Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan.
Nucl Med Biol. 2013 Feb;40(2):214-20. doi: 10.1016/j.nucmedbio.2012.11.008. Epub 2012 Dec 21.
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-[(11)C]methoxy-N-methylbenzamide ([(11)C]ITMM) to map metabotropic glutamate receptor type 1 (mGluR1) in the human brain.
[(11)C]ITMM was synthesized by O-methylation of the desmethyl precursor with [(11)C]methyl triflate in the presence of NaOH at room temperature. In vitro selectivity and brain distributions of [(11)C]ITMM in mice were characterized. Radiation absorbed-dose by [(11)C]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 [(11)C]ITMM) was evaluated. Mutagenicity of ITMM was studied by the Ames test. Clinical PET imaging of mGluR1 with [(11)C] ITMM was performed in a healthy volunteer.
ITMM had low activity for a 28-standard receptor binding profile. Regional brain uptake of [(11)C]ITMM in mice was heterogeneous and consistent with known mGluR1 distributions. The radiation absorbed-dose by [(11)C]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 [(11)C]ITMM in a healthy volunteer showed a gradual increase of radioactivity in the cerebellum. Total distribution volume of [(11)C]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, [(11)C]ITMM was stable in humans: 60% of the plasma radioactivity remained in the unchanged form for 60 min.
[(11)C] ITMM is a suitable radioligand for imaging mGluR1 in the human brain providing acceptable dosimetry and pharmacological safety at the dose required for PET.
使用 N-[4-[6-(异丙基氨基)嘧啶-4-基]-1,3-噻唑-2-基]-4-[(11)C]甲氧基-N-甲基苯甲酰胺([(11)C]ITMM)进行了临床前研究和首次正电子发射断层扫描(PET)成像研究，以在人体大脑中绘制代谢型谷氨酸受体 1(mGluR1)。
在室温下，使用 [(11)C]甲基三氟甲磺酸和 NaOH 将去甲甲基前体 O-甲基化，合成 [(11)C]ITMM。在小鼠中表征了 [(11)C]ITMM 的体外选择性和脑分布。从小鼠分布数据计算 [(11)C]ITMM 在人体内的辐射吸收剂量。以 4.72mg/kg 体重（超过 [(11)C]ITMM 的临床等效剂量的 74,000 倍以上）评估 ITMM 的急性毒性。通过 Ames 试验研究 ITMM 的致突变性。在健康志愿者中进行了 [(11)C]ITMM 与 mGluR1 的临床 PET 成像。
ITMM 对 28 个标准受体结合谱的活性较低。在小鼠中，[(11)C]ITMM 的脑内摄取不均匀，与已知的 mGluR1 分布一致。[(11)C]ITMM 在人体内的辐射吸收剂量足够低，可用于临床，ITMM 无急性毒性或致突变性。健康志愿者的 90 分钟动态 PET 扫描显示，小脑的放射性逐渐增加。[(11)C]ITMM 的总分布容积在小脑最高，其次是丘脑、大脑皮层和纹状体；大脑放射性的区域差异与大脑中的 mGluR1 分布相对应。在人体中，[(11)C]ITMM 是稳定的：60 分钟时，60%的血浆放射性仍以未改变的形式存在。
[(11)C]ITMM 是一种合适的放射性配体，可用于在人体大脑中成像 mGluR1，在 PET 所需剂量下提供可接受的剂量测定和药理安全性。
