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

描述（由申请人提供）：该提案的总体目标是对[18F](-)- jhu87522 （[18F]JHU）进行临床前评估，[18F]JHU是我们的新型未发表的放射配体，具有用于中央尼古丁乙酰胆碱受体（nAChR）定量正电子发射断层扫描（PET）成像的非凡特性。目前迫切需要对nAChR进行PET成像，以研究尼古丁系统在阿尔茨海默病和帕金森病、精神分裂症、药物依赖等许多疾病中的作用。更好地了解尼古丁系统的潜在机制可以指导治疗这些疾病的药物的发展。中枢nachr也有助于多种大脑功能，包括学习和记忆，它们可以介导抗感觉。目前，用于PET研究人脑nachr的放射性示踪剂只有2-[18F]FA和6-[18F]FA两种。然而，这些放射性示踪剂的“缓慢”脑动力学妨碍了数学建模和动力学参数的可靠测量，因为示踪剂需要5-7小时的PET扫描才能达到稳定状态。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均存在低结合电位（BP）。在初步研究中，我们合成了一种新的放射性标记nAChR拮抗剂[18F]JHU。在最初的狒狒PET研究中[18F]， JHU显示出特殊的成像特性。仅用[18F]JHU进行90分钟的PET扫描就足以对狒狒脑内的nAChR进行稳健的量化。[18F]JHU的血压值比2-[18F]FA高250%。[18F]JHU与狒狒nAChR的特异性结合在选择性nAChR激动剂cytisine的阻断研究中得到证实。这些初步研究表明[18F]JHU优于2-[18F]FA和6-[18F]FA。这一评价将成为今后人体研究的基础。具体目标是：1。合成更大量的：a)本提案中用于放射性标记[18F]JHU的前体；b)用于未来毒理学研究的“冷”(-)- jhu87522。2. 表征小鼠[18F]JHU的药理学、代谢和辐射剂量学特征。阻断实验是为了确定[18F]JHU是否选择性地与中心nachr结合。代谢研究将证明[18F]JHU是否会产生穿透血脑屏障的放射性代谢物。辐射剂量学实验将为[18F]JHU在未来的人体研究中是安全的提供证据。3. 在几只狒狒的PET基线和阻断研究中确定[18F]JHU具有最佳的快速脑动力学，高结合电位和特异性体内结合nachr。

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The overall objective of the proposal is to perform pre-clinical evaluation of [18F](-)-JHU87522 ([18F]JHU), our novel unpublished radioligand with extraordinary properties for quantitative positron emission tomography (PET) imaging of the central nicotinic acethylcholine receptor (nAChR).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.