Clemente Gonçalo S, Rickmeier Jens, Antunes Inês F, Zarganes-Tzitzikas Tryfon, Dömling Alexander, Ritter Tobias, Elsinga Philip H
Department of Nuclear Medicine and Molecular Imaging - University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany.
EJNMMI Res. 2020 Apr 15;10(1):34. doi: 10.1186/s13550-020-00622-4.
Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. However, a considerable group of patients does not respond to statin treatment, and the reason for this is still not completely understood. [F]Atorvastatin, the F-labeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research.
[F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage F-deoxyfluorination. The defluoro-hydroxy precursor was produced via Paal-Knorr pyrrole synthesis and was followed by coordination of the phenol to a ruthenium complex, affording the labeling precursor in approximately 10% overall yield. Optimization and automation of the labeling procedure reliably yielded an injectable solution of [F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol. Incubation of [F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [F]atorvastatin to cross the hepatic cell membrane to the cytosolic and microsomal fractions where HMG-CoA reductase is known to be highly expressed. Blocking assays using rat liver sections confirmed the specific binding to HMG-CoA reductase. Autoradiography on rat aorta stimulated to develop atherosclerotic plaques revealed that [F]atorvastatin significantly accumulates in this tissue when compared to the healthy model.
The improved ruthenium-mediated F-deoxyfluorination procedure overcomes previous hurdles such as the addition of salt additives, the drying steps, or the use of different solvent mixtures at different phases of the process, which increases its practical use, and may allow faster translation to clinical settings. Based on tissue uptake evaluations, [F]atorvastatin showed the potential to be used as a tool for the understanding of the mechanism of action of statins. Further knowledge of the in vivo biodistribution of [F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.
他汀类药物是抑制胆固醇合成的降脂药物，临床上用于心血管疾病的一级和二级预防。然而，有相当一部分患者对他汀类药物治疗无反应，其原因仍未完全明确。[F]阿托伐他汀是最常用的他汀类药物之一的氟标记版本，可能是他汀类药物相关研究的有用工具。
[F]阿托伐他汀通过优化的钌介导的后期氟脱氧氟化反应合成。脱氟羟基前体通过帕尔-克诺尔吡咯合成法制备，然后酚与钌配合物配位，以约10%的总收率得到标记前体。标记过程的优化和自动化可靠地产生了[F]阿托伐他汀的可注射溶液，放化产率为19%±6%（衰变校正），摩尔活度为65±32 GBq·μmol。[F]阿托伐他汀在人血清中孵育不会导致分解。此外，我们已经证明[F]阿托伐他汀能够穿过肝细胞膜进入胞质和微粒体部分，已知羟甲基戊二酰辅酶A还原酶在这些部分高度表达。使用大鼠肝脏切片的阻断试验证实了其与羟甲基戊二酰辅酶A还原酶的特异性结合。对诱发动脉粥样硬化斑块的大鼠主动脉进行放射自显影显示，与健康模型相比，[F]阿托伐他汀在该组织中显著蓄积。
改进的钌介导的氟脱氧氟化反应方法克服了先前的障碍，如添加盐添加剂、干燥步骤或在过程的不同阶段使用不同的溶剂混合物，这增加了其实际应用价值，并可能允许更快地转化到临床应用中。基于组织摄取评估，[F]阿托伐他汀显示出作为了解他汀类药物作用机制工具的潜力。对[F]阿托伐他汀体内生物分布的进一步了解可能有助于更好地理解脱靶效应的起源，并有可能区分他汀类药物抵抗和非抵抗患者。
