Synthesis and preclinical evaluation of a selective MET kinase positron emission tomography tracer

Abstract

The tyrosine kinase MET (hepatocyte growth factor receptor) is activated or mutated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [¹⁸F]2. [¹⁸F]2 could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/μmol. In vitro autoradiography indicated that [¹⁸F]2 selectively binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs.