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的活体受试者体内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已经产生了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、帕金森氏病和创伤后应激障碍。高比活性、放射性标记、选择性的PET CRF1受体拮抗剂的开发，将使其能够在体内反复定量结合CRF1受体，这将为脑成像和基础研究开辟许多临床领域

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.