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](-)-JHU87522([18F]JHU)是我们尚未发表的新型放射配基，具有非凡的性能，可用于中枢烟碱乙酰胆碱受体(NAChR)的正电子发射断层扫描(PET)成像。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氏症和帕金森氏症、精神分裂症、药物依赖和许多其他疾病中的作用。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开发。中枢nAChRs还有助于大脑的各种功能，包括学习和记忆，它们可以介导抗伤害性感觉。目前，只有2-[18F]FA和6-[18F]FA两种示踪剂可用于用正电子发射计算机断层扫描研究人脑中的nAChRs。然而，这些放射性示踪剂“缓慢”的大脑动力学阻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个小时的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在除丘脑以外的所有脑区的低结合电位(BP)。在初步研究中，我们合成了一种新型的放射性标记的nAChR拮抗剂[18F]JHU。在最初的狒狒PET研究[18F]中，JHU展示了出众的成像特性。用[18F]JHU进行90分钟的正电子发射计算机断层扫描，就足以对狒狒脑中的nAChR进行可靠的定量。[18F]JHU的BP值比2-[18F]FA高250%。在选择性nAChR激动剂Cytisine的阻断研究中，证实了[18F]JHU与恒河猴nAChR的特异性结合。这些初步研究表明，[18F]JHU优于2-[18F]FA和6-[18F]FA。这一评估将成为未来人类研究的基础。具体目标是：1.合成更大数量的：a)用于本建议的[18F]JHU的放射性标记前体和b)“COLD”(-)-JHU87522，用于未来的毒理学研究。2.[18F]JHU在小鼠体内的药理、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nAChRs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。辐射剂量学实验将提供证据，证明[18F]JHU对未来的人体研究是安全的。3.在PET基线和对几只狒狒的阻断研究中，确定[18F]JHU具有最佳的快速脑动力学、高结合电位和体内与nAChRs的特异性结合。 公共卫生评价：这项临床前评估将确定[18F](-)-JHU87522([18F]JHU)在人体研究方面有希望。开发用于烟碱乙酰胆碱受体(NAChR)正电子发射断层扫描(PET)成像的放射性配体对于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中的作用以及开发治疗这些疾病的尼古丁药物具有重要意义。

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The overall objective of the proposal is to perform pre-clinical evaluation of [18F](-)-JHU87522 ([18F]JHU), our novel unpublished radioligand with extraordinary properties for quantitative positron emission tomography (PET) imaging of the central nicotinic acethylcholine receptor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