Neuromelanin-targeted 18 F-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 imaging-base biomarker for neurological diseases. We previously developed a melanin-specific probe N-(2-(diethylamino)-ethyl)-¹⁸F-5-fluoropicolinamide (¹⁸F-P3BZA), which was initially developed for the imaging of melanoma. ¹⁸F-P3BZA exhibited high levels of binding to the melanin in vitro and in vivo with high retention and favorable pharmacokinetics. In this study we further 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 readily crossed the blood-brain barrier with brain transport coefficients (Kin) of 40 ± 8 µL g-1s-1. ¹⁸F-P3BZA accumulated specifically in neuromelanotic PC12 cells, melanin-rich melanoma cells, and melanoma xenografts. Binding of ¹⁸F-P3BZA to B16F10 cells was much higher than to SKOV3 cells at 60 min (6.17 ± 0.53%IA and 0.24 ± 0.05%IA, respectively). In the biodistribution study, ¹⁸F-P3BZA had higher accumulation in B16F10 tumors (6.31 ± 0.99%IA/g) than in SKOV3 tumors (0.25 ± 0.09%IA/g). Meanwhile, ¹⁸F-P3BZA uptake in B16F10 tumors could be blocked by excess cold ¹⁹F-P3BZA (0.81 ± 0.02%IA/g, 88% inhibition, p < 0.05). PET/MRI ¹⁸F-P3BZA provided clear visualization of neuromelanin-rich SN at 30-60 min after injection in healthy macaques. The SN to cerebella ratios were 2.7 and 2.4 times higher at 30 and 60 min after injection. 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 early diagnosis of neurological diseases associated with abnormal neuromelanin expression.