Development of radioligands with improved brain kinetics for imaging nAChR by PET

描述（由申请方提供）：该提案的总体目的是对[18 F]（-）-JHU 87522（[18 F]JHU）进行临床前评价，[18 F] JHU是我们的新型未发表放射性配体，具有用于中枢烟碱乙酰胆碱受体（nAChR）定量正电子发射断层扫描（PET）成像的特殊特性。迫切需要nAChR的PET成像来研究烟碱系统在阿尔茨海默病和帕金森病、精神分裂症、药物依赖和许多其他疾病中的作用。更好地理解烟碱系统的潜在机制可以指导治疗这些疾病的药物的开发。中枢nAChR还有助于多种脑功能，包括学习和记忆，并且它们可以介导抗伤害感受。目前，只有两种放射性示踪剂，2-[18 F]FA和6-[18 F]FA，可用于使用PET研究人脑中的nAChR。然而，这些放射性示踪剂的“慢”脑动力学妨碍了动力学参数的数学建模和可靠测量，因为示踪剂达到稳态需要5-7小时的PET扫描。另一个严重的问题是2- [18F]FA和6-[18F]FA在除丘脑外的所有脑区中的低结合电位（BP）。在初步研究中，我们合成了[18F]JHU，一种新型放射性标记的nAChR拮抗剂。在最初的狒狒PET研究[18F]中，JHU表现出卓越的成像特性。仅用[18 F]JHU进行90分钟的PET扫描就足以对狒狒脑中的nAChR进行稳健定量。[18F]JHU的血压值比2-[18F]FA高250%。在用选择性nAChR激动剂金雀花碱进行的阻断研究中，证明了[18 F]JHU与狒狒nAChR的特异性结合。这些初步研究表明，[18 F]JHU上级2-[18 F]FA和6-[18 F]FA。该评价将成为未来人体研究的基础。具体目标是：1.合成更大量的：a）用于本提案的[18 F]JHU放射性标记的前体和B）“冷”（-）-JHU 87522，用于未来的毒理学研究。2.表征小鼠中[18 F]JHU的药理学、代谢和辐射剂量测定特征。阻断实验旨在确定[18 F]JHU是否选择性结合中央nAChR。代谢研究将证明[18F]JHU是否产生穿透血脑屏障的放射性代谢物。辐射剂量学实验将提供证据证明[18F]JHU对未来的人体研究是安全的。3.在几只狒狒的PET基线和阻断研究中确定[18 F]JHU具有最佳的快速脑动力学、高结合潜力和与nAChR的特异性体内结合。 公共卫生宣传：本临床前评价将确定[18 F]（-）-JHU 87522（[18 F]JHU）有望用于人体研究。烟碱乙酰胆碱受体（nAChR）的正电子发射断层扫描（PET）成像的放射性配体的发展是非常重要的研究尼古丁能系统在神经退行性疾病和神经精神疾病，药物依赖和各种其他疾病的作用，以及开发尼古丁药物治疗这些条件。

DESCRIPTION (provided by applicant): The overall objective of the proposal is to perform pre-clinical evaluation of [18F](-)-JHU87522 ([18F]JHU), our novel unpublished radioligand with extraordinary properties for quantitative positron emission tomography (PET) imaging of the central nicotinic acethylcholine receptor (nAChR). There is an urgent need for PET imaging of the nAChR to study the role of the nicotinic system in Alzheimer's and Parkinson's diseases, schizophrenia, drug dependence and many other disorders. Greater understanding of the underlying mechanisms of the nicotinic system could direct the development of medications to treat these disorders. Central nAChRs also contribute to a variety of brain functions, including learning and memory, and they can mediate antinociception. Currently, only two radiotracers, 2-[18F]FA and 6-[18F]FA, are available for studying nAChRs in human brain using PET. However, the "slow" brain kinetics of these radiotracers hamper mathematical modeling and reliable measurement of kinetic parameters since it takes 5-7 hours of PET scanning for the tracer to reach a steady state. Another serious problem is the low binding potentials (BP) of 2- [18F]FA and 6-[18F]FA in all brain regions except the thalamus. In Preliminary Studies we synthesized [18F]JHU, a novel radiolabeled nAChR antagonist. In an initial baboon PET study [18F]JHU demonstrated exceptional imaging properties. Only 90 min of PET scanning with [18F]JHU was sufficient for robust quantification of nAChR in baboon brain. The BP values of [18F]JHU were 250% higher than those of 2-[18F]FA. The specific binding of [18F]JHU to nAChR in baboon was demonstrated in a blockade study with the selective nAChR agonist cytisine. These initial studies suggest that [18F]JHU is superior to 2-[18F]FA and 6-[18F]FA. This evaluation will become a basis for the future human studies. The specific aims are to: 1. Synthesize larger quantities of: a) the precursor for radiolabeling of [18F]JHU for this proposal and b) "cold" (-)-JHU87522 to use in future toxicology studies. 2. Characterize pharmacological, metabolic and radiation dosimetry profiles of [18F]JHU in mice. Blocking experiments are to determine if [18F]JHU selectively binds to central nAChRs. Metabolic studies will prove whether or not [18F]JHU generates radioactive metabolites that penetrate the blood-brain barrier. Radiation dosimetry experiments will provide evidence that [18F]JHU is safe for the future human studies. 3. Determine in the PET baseline and blocking studies in several baboons that [18F]JHU has optimally rapid brain kinetics, high binding potentials and specific in vivo binding to nAChRs. PUBLIC HEALTH REVELANCE: This preclinical evaluation will establish that [18F](-)-JHU87522 ([18F]JHU) has promise for human studies. Development of radioligands for positron emission tomography (PET) imaging of the nicotinic acethylcholine receptor (nAChR) is of great importance for studying the role of the nicotinergic system in neurodegenerative and neuropsychiatric disorders, drug dependence and a variety of other disorders as well as for developing nicotinic medications to treat these conditions.