Project 3: CRF1 recoptor PET Ligand Development

这个修订项目的前提仍然是，针对脑CRF的药物的开发- CRFi受体的有效性依赖于新的、经验证的CRFi受体PET配体的可用性。支持 这种配体的应用包括测试作用机制假设，其中剂量和时间效应 候选CRF α受体拮抗剂的关系由受体的百分比占有率定义。 脑CRF受体。与治疗和副作用相关的剂量探索研究（作为百分比的函数） 将启用并指导第二阶段试验。评估重度抑郁或焦虑 疾病或CRF受体基因变异与体内脑CRF α受体改变有关 可用性代表了这种PET配体应用于病理生理学测试模型的实例， 药物遗传学。我们建议在通用报告格式正在进行的努力的基础上再接再厉！受体PET 配体开发计划作为目前U19奖的补充。修订后的项目3仍然是 作为分子设计、化学以及体外和体内候选物评价的迭代计划， 两种不同但平行的方法从常见的吡啶并吡嗪酮CRF-1受体拮抗剂开始。 所提出的方法代表了吡啶并吡嗪酮起始分子的计划修饰， 操纵面外芳环对CRF 1受体结合作用的特异性表征 亲和力提出了五个具体的目标，以产生11 C和18F标记的脑CRF α受体PET版本 配体产生的相互作用之间提出的化学合成计划和逐步 候选CRFi受体PET配体的评价。候选人评估将涉及9个步骤 具有良好定义的标准作为跨越转染细胞系统、啮齿动物 以及在非人灵长类动物中进行体外和体内评估以优化CRFi的靶配体性质 受体亲和力、亲脂性和代谢稳定性。不断发展的结构-活性关系（SAP）数据将 完善合成化学方案，以产生新的候选方案，重新进入评估方案， 并将与QSAR分子建模/药物合作发展分子建模方法 化学/药理学联合埃默里倡议的发现计划。最终阶段候选人评估 将涉及在猴子体内microPET成像，以建立定量的可行性和模型， 脑发射数据，剂量和时间依赖性脑CRF的评价，GSK-008的受体占有率， 和器官剂量测定。支持人用IND申请的最后阶段测试将是 在这一合作协议中，GSK的合作伙伴关系使我们能够。项目3的目标是： 表征GSK-008与灵长类动物脑CRF α受体的相互作用，并提供有价值的研究。 新型、有效的PET配体应用于CRF研究领域。

The premise of this revised project remains that the development of medications targeting the brain CRF-\ receptor is dependent on the availability of a novel, validated CRFi receptor PET ligand. Supporting applications of such a ligand include testing mechanism of action hypotheses in which the dose- and timeeffect relationships of candidate CRF^ receptor antagonists are defined by the percent occupancy of the brain CRF, receptor. Dose finding studies related to therapeutic and side effects as a function of percent occupancy would be enabled and guide Phase II trials. Assessing whether major depression or anxiety disorders, or CRF, receptor gene variation, are associated with altered in vivo brain CRF^ receptor availability represent examples of the application of such a PET ligand to test models of pathophysiology and pharmacogenetics, respectively. We propose to build on the ongoing efforts of the CRF! receptor PET ligand development initiative funded as a supplement to the current U19 award. Revised Project 3 remains as an iterative plan of molecular design, chemistry, and in vitro and in vivo candidate evaluation based on two distinct but paralleling approaches starting from common pyridopyrazinone CRF-\ receptor antagonists. Proposed approaches represent planned modifications of the pyridopyrazinone starting molecule, and the specific characterization of the effect of manipulating the out-of-plane aryl ring on CRF1 receptor binding affinity. Five specific aims are proposed to yield 11C- and 18F-labeled versions of brain CRF^ receptor PET ligands resulting from the interactions between a proposed program of chemical synthesis and the step-wise evaluation of candidate CRFi receptor PET ligands. Candidate evaluation would involve a 9-step hierarchical model with well-defined criteria as branch points that spans transfected cell systems, rodents, and in vitro and in vivo assessments in non-human primates to optimize the target ligand properties of CRFi receptor affinity, lipophilicity and metabolic stability. Evolving structure-activity relationship (SAP) data would refine synthetic chemistry schemes to generate novel candidates for re-entry into the evaluation scheme, and would evolve a molecular modeling approach in collaboration with the QSAR molecular modeling/drug discovery program of the joint Chemistry/Pharmacology Emory initiative. End stage candidate evaluation would involve in vivo microPET imaging in monkeys to establish the feasibility and models for quantitating brain emission data, evaluation of dose-and time-dependent brain CRF, receptor occupancy for GSK-008, and organ dosimetry. The final stage of testing in support of an IND application for human use would be enabled by the GSK partnership in this cooperative agreement. The goals of this proposed project 3 are to characterize the interactions of GSK-008 with the primate brain CRF^ receptor, and to provide a valuable novel, valid PET ligand to the field of CRF research.