DEVELOPMENT OF PET AND SPECT LIGANDS FOR mGluR5 IMAGING

描述(申请人提供)：代谢性谷氨酸受体亚型5(MGluR5)与许多精神疾病有关，包括精神分裂症、情绪和焦虑症以及可卡因成瘾。尽管来自临床前和精神药理学研究的大量证据表明，在这些毁灭性的神经精神障碍中，谷氨酸能功能失调，然而，到目前为止，还没有合适的配体。我们建议测试鉴定一个放射性配基的可行性，该配基可以发展成放射性药物，用PET或SPECT在体内对mGluR5进行成像。mGluR5蛋白的结构特征是一个大的胞外结构域和七个跨膜区。到目前为止，大多数配体都是氨基酸，它们结合在细胞外区域，通常只有微摩尔亲和力。已报道的最好的配体(如MPEP)是非氨基酸，并结合在跨膜区。我们的设计策略是修改碱基结构，例如在跨膜区引入额外的氨基酸残基，从而增加mGluR5结合的亲和力和选择性。 在这项建议的第一阶段(R21)，我们的目标是1)合成和评估新的mGluR5配体的体外药理作用，这些配体可以用C和F标记用于PET或用I标记用于SPECT；以及2)放射性标记具有最佳药理学特性的配体并测量它们在啮齿类动物的局部脑摄取。定位于适当大脑区域的化合物将通过药理学挑战进行进一步评估，以评估其体内特异性。在这一阶段结束时，将完成对这一方法的可行性的最终测试。如果被定义为R21项目里程碑的定量标准被满足，R33组件将3)在非人类灵长类动物中进行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，为IND应用做准备，以及5)在健康人身上进行初步成像试验。 本文提出的研究将产生第一个适合于对活体人类的mGluR5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.