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Updated: Mar 3, 2026
Automation of a Positron-emission Tomography PET Radiotracer Synthesis Protocol for Clinical Production
Published on: October 26, 2018
Design and synthesis of a fluorinated quinazoline-based type-II Trk inhibitor as a scaffold for PET radiotracer
Vadim Bernard-Gauthier1, Anne Mahringer2, Matthew Vesnaver3
1Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, AB T6G 2R3, Canada.
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 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.
Insights
Researchers developed [18F]QMICF, a novel radiotracer for imaging tropomyosin receptor kinase (Trk) fusions. This tracer shows promise for detecting NTRK gene fusions in various cancers, aiding in targeted therapy selection.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- NTRK1/2/3 gene fusions are low-incidence oncogenic drivers across diverse tumor types.
- Tropomyosin receptor kinase (Trk) inhibitors show clinical promise for NTRK-driven cancers.
Purpose of the Study:
- To develop a novel positron emission tomography (PET) radiotracer for imaging Trk fusions.
- To evaluate the preclinical characteristics of the developed radiotracer, [18F]QMICF.
Main Methods:
- Design and synthesis of a quinazoline-based type-II pan-Trk radiotracer, [18F]QMICF ([18F]-(R)-9).
- Evaluation of nanomolar potencies for TrkA/B/C and TrkA fusions.
- Assessment of kinase selectivity profile, including FLT3.
Main Results:
- [18F]QMICF demonstrated nanomolar potencies against TrkA/B/C (IC50=85-650nM) and TrkA-TPM3 fusions (IC50=162nM).
- The synthesized compound (R)-9 exhibited favorable selectivity over FLT3 (>37-fold for TrkB/C).
- Radiosynthesis precursor was obtained in 36% overall yield over six steps.
Conclusions:
- [18F]QMICF is a promising quinazoline-based radiotracer for in vivo imaging of Trk fusions.
- The tracer's development supports its further investigation for clinical applications in NTRK-driven cancers.
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