Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
J Nucl Med. 2011 Sep;52(9):1449-56. doi: 10.2967/jnumed.111.088815. Epub 2011 Aug 9.
Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)nAChR binding in humans and to measure α(7)nAChR occupancy of α(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective α(7)nAChR PET radioligand.
The high-affinity α(7)nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; (11)C-NS14492 regional distribution volumes were calculated, and α(7)nAChR occupancy was determined using an occupancy plot.
(11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α(7)nAChR in vivo.
We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for α(7)nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α(7)nAChR binding in the human brain.
小分子 α（7）烟碱型乙酰胆碱受体（α（7）nAChR）激动剂目前被验证可用于治疗精神分裂症和阿尔茨海默病的认知障碍。合适的放射性标记 α（7）nAChR PET 示踪剂对于在体定量人类 α（7）nAChR 结合以及测量 α（7）nAChR 候选药物对 α（7）nAChR 的占有率非常重要。在此，我们介绍了高亲和力 α（7）nAChR 选择性部分激动剂 NS14492 作为一种选择性 α（7）nAChR PET 放射性配体的放射合成和体内评价。
用（11）C-甲基三氟甲磺酸对其去甲基前体进行甲基化，标记高亲和力 α（7）nAChR 选择性部分激动剂 NS14492。在基线和静脉注射 α（7）nAChR 部分激动剂 SSR180711 或未标记 NS14492 的阻断剂量后，对雌性丹麦 Landrace 猪进行研究。（11）C-NS14492 作为静脉推注给药，在基线和阻断条件下对猪进行 90 分钟扫描。扫描过程中采集动脉血，计数血浆，并通过放射性高效液相色谱法确定母体化合物分数。用带动脉输入的图形分析对 PET 数据进行定量；计算（11）C-NS14492 的局部分布容积，并使用占有率图确定 α（7）nAChR 的占有率。
（11）C-NS14492 在猪脑中的摄取量很高，与 α（7）nAChR 分布一致，在大脑皮层和丘脑的结合最高。NS14492 和 SSR180711 的预处理一致地以剂量依赖性方式降低了所有检查区域（11）C-NS14492 的分布容积，支持该放射性配体在体内选择性结合 α（7）nAChR 的发现。
我们在此报告，（11）C-NS14492 是迄今为止报道的第一个用于 α（7）nAChR 的 PET 放射性配体，在受体阻断后其脑结合呈剂量依赖性下降。该化合物被认为是一种有前途的用于在人类大脑中测量 α（7）nAChR 结合的 PET 示踪剂。
