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.

该项目的总体目的是开发PET成像探针，以量化从小鼠到人类的生物受试者中CRF1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提出了假设，即Abnorma CRF功能可能有助于多种神经精神疾病的发病机理，例如焦虑，抑郁，抑郁，抑制性抑制性疾病，神经退行性疾病，如Alzheimer's Disease，Parkinson's Parkinson，Parkinson's Parkinson，和创伤后应激障碍。开发高特异性活性，放射性标记的，选择性的CRF1受体拮抗剂的PET可以反复地量化与体内CRF1受体的结合，这将打开脑成像中的许多临床区域以及基础研究中的许多临床区域，以研究研究的病理生理学 抑郁，焦虑和其他神经退行性疾病。这样的PET探针必须具有出色的受体亚型选择性（CRF1/CRF2），水生溶解度和跨BBB的快速渗透性。在迄今为止报道的各种类别的CRF1拮抗剂中，只有少数人具有较高的效力（CRF1 IC50 <10 nm），选择性（CRF1/CRF2 IC50> 1000），具有穿透脑血脑屏障和水溶性的能力。我们选择了（7-二吡咯氨基）-2,5-二甲基-3- [2-（二甲基 - 氨基）-5-吡啶基] -Pyrazolo [1,5a]嘧啶（R121920），作为我们的潜在候选者，是我们的潜在候选者。 CRF1拮抗剂。 R121920很高 亲和力，CRF1受体选择性拮抗剂（Ki值（NMOL/L）：CRF1 = 4; CRF2> 10000）具有良好的水溶性（> 20 mg/ml），并且还横穿BBB。我们已经设计了一种新型的钯催化的双轴耦合，作为[11C] R121920的合成的关键策略。因此，通过此探测，体内定量测量CRF1受体的能力将使人们更好地理解神经精神疾病和神经抑制性疾病的进展，回归和各种病理生理方面的事件。还可以量化CRF1受体阻塞之间的相对启动 抗抑郁药的幼体。 CRF1受体拮抗剂的PET图像探针还将提供有价值，有效的帮助，以指导神经精神和神经退行性疾病的药物开发。 该应用程序寻求支持，以涵盖从啮齿动物阶段到第一个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