Sadeghzadeh Masoud, Moldovan Rareş-Petru, Fischer Steffen, Wenzel Barbara, Ludwig Friedrich-Alexander, Teodoro Rodrigo, Deuther-Conrad Winnie, Jonnalagadda Shirisha, Jonnalagadda Sravan K, Gudelis Emilis, Šačkus Algirdas, Higuchi Kei, Ganapathy Vadivel, Mereddy Venkatram R, Drewes Lester R, Brust Peter
Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Leipzig, Germany.
Department of Chemistry and Biochemistry, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, Duluth, Minnesota, USA.
J Labelled Comp Radiopharm. 2019 Jun 30;62(8):411-424. doi: 10.1002/jlcr.3739.
Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [ F]FACH ((E)-2-cyano-3-{4-[(3-[ F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[ C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[ F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[ F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[ F]F-K -carbonate or [ F]TBAF. The final deprotected product [ F]FACH was only obtained when [ F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [ F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).
单羧酸转运蛋白1和4（MCT1和MCT4）参与肿瘤的发生和发展。它们的表达水平与临床疾病预后相关。因此，这两种MCT都是治疗多种人类癌症的有前景的药物靶点。在癌症中对这些MCT进行无创成像被认为有利于评估使用特定MCT抑制剂时MCT介导的化疗和放射增敏作用。在此，我们描述了一种用于放射性合成[F]FACH（(E)-2-氰基-3-{4-[(3-[F]氟丙基)(丙基)氨基]-2-甲氧基苯基}丙烯酸）的方法，[F]FACH是一种用于PET成像的新型放射性标记的MCT1/4抑制剂。合成了α-氰基-4-羟基肉桂酸（FACH）的氟化类似物，并通过L-[C]乳酸摄取试验测量对MCT1和MCT4的抑制作用。放射性标记通过两步方案进行，包括中间体(E)/(Z)-[F]叔丁基-FACH（叔丁基(E)/(Z)-2-氰基-3-{4-[(3-[F]氟丙基)(丙基)氨基]-2-甲氧基苯基}丙烯酸酯）的放射性合成，然后对叔丁基进行脱保护。使用K[F]F-K-碳酸盐或[F]TBAF成功实现了放射性氟化。只有当通过后一种方法形成[F]叔丁基-FACH时，才能得到最终的脱保护产物[F]FACH。在优化脱保护反应后，以高放射化学产率（轰击结束时（EOB）为39.6±8.3%）和放射化学纯度（大于98%）获得了[F]FACH。
