Design/charcterization of alpha-7 nicotinic radioprobes

α-7 烟碱放射性探针的设计/表征

• 批准号: 6323727
• 负责人: Robert F Dannals
• 金额: $ 12.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6323727
• 关键词: acetylcholine; analog; argon; autoradiography; bungarotoxins; carbon; chemical binding; chemical synthesis; fluorine; iodine; laboratory mouse; laboratory rat; neural degeneration; nicotine; nicotinic receptors; pharmacokinetics; positron emission tomography; radionuclides; radiotracer; receptor sensitivity; single photon emission computed tomography; smoking cessation

DESCRIPTION (Verbatim from the Applicant's Abstract): The project goal is to develop the first low molecular weight (< 500) radioligands that bind with high affinity and selectivity to neuronal alpha-7 nicotinic acetylcholine receptors (nAChRs). Ultimately, the developed radioligands may prove useful for in vivo tomographic imaging studies of this important nAChR subtype in humans. Interest in such studies is warranted for several reasons. First, these homomeric channels appear to mediate some of the presynaptic effects of nicotine; therefore, an in vivo probe for alpha-7 nAChRs would enable non-invasive study of a principal site of pharmacological action of nicotine. For example, the proposed alpha-7 radioligands might enable measurement of dose occupancy of nicotine at the alpha-7 site in tobacco users and patients undergoing nicotine-replacement therapy. Second, alpha-7-imaging tracers might aid in the validation of new alpha-7 therapeutic agents for the treatment of neurodegenerative disease and alcohol abuse. Third, such radioligands would aid in corroborating in the living brain the purported deficit of alpha-7 nAChRs in schizophrenia. Presently, alpha-7 radioligands are limited to high molecular weight probes (e.g. I-125 alpha-bungarotoxin, [I-125]otBTX) that are unable to cross the blood-brain barrier and suffer from a high degree of non-specific binding in in vitro assays. This proposal seeks to overcome the deficiencies of the existing alpha-7 radioligands and to explore the potential of the proposed alpha-7 radioligands to label the target nAChR subtype in vivo. High affinity alpha-7 ligands from a 3-(cinnamylidene)anabaseine and quinuclidine-based series will be synthesized. These two structural classes of alpha-7 specific nAChR agonists will be screened in in vitro homogenate binding assay. (Such assays will enable us to report the first qualitative structure-alpha-7 affinity relationship for these potent alpha-7 ligands). Alpha-7 ligands that possess high affinity and selectivity for the alpha-7 nAChR subtype will be labeled with positron emitting radionuclides (C-ll, F-18) or with radioiodine (I-125, I-123). The most promising I-125 labeled alpha-7 ligands will be tested in saturation binding assay and autoradiography assay using rat brain. From these studies, the specific binding signal afforded with the novel radioligands will be compared to the commonly used [I-125]a-BTX. The radioligands will be tested in rodent biodistribution studies to detenrune if the developed radioligands can localize alpha-7 sites in vivo. Completion of the project should provide the neuroscience research community with new and improved radioprobes that can be used for in vitro studies of the alpha-7 nAChR subtype. Additionally, this exploratory project will address the feasibility of in vivo labeling of alpha-7 nAChR sites.

描述（逐字研究申请人的摘要）：项目目标是 发展第一个低分子量（<500）放射性物体，该辐射体与高 对神经元α-7烟碱乙酰胆碱受体的亲和力和选择性 （nachrs）。最终，发达的放射线可能对体内有用 对人类这种重要NACHR亚型的层析成像研究。兴趣 在这样的研​​究中，有必要有多种原因。首先，这些同源物 通道似乎介导了尼古丁的一些突触前作用。 因此，α-7 NACHR的体内探针将实现非侵入性研究 尼古丁药理作用的主要部位。例如， 拟议的α-7放射线可能可以测量 烟草用户和正在接受的患者的alpha-7网站上的尼古丁 尼古丁替代疗法。第二，α-7成像示踪剂可能有助于 验证新的alpha-7治疗剂用于治疗 神经退行性疾病和酗酒。第三，这样的放射线会有助于 在佐证活体大脑中，据称α-7 nachrs的赤字 精神分裂症。 目前，alpha-7放射线量仅限于高分子量探针 （例如i-125α-甲状腺毒素，[i-125] otbtx）无法越过 血脑屏障并受到高度非特异性结合 体外测定。该建议旨在克服现有的缺陷 alpha-7放射线并探索所提出的alpha-7的潜力 放射性物体在体内标记目标NACHR亚型。高亲和力alpha-7 来自3-（cinnamylidene）同生和基核素定系列的配体的配体将 合成。这两个结构类别的alpha-7特异性NACHR激动剂 将在体外匀浆结合测定中进行筛选。 （此类测定将启用 美国报告第一个定性结构 - α-7亲和力关系 这些有效的alpha-7配体）。具有高亲和力的alpha-7配体 Alpha-7 NACHR亚型的选择性将标记为正电子 发射放射性核素（C-LL，F-18）或放射性碘（I-125，I-123）。这 最有前途的I-125标记为alpha-7配体的配体将以饱和度进行测试 使用大鼠脑的结合测定和放射自显影测定。从这些研究， 与新型放射性配体提供的特定结合信号将是 与常用的[I-125] A-BTX相比。放射线将在 如果开发的放射线可以 在体内将alpha-7位置定位。项目的完成应提供 具有新的和改进的放射线探针的神经科学研究社区可以是 用于α-7 NACHR亚型的体外研究。另外，这个 探索性项目将解决alpha-7体内标签的可行性 NACHR站点。