Synthesis, radiolabeling, and evaluation of a 68Ga-labeled tyrosine kinase inhibitor for detecting EGFRT790M mutations in vivo

Radiolabeled tyrosine kinase inhibitors (TKIs) have been used in clinics for the detection of epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) patients by positron emission tomography (PET), and the potential responder for TKI targeted therapy can be selected and benefited in subsequent TKI-based anti-tumor treatment. However, as activated T790M resistance mutation is often observed in NSCLC patients underwent EGFR TKI based therapies, the detection of EGFR mutation status is of great importance to evaluate therapeutic efficacy and prolongs overall survival with these patients. In addition, no radiotracer has been reported with the ability to detect EGFR^T790M mutation <i>in vivo</i> at present. Based on the chemical structure of Rociletinib, a novel radiolabeled PET tracer (⁶⁸Ga-<b>1</b>) was developed with potent binding affinity <i>in vitro (</i>with IC₅₀ value of 9.21 nM<i>)</i>. In addition, ⁶⁸Ga-<b>1</b> also showed promising properties in detection EGFR^T790M mutation in the subsequent <i>in vitro</i> and <i>in vivo</i> evaluations. Herein we report the synthesis, radiolabeling, and preclinical evaluation of ⁶⁸Ga-<b>1</b> for detecting EGFR^T790M mutation, and our result indicated that Rociletinib may be regarded as a lead compound to develop a selective EGFR^T790M PET tracer with further modification and optimizations.