Synthesis and evaluation of [11C]MMPIP as a potential radioligand for imaging of metabotropic glutamate 7 receptor in the brain.

Abstract

BACKGROUND:

Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant KB = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques.

METHODS:

[11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains.

RESULTS:

[11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/μmol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions.

CONCLUSION:

Despite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.

• Authors: Tomoteru Yamasaki, Katsushi Kumata, Joji Yui, Masayuki Fujinaga, Kenji Furutsuka, Akiko Hatori, Lin Xie, Masanao Ogawa, Nobuki Nengaki, Kazunori Kawamura, Ming-Rong Zhang
• Journal: EJNMMI research (EJNMMI Res) Vol. 3 Issue 1 Pg. 54 (Jul 22 2013) ISSN: 2191-219X [Print] Germany
• PMID: 23870677 (Publication Type: Journal Article)