Gündisch Daniela, Koren Andrei O, Horti Andrew G, Pavlova Olga A, Kimes Alane S, Mukhin Alexey G, London Edythe D
Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland 21224, USA.
Synapse. 2005 Feb;55(2):89-97. doi: 10.1002/syn.20096.
Nicotinic acetylcholine receptors are involved in tobacco dependence and several other neuropathologies (e.g., Alzheimer's disease, Parkinson's disease), as well as in attention, learning, and memory. Performing in vivo imaging of these receptors in humans holds great promise for understanding their role in these conditions. Recently, three radiohalogenated analogs of 3-(2(S)-azetidinylmethoxy)pyridine (A- 85380) were used successfully for the in vivo visualization of alpha4beta2* nicotinic receptors in the human brain with PET/SPECT. Herein, we present the results of the in vitro characterization of one of these radioligands, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)-pyridine (6-[18F]fluoro-A-85380), which is a fluoro-analog of the potent nonopioid analgesic ABT-594. In human postmortem cortical tissue, 6-[18F]fluoro-A-85380 reversibly binds with high affinity to a single population of sites (Kd = 59 pM at 37 degrees C, Bmax = 0.7 pmol/g tissue). The binding is fully reversible and is characterized at 37 degrees C by T(1/2assoc) = 2.2 min (at a ligand concentration of 39 pM) and by T(1/2dissoc) = 3.6 min. 6-Fluoro-A-85380 exhibits clear selectivity for alpha4beta2* over the other major mammalian nicotinic receptor subtypes: alpha7, alpha3beta4, and muscle-type. These results suggest that 6-[18F]fluoro-A-85380 is a promising radioligand for in vivo imaging of brain alpha4beta2* nicotinic receptors.
烟碱型乙酰胆碱受体与烟草依赖及其他几种神经病理学疾病（如阿尔茨海默病、帕金森病）有关，还涉及注意力、学习和记忆。对这些受体进行人体活体成像，对于理解它们在这些病症中的作用具有很大的前景。最近，3-(2(S)-氮杂环丁烷甲氧基)吡啶（A-85380）的三种放射性卤代类似物已成功用于通过正电子发射断层扫描/单光子发射计算机断层扫描对人脑中α4β2烟碱型受体进行活体可视化。在此，我们展示了其中一种放射性配体6-[18F]氟-3-(2(S)-氮杂环丁烷甲氧基)吡啶（6-[18F]氟-A-85380）的体外特性研究结果，它是强效非阿片类镇痛药ABT-594的氟代类似物。在人类死后皮质组织中，6-[18F]氟-A-85380以高亲和力与单一的位点群体可逆性结合（37℃时Kd = 59 pM，Bmax = 0.7 pmol/g组织）。这种结合是完全可逆的，在37℃时，其结合半衰期T(1/2assoc) = 2.2分钟（配体浓度为39 pM时），解离半衰期T(1/2dissoc) = 3.6分钟。6-氟-A-85380对α4β2的选择性明显高于其他主要的哺乳动物烟碱型受体亚型：α7、α3β4和肌肉型。这些结果表明，6-[18F]氟-A-85380是一种有前景的用于脑α4β2*烟碱型受体活体成像的放射性配体。
