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

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