Design and synthesis of a fluorinated quinazoline-based type-II Trk inhibitor as a scaffold for PET radiotracer development

摘要: Abstract NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in clinic for treatment cancer patients whose diseases harbor NTRK drivers. We describe herein development [18F]QMICF ([18F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies (IC50 = 85–650 nM) and relevant TrkA including TrkA-TPM3 (IC50 = 162 nM). Starting from racemic FLT3 (fms like tyrosine 3) inhibitor lead off-target activity ((±)-6), we developed synthesized fluorinated derivative (R)-9 three steps 40% overall chemical yield. Compound displays favorable selectivity profile on diverse set kinases (>37-fold TrkB/C). The mesylate precursor 16 required radiosynthesis was obtained six 36% results presented support further exploration imaging Trk vivo.