic glutamate receptor 2 (mGluR2) is predominantly presynaptic and modulates the release of glutamate and GABA through feedback inhibition. In the brain, mGluR2 is abundant mainly in the cerebral cortex, caudate-putamen and nucleus accumbens, hippocampus and amygdala. It has been reported that mGluR2 is involved in numerous brain functions and is a promising target for the treatment of brain disorders such as anxiety, schizophrenia and addiction. As the first mGluR2 radioprobe used for clinical study, 11C-JNJ42491293 is not suitable for imaging mGluR2 in human brain due to off-target binding. Another new PET probe for human mGluR2 study was reported, but its chemical structure remains unknown. Here, we radiosynthesized four new 11C/18F-labeled phenylpiperidine analogs and evaluated their potentials as PET radioprobes for imaging mGluR2 in the rat brain. METHODS: Four phenylpiperidine analogs and their phenol or phenylstannyl precursors for radiolabeling were synthesized using commercially available compounds. The radioprobes were synthesized via C- or O-11C-methylation of the corresponding precursors with 11C-methyl iodide, or O-18F-fluoroethylation with 18F-fluoroethyl bromide. In vitro binding of these radioprobes to mGluR2 was characterized by autoradiography using rat brain sections. In vivo brain regional distribution was determined by small-animal PET assessments. RESULTS: 11C/18F-labeled phenylpiperidine probes were synthesized with 10–40 % radiochemical yield based on 11C-CO2 or 18F-F- and 50–320 GBq/µmol specific activity at the end of synthesis. In vitro autoradiography with these radioprobes exhibited heterogeneous distribution pattern of radioactivity in the rat brain sections, with high expression in the cerebral cortex, striatum, hippocampus and granular layer of the cerebellum. This distribution pattern was consistent with the distribution of mGluR2 in the rodent brain. Co-incubation with the corresponding unlabeled compounds decreased radioactivity (binding) in brain sections to 30–70% of control (total) radioactivity. PET imaging studies showed that the site of highest radioactivity was presented in the cerebral cortex, followed by the cerebellum, striatum and hippocampus. The maximum regional uptake was 0.5–0.7 SUV in the cerebral cortex. Self-blocking treatment abolished differences in radioactivity uptake between brain regions and thus produced fairly uniform distribution of radioactivity across all regions. CONCLUSIONS: In vitro autoradiography showed that four radioprobes have high specific bindings to mGluR2, but PET study showed relatively low in vivo specific bindings in the rat brain. These radioprobes could become a useful lead compound for the development of new PET imaging agents with improved behaviors and more in vivo specific bindings to mGluR2 in the living brain.
SNMMI 2017 Annual Meeting

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