Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
Department of Nuclear Medicine, Friedrich-Alexander-Universität, Ulmenweg 18, Erlangen 91054, Germany ; Department of Pharmacology and Neuroscience, Copenhagen University, Blegdamsvej 3B, Copenhagen 2200, Denmark.
EJNMMI Res. 2014 Aug 5;4:43. doi: 10.1186/s13550-014-0043-5. eCollection 2014.
The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.
Automated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq μmol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions.
The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained.
[(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.
α7 烟碱型乙酰胆碱受体 (nAChR) 是神经精神药理学和肿瘤学的重要分子靶点。由于蛋白表达相对较低，开发适用的高度特异性放射性示踪剂一直具有挑战性。为了寻找新的配体作为正电子发射断层扫描 (PET) 的候选物，对一系列二氮杂双环壬烷化合物库进行了筛选，以评估其对 α7 nAChR 的亲和力和特异性。在这些化合物中，[(18)F]NS14490 已被证明在器官分布研究中可获得可靠的结果；然而，[(18)F]NS14490 的放射合成需要优化和自动化，以获得允许在仔猪中进行动态 PET 研究的放射性示踪剂数量。
采用 [(18)F] 氟化物对 tosylate 前体进行自动化放射合成，在 TRACERlab™ FX F-N 合成模块（美国威斯康星州沃基肖）中进行。经过优化后，[(18)F]NS14490 的放射化学产率始终约为 35%，总合成时间约为 90 分钟。放射性示踪剂的放射化学纯度大于 92%，合成结束时的比活度为 226±68GBq·μmol(-1)。在年轻仔猪中进行 PET 测量，以研究 [(18)F]NS14490 的代谢稳定性和脑内结合情况，以及在无和有 α7 nAChR 部分激动剂 NS6740 给药的情况下进行基础状态和阻断条件下的 [(18)F]NS14490 脑内结合情况。
整个端脑的总分布容积相对于代谢校正后的动脉输入为 3.5 至 4.0 mL·g(-1)，在给予 NS6740 的动物中降至 2.6 mL·g(-1)。假设完全阻断，这一位移表明活猪脑中的结合潜能 (BPND) 约为 0.5。此外，还获得了在主要脑动脉中存在特异性结合的证据。
[(18)F]NS14490 不仅可与其他用于脑内 α7 nAChR 成像的临床前研究的 PET 放射性示踪剂相媲美，而且还可能成为用于成像病变血管中脆弱斑块内 α7 nAChR 的潜在 PET 放射性示踪剂。
