Indole Glyoxylamides Peripheral Benzodiazepine Receptor Radiotracers

本研究项目的目标是确定配体的结构和放射性标记，以便通过正电子(PET)或单光子(SPECT)发射断层扫描的外部成像来定量测量活体大脑中的外周苯二氮卓受体(PBR)。与PBR特异结合的放射性示踪剂将在神经精神疾病的诊断、监测治疗和病因学研究中发挥重要作用，如脑损伤、神经退行性疾病、焦虑和应激障碍。PBR被认为与许多生物学功能有关，包括调节细胞增殖、免疫调节、卟啉转运、血红素生物合成、阴离子转运、调节类固醇合成和细胞凋亡。例如，在艾滋病毒/艾滋病、阿尔茨海默病、亨廷顿病、多发性硬化症和胶质增生症患者的脑组织中观察到PBR的增加。一项对艾滋病患者的PET研究显示，皮质和皮质下PBR受体结合增加，支持胶质细胞激活在HIV痴呆患者中的作用。这项研究强调了目前使用的放射性配基的局限性，并指出有必要进一步优化PBR的定量。我们发现某些吲哚乙醛酰胺类化合物对PBR表现出纳摩尔亲和力。然而，在非人灵长类动物中，其中两个被标记为123I的大脑摄取率很低。这些结果提出的关键问题是：a)能否提高PBR的亲和力和选择性，同时降低不同杂环取代基的亲油性？以及b)匀浆结合结果是否适用于体内摄取和分布？在本应用中，我们建议检验以下假设：1)N，N-二烷基吲哚乙二酰胺在吲哚的2-位上具有适当官能化的杂环取代基相对于CBR更有利于与PBR的结合；2)这些杂芳环的引入将改变我们化合物的亲脂性，从而具有更低的非特异性结合和更高的脑摄取。 我们将合成一系列N，N-二烷基-2-杂环取代吲哚乙醛酰胺类化合物。将用F-18或I-123标记与PBR的结合亲和力低于10 nM、对CBR的选择性高于100的候选化合物，并测量它们的亲脂性(LogD)。在非人类灵长类动物体内的结合将通过成像在控制条件下和特定药理学挑战下放射性示踪剂的区域大脑分布来测量。将评估LOG D、体外亲和力和体内选择性的相关性。 在这个项目期结束时，我们预计已经确定了一种适合于对神经艾滋病、痴呆和其他疾病的PBR进行成像的放射性配基。

The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of the peripheral benzodiazepine receptor (PBR ) in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radio-tracer binding specifically to PBR would be of great utility in diagnosis, monitoring treatment, and etiological research of neuropsychiatric disorders such as brain damage, neurodegenerative diseases, anxiety and stress disorders. The PBR is thought to be associated with many biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport, heme biosynthesis, anion transport, regulation of steroidogenesis, and apoptosis. For example, increases in PBR have been observed in brain tissue from patients with HIV/AIDS, Alzheimer's disease, Huntington's disease, multiple sclerosis, and gliosis. A PET study in patients with AIDS showed increased cortical and subcortical PBR receptor binding, supporting the role of glial cell activation in HIV patients with dementia. This study highlights the limitations of current radioligands used and points out the need to further optimize quantitation of PBR. We found that certain indole glyoxylamide derivatives showed nanomolar affinity to PBR. However, brain uptake of two of them labeled with 123I was low in nonhuman primate. Key questions posed by these results are: a) Can PBR affinity and selectivity be increased while reducing lipophilicity with different heterocyclic substituents? And b) are the homogenate binding results applicable to in vivo uptake and distribution? In this application we propose to test the following hypotheses: 1) N,N-dialkyl indolylglyoxylamides with appropriately functionalized heterocyclic substituents on the 2-position of indole will favor binding to PBR relative to CBR; and 2) introduction of these heteroaromatic rings will alter the lipophilicity of our compounds so as to have lower nonspecific binding and higher brain uptake. We will synthesize a series of N,N-dialkyl-2-heterocyclic substituted indolylglyoxylamides. The candidates with binding affinities below 10 nM for PBR and selectivity vis-a-vis CBR above 100 will be radiolabeled with F-18 or I-123 and their lipophilicity (log D) will be measured. In vivo binding will be measured in nonhuman primates by imaging regional brain distribution of the radio-tracer under control conditions and with specific pharmacological challenges. Correlation of log D, in vitro affinity, and in vivo selectivity will be evaluated. At the conclusion of this project period, we expect to have identified a radioligand suitable for imaging the PBR in NeuroAIDS, dementia and other diseases.