DEVELOPMENT OF PET AND SPECT LIGANDS FOR mGluR5 IMAGING

描述（由申请人提供）：代谢型谷氨酸受体亚型5（mGluR 5）与许多精神疾病有关，包括精神分裂症、心境和焦虑障碍以及可卡因添加。 尽管从临床前和精神药理学研究中获得的大量证据表明，在这些毁灭性的神经精神疾病中，功能失调的多巴胺能功能，然而，迄今为止，还没有合适的配体。 我们建议测试的可行性，确定一个放射性配体，可以开发成一个放射性药物成像mGluR 5在体内与PET或SPECT。mGluR 5蛋白质结构的特点是由一个大的胞外结构域和七个跨膜区域。 迄今为止，大多数配体是氨基酸，其结合在细胞外结构域并且通常仅具有微摩尔亲和力。 已报道的最佳配体（例如MPEP）是非氨基酸并结合在跨膜区。 我们的设计策略是以这样的方式修饰碱基结构，以在跨膜区中涉及额外的氨基酸残基，从而增加mGluR 5结合的亲和力和选择性。 本提案的第一阶段（R21）旨在1）合成和评价mGluR 5的新配体的体外药理学，这些配体可以用C和F标记（用于PET）或用I标记（用于SPECT）; 2）放射性标记具有最佳药理学特性的配体，并测量其在啮齿动物中的局部脑摄取。 将通过药理学挑战进一步评价定位于适当脑区域的化合物，以评估其体内特异性。 在这一阶段结束时，将完成对这一方法可行性的最终测试。 如果满足定义为R21项目里程碑的定量标准，则R33组件将3）在非人灵长类动物中进行PET/SPECT成像和药代动力学分析。4)将所选择的放射性示踪剂开发成放射性药物，进行毒性和安全性测试以准备IND申请，以及5）在健康人类受试者中进行初始成像试验。 本文提出的研究将产生第一种适合对活体mGluR 5受体进行成像的放射性示踪剂，并必将成为探索健康和疾病情况下活体人脑中谷氨酸能系统功能状态的门户。

DESCRIPTION (provided by applicant): The metabotropic glutamate receptor subtype 5 (mGluR5) is implicated in many psychiatric disorders, including schizophrenia, mood and anxiety disorders, and cocaine addition. Despite the wealth of evidence from preclinical and psychopharmacology studies demonstrating dysfunctional glutamatergic function in these devastating neuropsychiatric disorders, however, to date there is no suitable ligand. We propose to test the feasibility of identifying a radioligand that can be developed into a radiopharmaceutical to image the mGluR5 in vivo with PET or SPECT.The mGluR5 protein structure is characterized by a large extracellular domain and seven transmembrane regions. Most ligands to date are amino acids, which bind at the extracellular domain and generally have only micromolar affinity. The best ligands reported (e.g. MPEP) are non-amino acids and bind in the transmembrane region. Our design strategy is to modify the base structure in such as ways to involve additional amino acids residues in the transmembrane region, thus increasing affinity and selectivity of mGluR5 binding. The first (R21) phase of this proposal we aim to 1) synthesize and evaluate the in vitro pharmacology of new ligands for mGluR5 that can be labeled either with C and F for PET or with I for SPECT; and 2) Radiolabel the ligands with the best pharmacological properties and measure their regional brain uptake in rodents. Compounds that localize in the appropriate brain regions will be further evaluated with pharmacological challenge to assess their vivo specificity. At the end of the this phase, definitive testing of the feasibility of this approach will have been accomplished. If the quantitative criteria defined as milestones for the R21 projects are met, the R33 component will 3) perform PET/SPECT imaging and pharmacokinetic analysis in non-human primates. 4) develop the selected radiotracer into a radiopharmaceutical, perform toxicity and safety tests in preparation for an IND application, and 5) carry out initial imaging trials in healthy human subjects. The studies proposed herein will produce the first radiotracer suitable for imaging the mGluR5 receptor in living humans and will surely serve as the gateway for exploration of the functional state of the glutamatergic system in the living human brain in health and disease.