5-Iodo-A-85380 binds to α-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as α4β2*subtypes
5-Iodo-A-85380 binds to α-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as α4β2*subtypes
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DOI：
10.1046/j.1471-4159.2002.00868.x
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发表时间：
2002-04-01
影响因子：
4.7
通讯作者：
Quik, M
中科院分区：
文献类型：
--
作者：
Kulak, JM;Sum, J;Quik, M
最近的工作表明，5-碘-A-85380，3-吡啶基醚A-85380的放射性碘化类似物，代表了一种有前途的成像剂，用于非侵入性，在体内研究的α 4 β 2 * 烟碱乙酰胆碱受体（nAChR; * 表示受体含有指定的亚基），因为它的非特异性结合低，体内毒性低和高选择性的α 4 β 2 * nAChR。作为阐明纹状体中表达的nAChR亚型的方法，我们使用5-[I-125]碘-A-85380（[I-125]A-85380）和[I-125] α-芋螺毒素MII（一种与α 6 * 和α 3 * nAChR高亲和力结合但不与α 4 β 2 * nAChR结合的配体）在猴和大鼠脑中进行了竞争性放射自显影。尽管据报道A-85380对α 4 β 2 * nAChR具有选择性，但我们观察到A-85380完全抑制大鼠纹状体中的[I-125] α-芋螺毒素MII结合，并且A-85380阻断猴尾状核和壳核中>90%的[I-125] α-芋螺毒素MII位点。这些结果表明，A-85380与非α 4 β 2 * nAChR结合，包括推定的α 6 * nAChR。测定含有α-芋螺毒素MII-敏感（α 6 β 2 *）nAChR的[I-125]A-85380位点的百分比的实验表明，它们代表啮齿动物纹状体中约10%的[I-125]A-85380位点和猴尾状核和壳核中约30%的位点。这些数据对于在体外和体内成像研究中识别帕金森病和其他基底神经节疾病中尼古丁受体亚型的变化非常重要。
Recent work suggests that 5-iodo-A-85380, a radioiodinated analog of the 3-pyridyl ether A-85380, represents a promising imaging agent for non-invasive, in vivo studies of alpha4beta2* nicotinic acetylcholine receptors (nAChRs; *denotes receptors containing the indicated subunits), because of its low non-specific binding, low in vivo toxicity and high selectivity for alpha4beta2* nAChRs. As an approach to elucidate nAChR subtypes expressed in striatum, we carried out competitive autoradiography in monkey and rat brain using 5-[I-125]iodo-A-85380 ([I-125]A-85380) and [I-125]alpha-conotoxin MII, a ligand that binds with high affinity to alpha6* and alpha3* nAChRs, but not to alpha4beta2* nAChRs. Although A-85380 is reported to be selective for alpha4beta2* nAChRs, we observed that A-85380 completely inhibited [I-125]alpha-conotoxin MII binding in rat striatum and that A-85380 blocked >90% of [I-125]a-conotoxin MII sites in monkey caudate and putamen. These results suggest that A-85380 binds to non-alpha4beta2* nAChRs, including putative alpha6* nAChRs. Experiments to determine the percentage of [I-125]A-85380 sites that contain a-conotoxin MII-sensitive (alpha6beta2*) nAChRs indicate that they represent about 10% of [I-125]A-85380 sites in rodent striatum and about 30% of sites in monkey caudate and putamen. These data are important for identifying alterations in nicotinic receptor subtypes in Parkinson's disease and other basal ganglia disorders both in in vitro and in in vivo imaging studies.