Development and characterization of a novel TDP-43 positron emission tomography tracer: [¹⁸F]JNJ-TDP43-1

Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (K_d = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

[¹⁸F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.