Kinetic modelling and evaluation of the TrkA/B/C radioligand [¹⁸F]TRACK in the pig brain

Tropomyosin receptor kinase B (TrkB) is a critical mediator of neuronal growth, survival, and synaptic plasticity, which is activated by the endogenous ligand, brain-derived neurotrophic factor (BDNF). TrkB has been implicated in a wide range of neurological conditions, including neurodegenerative, psychiatric, and proliferative disorders. Non-invasive imaging of TrkB using positron emission tomography (PET) has been pursued to enhance understanding of its role in disease and support therapeutic development. Here, we investigated the in vitro and in vivo properties of [¹⁸F]TRACK, a fluorine-18 labeled radioligand for TrkB, in pig brain and human glioblastoma tissue. Autoradiography revealed high specific binding of [¹⁸F]TRACK in both pig brain and glioblastoma biopsy samples, suggesting robust target engagement. In vivo PET imaging in pigs demonstrated moderate brain uptake (peak standardized uptake value of 1.2), widespread cortical distribution, and slow washout. Kinetic modelling favored the two-tissue compartment model (2TCM) for quantification. Despite high in vitro specificity, within-scan displacement with the TrkB antagonist ANA-12 failed to produce measurable changes in tracer binding, indicating a need for further validation of in vivo specificity. Moreover, both in vivo and in vitro, [¹⁸F]TRACK binding was consistently highest in the white matter. These findings encourage a continued search for novel molecular neuroimaging radioligands to image TrkB in disease models and humans.