Helbert Hugo, Deuther-Conrad Winnie, de Haan Michel, Wenzel Barbara, Luurtsema Gert, Szymanski Wiktor, Brust Peter, Dierckx Rudi A J O, Feringa Ben L, Elsinga Philip H
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands.
EJNMMI Radiopharm Chem. 2025 Feb 2;10(1):7. doi: 10.1186/s41181-025-00327-w.
Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelling methods and selectivity for VAChT against σ receptors being a common pitfall of such compounds, the development of selective VAChT tracers remains a challenge. Modern labelling techniques, in this case the [C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers.
A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-4) was the most promising with a 16 ± 4 nM affinity towards VAChT, a 29-fold weaker affinity for σ1 receptors and negligible binding (> 1 μM) towards σ2 receptors. The radiolabelling was performed from the corresponding bromide using a [C]MeLi cross-coupling protocol, yielding 2-[C]methylspirobenzovesamicol in 32-37% RCY. New in vitro binding data is also made available for (-)-FEOBV with human-sourced σ1 receptors, revealing a 300-fold stronger affinity for VAChT compared to σ receptors.
(-)-2-methylspirobenzovesamicol was identified as a potent and selective VAChT ligand, with moderate to low affinity for σ receptors, and its racemate was radiolabeled in good radiochemical yields with Carbon-11. At this stage, [C]-methyl-2-methylspirobenzovesamicol appears a promising C-PET tracer for VAChT imaging.
通过在神经传递中的核心作用，囊泡乙酰胆碱转运体（VAChT）正成为正电子发射断层扫描（PET）中越来越有价值的靶点。VAChT配体大多源自vesamicol结构，但由于可用标记方法存在局限性，且此类化合物对VAChT相对于σ受体的选择性是常见缺陷，因此开发选择性VAChT示踪剂仍然是一项挑战。现代标记技术，在此情况下即[C]MeLi交叉偶联方法，扩展了标记机会，使得能够探索新型基于vesamicol的结构作为潜在的PET示踪剂。
合成了一系列vesamicol衍生物，并评估了它们与VAChT、σ1和σ2受体的结合情况。在所有测试化合物中，（-）-2-甲基螺苯并vesamicol（（-）-4）最具前景，对VAChT的亲和力为16±4 nM，对σ1受体的亲和力弱29倍，对σ2受体的结合可忽略不计（>1μM）。使用[C]MeLi交叉偶联方案从相应的溴化物进行放射性标记，以32 - 37%的放射性化学产率得到2-[C]甲基螺苯并vesamicol。还提供了（-）-FEOBV与人源σ1受体的新体外结合数据，显示其对VAChT的亲和力比对σ受体强300倍。
（-）-2-甲基螺苯并vesamicol被鉴定为一种强效且选择性的VAChT配体，对σ受体具有中度至低度亲和力，其外消旋体用碳-11以良好的放射性化学产率进行了放射性标记。在这个阶段，[C]-甲基-2-甲基螺苯并vesamicol似乎是一种用于VAChT成像的有前景的碳-11 PET示踪剂。
