Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner-Wadsworth-Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki-Miyaura cross-coupling from the corresponding brominated pyrazole-azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

Development and radiosynthesis of the first 18 F-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 [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-K2.2.2 -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%).