Development and radiosynthesis of the first 18 F-labeled inhibitor of monocarboxylate transporters (MCTs)

Abstract

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 [¹⁸ F]FACH ((E)-2-cyano-3-{4-[(3-[¹⁸ 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-[¹⁴ C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[¹⁸ F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[¹⁸ F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[¹⁸ F]F-K_2.2.2 -carbonate or [¹⁸ F]TBAF. The final deprotected product [¹⁸ F]FACH was only obtained when [¹⁸ F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [¹⁸ F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).

Keywords: [18F]FACH; monocarboxylate transporters (MCTs); positron emission tomography (PET); radiofluorination; α-cyano-4-hydroxycinnamic acid (α-CHC).