Neuromelanin-Targeted 18F-P3BZA PET/MR Imaging of the Substantia Nigra in Rhesus Macaques

Abstract

Background Neuromelanin is mostly located in dopaminergic neurons in the substantia nigra (SN) pars compacta, and can be detected by magnetic resonance imaging (MRI). It is a promising biomarker for Parkinson’s disease imaging. We previously developed N-(2-(diethylamino)-ethyl)-18F-5-fluoropicolinamide (18F-P3BZA) as a potential melanin-specific probe for detection of melanoma in living humans. In the current study we investigated whether 18F-P3BZA could be used to quantitatively detect neuromelanin in the SN in healthy rhesus macaques. Results 18F-P3BZA exhibited desired hydrophobicity with estimated log Know 5.08 and log D7.4 1.68. 18F-P3BZA accumulated specifically in neuromelanotic PC12 cells, melanin-rich melanoma cells, and melanoma xenografts. 18F-P3BZA readily crossed the blood-brain barrier with brain transport coefficients (Kin) of 40 ± 8 µL g-1s-1. PET/MRI 18F-P3BZA provided clear visualization of neuromelanin-rich SN at 30–60 min after injection in healthy macaques. In in vitro autoradiography studies 18F-P3BZA exhibited high levels of binding to the SN, and almost no binding to surrounding midbrain tissues. Conclusion 18F-P3BZA PET/MRI clearly images neuromelanin in the SN, and may assist in the diagnosis of neurological diseases associated with abnormal neuromelanin expression such as Parkinson’s disease.