Preclinical and the first clinical studies on [11C]ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography

Introduction: Preclinical studies and first positron emission tomography (PET) imaging studies were performed using N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4[C-11]methoxy-N-methylbenzamide ([C-11]ITMM) to map metabotropic glutamate receptor type 1 (mGluR1) in the human brain. Methods: [C-11]ITMM was synthesized by O-methylation of the desmethyl precursor with [C-11]methyl triflate in the presence of NaOH at room temperature. In vitro selectivity and brain distributions of[C-11]ITMM in mice were characterized. Radiation absorbed-dose by [C-11]ITMM in humans was calculated from mouse distribution data. Acute toxicity of ITMM at 4.72 mg/kg body weight (>74,000-fold clinical equivalent dose of [C-11]ITMM) was evaluated. Mutagenicity of ITMM was studied by the Ames test. Clinical PET imaging of mGluR1 with [C-11]ITMM was performed in a healthy volunteer. Results: ITMM had low activity for a 28-standard receptor binding profile. Regional brain uptake of [C-11]ITMM in mice was heterogeneous and consistent with known mGluR1 distributions. The radiation absorbed-dose by [C-11]ITMM in humans was sufficiently low for clinical use, and no acute toxicity or mutagenicity of ITMM occurred. A 90-min dynamic PET scan with [C-11]ITMM in a healthy volunteer showed a gradual increase of radioactivity in the cerebellum. Total distribution volume of [C-11]ITMM was highest in the cerebellum, followed by thalamus, cerebral cortex, and striatum; regional differences in brain radioactivity corresponded to the mGluR1 distribution in the brain. Peripherally, [C-11]ITMM was stable in humans: 60% of the plasma radioactivity remained in the unchanged form for 60 min. Conclusions: [C-11]ITMM is a suitable radioligand for imaging mGluR1 in the human brain providing acceptable dosimetry and pharmacological safety at the dose required for PET. (C) 2013 Elsevier Inc. All rights reserved.