Trk neurotrophin receptors mediate the survival, differentiation, axon and dendrite growth and maintenance of many neuronal populations in the central (CNS) and peripheral nervous system (PNS). Trks comprise three full-length family members, TrkA, TrkB and TrkC, which share structurally similar intracellular kinase and extracellular domains. Alterations in the expression or activity of TrkA and TrkB have been linked to many neurological and psychiatric disorders including Alzheimer’s disease (AD). We have designed two new ligands for Positron Emission Tomography (PET) that are cell-permeable and bind the intracellular domain of Trk and have the potential to be the first PET imaging agents to allow for the assessment of TrkB/C levels in live mammals and humans in a wide variety of neurological disorders. The discovery of [11C]-(R)-IPMICF16 and [18F]TRACK, first-in-class PET TrkB/C-targeting radiolabeled kinase inhibitor leads and their molecular imaging characterisation in four species including first-in-human PET imaging showcases the development of a new PET radiotracer from bench to bedside over a period of 7 years.
[11C]-(R)-IPMICF16 and [18F]TRACK are able to cross the blood-brain barrier (BBB) and selectively bind to TrkB/C receptors in vivo, as proven by blocking studies in mice. The brain distribution of [11C]-(R)-IPMICF16 and [18F]TRACK was found to be similar in rhesus-monkeys and humans. TrkB/C-specific binding in human brain tissue was observed in vitro, with characteristic reduction in the hippocampus of AD compared to healthy brains. The accumulated preclinical and clinical data show that [11C]-(R)-IPMICF16 and [18F]TRACK are promising leads to assess neurotrophin receptors in vivo non-invasively with PET providing a strong basis for any future efforts to study Trk receptor interactions in neurological diseases. Extensive structural optimisation and molecular modeling was necessary to finally obtain these first lead compounds for Trk neuroimaging with PET illustrating the pivotal role of organic/medicinal chemistry in the development of a molecular imaging probe.