Development of 11C-labeled probes for imaging CRF

该项目的总体目标是开发PET成像探针，以量化从小鼠到人的活体受试者中CRF1受体结合的活体水平。对CRF激动剂和拮抗剂的大量临床前和临床研究已经产生了假设，即CRF功能异常可能参与了一系列神经精神疾病的发病机制，如焦虑、抑郁、强迫症、神经退行性疾病如阿尔茨海默病、疾病、帕金森病和创伤后应激障碍。开发高比活性、放射性标记、选择性的CRF1受体拮抗剂用于PET，将使在体内重复定量与CRF1受体的结合成为可能，这将在脑成像和基础研究中开辟许多临床领域，以研究脑血管疾病的病理生理学。 抑郁症、焦虑症和其他神经退行性疾病。这样的PET探针必须具有良好的受体亚型选择性(CRF1/CRF2)、水溶性和快速穿透血脑屏障。在迄今报道的各类CRF1拮抗剂中，只有少数被证明具有高效力(CRF1IC50和10 NM)、选择性(CRF1/CRF2IC50和1000)、穿透脑血脑屏障的能力和水溶解能力。我们选择了(7-dipropylamino)-2，5-dimethyl-3-[2-(dimethyl-amino)-5-pyridyl]-吡唑并[1，5a]嘧啶(R121920)作为潜在的CRF1拮抗剂的正电子发射体层析探针。R121920是一个高点 亲和力，CRF1受体选择性拮抗剂(Ki值(nmol/L)：CRF1=4；CRF2&gt；10000)，具有良好的水溶解性(&gt；20 mg/mL)，也与血脑屏障交叉。我们设计了一种新型的钯催化联芳基偶联反应作为合成[11C]R121920的关键策略。因此，有了这个探针，能够在体内定量测量CRF1受体将有助于更好地了解神经精神和神经退行性疾病的进展、消退和各种病理生理学方面的基础事件。这也将有可能量化CRF1受体阻断之间的关系 一系列的抗抑郁药物。CRF1受体拮抗剂的PET图像探针也将为指导神经精神和神经退行性疾病的药物开发提供有价值和有效的帮助。这项申请寻求支持，以涵盖从啮齿动物阶段到第一次人类志愿者研究的实验工作。

The overall objective of this project is to develop PET imaging probes to quantify in vivo levels of CRF1 receptor binding in living subjects from mice to humans. Extensive preclinical as well as clinical studies of CRF agonists and antagonists have generated hypotheses that abnorma CRF function may contribute to the pathogenesis of a diverse range of neuropsychiatric disorders such as anxiety, depression, obsessivecompulsive disorder, neurodegenerative diseases such as Alzheimer's, disease, Parkinson's disease and posttraumatic stress disorder. Development of high specific activity, radiolabeled, selective CRF1 receptor antagonists for PET would make it possible to quantify binding to CRF1 receptors in vivo, repeatedly, which would open many clinical areas in brain imaging as well as in basic research to study the pathophysiology of depression, anxiety and other neurodegenerative diseases. Such a PET probe must have excellent receptor subtype selectivity (CRF1/CRF2), aquous solubility and rapid permeability across BBB. Among various classes of CRF1 antagonists reported to date, only a few are shown to possess high potency (CRF1 IC50 < 10 nM), selectivity (CRF1/CRF2 IC50 >1000), ability to penetrate cerebral blood brain barrier and aqueous solubility. We have chosen (7-dipropylamino)-2,5-dimethyl-3-[2-(dimethyl-amino)-5-pyridyl]- pyrazolo[1,5a] pyrimidine (R121920) as our potential candidate for the PET probe for CRF1 antagonist. R121920 is a high affinity, CRF1 receptor selective antagonist (Ki values (nmol/L): CRF1 = 4; CRF2 >10000) with good aqueous solubility (>20 mg/mL) and also crosses BBB. We have designed a novel palladium catalyzed biaryl coupling as a key strategy for the synthesis of [11C]R121920. Thus with this probe the ability to quantitatively measure CRF1 receptors in vivo will lead to a better understanding of the events that underlie the progression, regression and various pathophysiological aspects of neuropsychiatric and neurodegerative diseases. It will also possible to quantify the relatioinship between CRF1 receptor blockades during the cource of antidepresent medications. PET image probes for CRF1 receptor antagonists will also provide a valuable and efficient aid to guide drug development for neuropsychiatric and neurodegenerative diseases. This application seeks support to cover the experimental work from the rodent phase to the first human volunteer studies.