Development of 11C-labeled probes for imaging CRF

该项目的总体目标是开发 PET 成像探针，以量化从小鼠到人类等活体受试者体内 CRF1 受体结合水平。 CRF激动剂和拮抗剂的广泛临床前和临床研究提出了这样的假设：CRF功能异常可能导致多种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、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、选择性 CRF1 受体拮抗剂的开发将使体内反复量化与 CRF1 受体的结合成为可能，这将打开脑成像以及基础研究领域的许多临床领域，以研究 CRF1 受体的病理生理学。 抑郁症、焦虑症和其他神经退行性疾病。这样的 PET 探针必须具有优异的受体亚型选择性 (CRF1/CRF2)、水溶性和跨 BBB 的快速渗透性。迄今为止报道的各类CRF1拮抗剂中，只有少数具有高效力（CRF1 IC50 < 10 nM）、选择性（CRF1/CRF2 IC50 >1000）、穿透脑血脑屏障的能力和水溶性。我们选择(7-二丙氨基)-2,5-二甲基-3-[2-(二甲基氨基)-5-吡啶基]-吡唑并[1,5a]嘧啶(R121920)作为CRF1拮抗剂PET探针的潜在候选者。 R121920是高 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），并且还可以穿过 BBB。我们设计了一种新型钯催化联芳基偶联作为合成 [11C]R121920 的关键策略。因此，利用这种探针定量测量体内 CRF1 受体的能力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事件。还可以量化 CRF1 受体阻断期间的关系 抗抑郁药物的来源。 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且有效的帮助。 该申请寻求支持以涵盖从啮齿动物阶段到首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.