Design and synthesis of a fluorinated quinazoline-based type-II Trk inhibitor as a scaffold for PET radiotracer development
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 kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patie...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
21 April 2017
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| In: |
Bioorganic & medicinal chemistry letters
Year: 2017, Volume: 27, Issue: 12, Pages: 2771-2775 |
| ISSN: | 1464-3405 |
| DOI: | 10.1016/j.bmcl.2017.04.064 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.bmcl.2017.04.064 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0960894X17304419 
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| Author Notes: | Vadim Bernard-Gauthier, Anne Mahringer, Matthew Vesnaver, Gert Fricker, Ralf Schirrmacher |
| Summary: | 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 kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [18F]QMICF ([18F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50=85-650nM) and relevant TrkA fusions including TrkA-TPM3 (IC50=162nM). Starting from a racemic FLT3 (fms like tyrosine kinase 3) inhibitor lead with off-target TrkA activity ((±)-6), we developed and synthesized the fluorinated derivative (R)-9 in three steps and 40% overall chemical yield. Compound (R)-9 displays a favorable selectivity profile on a diverse set of kinases including FLT3 (>37-fold selectivity for TrkB/C). The mesylate precursor 16 required for the radiosynthesis of [18F]QMICF was obtained in six steps and 36% overall yield. The results presented herein support the further exploration of [18F]QMICF for imaging of Trk fusions in vivo. |
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| Item Description: | Gesehen am 18.05.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1464-3405 |
| DOI: | 10.1016/j.bmcl.2017.04.064 |