Identification of [¹⁸F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging

Abstract

Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first F-labeled optimized lead suitable for in vivo imaging of Trk, [F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads while displaying high on-target affinity and human kinome selectivity.

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

“…170 (Figure 18). 168,[178][179][180][181][182] These compounds demonstrated comparable activity and selectivity profiles to the unlabeled precursor. 180 Compound 16 displayed excellent TRK selectivity in a panel of brain and cancer relevant kinases and TRKspecific binding in vitro in rat brain and human neuroblastoma cryosections.…”

Efficient radiosynthesis and preclinical evaluation of [18F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

“…For the isolation of 18 F‐fluoride from the target [ 18 O]H 2 O, we applied the “minimalistic approach” originally reported by Zischler et al, which proved to be the most effective technique for the copper‐mediated synthesis of other 18 F‐labeled tracers in our hands . Briefly, [ 18 F]F − /H 2 O was passed through a Sep‐Pak Light QMA cartridge (46 mg, Waters) followed by anhydrous methanol (3 mL) to remove traces of water.…”

“…For the isolation of 18 reported by Zischler et al, 21 which proved to be the most effective technique for the copper-mediated synthesis of other 18 F-labeled tracers in our hands. 10 Briefly, [ 18 F]F − / H 2 O was passed through a Sep-Pak Light QMA cartridge (46 mg, Waters) followed by anhydrous methanol (3 mL) to remove traces of water. 18 F-fluoride was then eluted in the opposite direction with tetraethylammonium bicarbonate solution in methanol (450 μL, 1 mg/mL) followed by neat methanol (500 μL) into a reaction vial, and the solvent was removed at 90 C under vacuum and a sweep stream of argon.…”

“…Recently, several positron emission tomography (PET) tracers based on type‐I TrkB/C inhibitors have been developed and evaluated in preclinical and clinical settings . In particular, [ 11 C]IPMICF16 and [ 18 F]TRACK (Figure A) were the first type‐I TKI‐based PET tracers used for endogenous kinase neuroimaging in nonhuman primates and humans . Two putative selective tracers for in vivo imaging of CSF‐1R have been reported to date as attractive candidates for the PET imaging of microglial activation beyond translocator protein (TSPO) (Figure B).…”

A concise method for fully automated radiosyntheses of [18F]JNJ-46356479 and [18F]FITM via Cu-mediated 18F-fluorination of organoboranes

“…[4][5][6][7][8] Radiolabeling of (hetero)aryl uorides has improved signicantly, allowing incorporation of 18 F on precursors of aryliodonium salts, 9 aryliodonium ylides, 10 aryl-Pd/Ni complexes, 11,12 triarylsulfonium salts/diaryl sufoxides, 13,14 and aryl boronic acid/ ester/tin species. 15 Among these methods, the Cu-mediated 18 F-uorination of organoboranes has been used for the preparation of various radiopharmaceuticals under manual and automated settings, [16][17][18] including eight clinically relevant radioligands 19 and the recent publications on [ 18 F]TRACK, 20 a tropomyosin receptor kinase inhibitor, and [ 18 F]olaparib, 21 the poly(ADP-ribose) polymerase inhibitor (Fig. 1A).…”