Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

Abstract

The tropomyosin receptor kinases family (TrkA, TrkB, and TrkC) supports neuronal growth, survival, and differentiation during development, adult life, and aging. TrkA/B/C downregulation is a prominent hallmark of various neurological disorders including Alzheimer’s disease (AD). Abnormally expressed or overexpressed full-length or oncogenic fusion TrkA/B/C proteins were shown to drive tumorigenesis in a variety of neurogenic and non-neurogenic human cancers and are currently the focus of intensive clinical research. Neurologic and oncologic studies of the spatiotemporal alterations in TrkA/B/C expression and density and the determination of target engagement of emerging antineoplastic clinical inhibitors in normal and diseased tissue are crucially needed but have remained largely unexplored due to the lack of suitable non-invasive probes. Here, we review the recent development of carbon-11- and fluorine-18-labeled positron emission tomography (PET) radioligands based on specifically designed small molecule kinase catalytic domain-binding inhibitors of TrkA/B/C. Basic developments in medicinal chemistry, radiolabeling and translational PET imaging in multiple species including humans are highlighted.

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

“…Promising advances in neuroimaging may be eventually used to identify patients who might be most responsive to a therapeutic regimen incorporating agonists to TrkA. For instance, Trk-targeted radiotracers for positron emission tomography imaging may reveal spatiotemporal changes in TrkA receptor expression level-an early molecular alteration in mild cognitive impairment (MCI) and AD correlated with cognitive impairment (54). Alternatively, radioligands designed to quantify and map in vivo degeneration of cholinergic terminals in AD patients could be used for clinical identification, as well as monitoring the efficacy of TrkA-based interventions (55).…”

On the Biological Importance, Preparation, and Uses of Imidazo[1,2-b]pyridazine-Based Compounds

“…IMP is reported to be an inhibitor including, but not limited to, for the following enzymes: Break point cluster-Abelson (BCL-ABL) kinase (2), vascular endothelial growth factor (VEGF) Receptor 2 kinase (3), tumor necrosis factor alpha (4), Bruton's tyrosine kinase (BTK) (5), ATP-competitive mTOR (mammalian target of rapamycin) (6), PDE 10A (7), activin receptor-like kinase 2 (8), Pim kinase (9), deathassociated protein kinase (DAPK) (10), glycogen synthase kinase-3 (11), fibroblast growth factor receptor 1 (FGFR1) (12), dengue fever (13), tyrosine kinase 2 (2), and calcium-dependent protein kinase 1 (14). It has also been reported as an ingredient of anticancer drugs (15), antiparasitic (16), and antiproliferative agents (17), and used as radioligands for tropomyosin receptor kinase family (18). The review article also sheds light on the synthetic works, such as arene C-H functionalization (19), addition of osmium carbynes to conjugated systems (20), C-H silylation of IMP (21), photoelectrochemical C-H alkylation (22), photoinduced oxidative activation (23), ceric ammonium nitrate (CAN) oxidation (24), also bromination agents originating from IMP (25).…”

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

“…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 .…”

“…Recently, several positron emission tomography (PET) tracers based on type-I TrkB/C inhibitors have been developed and evaluated in preclinical and clinical settings. 8 In particular, [ 11 C]IPMICF16 9 and [ 18 F] TRACK 10 ( Figure 1A) were the first type-I TKI-based PET tracers used for endogenous kinase neuroimaging in nonhuman primates and humans. 11 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) 12 ( Figure 1B).…”