Development of 11C-labeled probes for imaging CRF

开发用于 CRF 成像的 11C 标记探针

• 批准号: 6800377
• 负责人: J. S. Dileep KUMAR
• 金额: $ 24.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-19 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6800377
• 关键词: baboons; bioimaging /biomedical imaging; blood brain barrier; brain imaging /visualization /scanning; carbon; corticotropin releasing factor; high performance liquid chromatography; hormone receptor; laboratory mouse; neuropsychology; positron emission tomography; pyrazolopyrimidine; radiotracer; technology /technique development; tissue /cell culture

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.

该项目的总体目标是开发PET成像探针，以量化从小鼠到人类的活体受试者中CRF 1受体结合的体内水平。CRF激动剂和拮抗剂的广泛临床前和临床研究已经产生了以下假设：CRF功能异常可能导致多种神经精神疾病的发病机制，例如焦虑症、抑郁症、强迫症、神经退行性疾病如阿尔茨海默病、帕金森病和创伤后应激障碍。用于PET的高比活性、放射性标记的、选择性CRF 1受体拮抗剂的开发将使得有可能在体内重复地定量与CRF 1受体的结合，这将打开脑成像以及基础研究中的许多临床领域，以研究脑梗死的病理生理学。 抑郁、焦虑和其他神经退行性疾病。这样的PET探针必须具有优异的受体亚型选择性（CRF 1/CRF 2）、水溶性和穿过BBB的快速渗透性。在迄今报道的各种类别的CRF 1拮抗剂中，只有少数显示出具有高效力（CRF 1 IC 50 < 10 nM）、选择性（CRF 1/CRF 2 IC 50>1000）、穿透脑血脑屏障的能力和水溶性。我们选择了（7-dipropylamino）-2，5-dimethyl-3-[2-（dimethyl-amino）-5-pyridyl]-pyrazole [1，5a] pyrimidine（R121920）作为CRF 1拮抗剂的PET探针。R121920高 亲和性，CRF 1受体选择性拮抗剂（Ki值（nmol/L）：CRF 1 = 4; CRF 2>10000），具有良好的水溶性（>20 mg/mL），也可穿过BBB。我们设计了一种新的钯催化联芳基偶联反应作为合成[11 C]R121920的关键策略。因此，用这种探针定量测量CRF 1受体在体内的能力将导致更好地理解的事件，神经精神和神经退行性疾病的进展，退化和各种病理生理方面的基础。也有可能量化CRF 1受体阻滞剂在治疗过程中的相关性。 抗抑郁药物的选择。CRF 1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的和有效的帮助。 该申请寻求支持，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。

项目成果

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

使用 [11C]R121920 和 [11C]DMP696 对 CRF1 进行 PET 成像：目标密度是否足够？

• DOI: 10.1016/j.nucmedbio.2007.01.012
• 发表时间: 2007
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Sullivan,GregoryM;Parsey,RaminV;Kumar,JSDileep;Arango,Victoria;Kassir,SuhamA;Huang,Yung-Yu;Simpson,NormanR;VanHeertum,RonaldL;Mann,JJohn
• 通讯作者: Mann,JJohn