The cannabinoid receptor 2 (CB2) has been implicated in a series of neurodegenerative disorders and has emerged as an interesting biological target for therapeutic as well as diagnostic purposes. In the present work, we describe an improved radiosynthetic approach to obtain the previously reported CB2-specific PET radioligand [¹⁸F]RS-126 in higher radiochemical yields and molar activities. Additionally, the study revealed that prolongation of the [¹⁸F]RS-126 fluoroalkyl side chain ultimately leads to an improved stability towards mouse liver enzymes but is accompanied by a reduction in selectivity over the cannabinoid receptor 1 (CB1). Huntington-related phenotypic changes as well as striatal D2R downregulation were confirmed for the transgenic R6/2 mouse model. CB2 upregulation in R6/2 Chorea Huntington mice was observed in hippocampus, cortex, striatum and cerebellum by qPCR, however, these results could not be confirmed at the protein level by PET imaging. Furthermore, we evaluated the utility of the newly developed [¹¹C]RS-028, a potent [¹⁸F]RS-126 derivative with increased polarity and high selectivity over CB1 in post-mortem human ALS spinal cord and control tissue. Applying in vitro autoradiography, the translational relevance of CB2 imaging was demonstrated by the specific binding of [¹¹C]RS-028 to post-mortem human ALS spinal cord tissue.

大麻素受体2（CB2）与一系列神经退行性疾病有关，并已成为治疗和诊断目的的有趣生物学靶标。在目前的工作中，我们描述了一种改进的放射合成方法，可以以更高的放射化学产率和摩尔活性获得先前报道的CB2特异性PET放射性配体[ ¹⁸ F] RS-126。此外，该研究还发现[ ¹⁸F] RS-126氟烷基侧链最终导致对小鼠肝酶的稳定性提高，但与大麻素受体1（CB1）相比，选择性降低。对于转基因R6 / 2小鼠模型，证实了亨廷顿相关的表型改变以及纹状体D2R下调。通过qPCR在R6 / 2 Chorea Huntington小鼠的海马，皮层，纹状体和小脑中观察到CB2上调，但是，通过PET成像无法在蛋白质水平上证实这些结果。此外，我们评估了新开发的[ ¹¹ C] RS-028的效用，这是一种强效的[ ¹⁸ F] RS-126衍生物，在死后人ALS脊髓和对照组织中具有比CB1更高的极性和更高的选择性。体外应用在放射自显影中，[ ¹¹ C] RS-028与死后人类ALS脊髓组织的特异性结合证明了CB2成像的翻译相关性。