Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
EJNMMI Res. 2013 Jul 22;3(1):54. doi: 10.1186/2191-219X-3-54.
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.
[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.
[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.
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.
代谢型谷氨酸受体 7（mGlu7）是开发中枢神经系统疾病治疗药物的关键靶标蛋白。在本研究中，我们合成了[11C]MMPIP，这是一种用于 mGlu7 的假定放射性配体（结合常数 KB = 30 nM），并通过体外和体内技术评估了其用于 mGlu7 成像的潜力。
通过酚前体 3 与[11C]CH3I 的反应合成[11C]MMPIP。在大鼠脑切片上进行[11C]MMPIP 的体外放射自显影。为了确定[11C]MMPIP 与 mGlu7 的体外特异性结合，通过与选择性 mGlu7 拮抗剂 AMN082 或未标记的 MMPIP 共孵育进行阻断研究。对大鼠脑进行正电子发射断层扫描（PET）研究和体外代谢产物分析。
获得了两种比活度（SA）水平的[11C]MMPIP，平均分别为 58（常规）和 3800（高 SA）GBq/μmol。在体外放射自显影中，高放射性信号来自于丘脑、延髓和纹状体中的常规[11C]MMPIP，与 mGlu7 的全面脑分布相对应。与 ANM082 或未标记的 MMPIP 共孵育分别降低了脑切片中的放射性信号。在使用[11C]MMPIP 的 PET 研究中，在所检查的脑区中未发现与 mGlu7 相关的特异性摄取。
尽管[11C]MMPIP 与 mGlu7 具有体外特异性结合，但使用 PET 对活脑中的 mGlu7 进行可视化并不成功。有必要开发对 mGlu7 具有更高亲和力的新配体候选物。
