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Background <p>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)-<sup>18</sup>F-5-fluoropicolinamide (<sup>18</sup>F-P3BZA), which was initially developed for the imaging of melanoma. <sup>18</sup>F-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 <sup>18</sup>F-P3BZA could be used to quantitatively detect neuromelanin in the SN in healthy rhesus macaques.</p> Results <p><sup>18</sup>F-P3BZA exhibited desired hydrophobicity with estimated log K ow 5.08 and log D7.4 1.68. <sup>18</sup>F-P3BZA readily crossed the blood-brain barrier with brain transport coefficients (Kin) of 40 ± 8 µL g-1s-1. <sup>18</sup>F-P3BZA accumulated specifically in neuromelanotic PC12 cells, melanin-rich melanoma cells, and melanoma xenografts. <sup>18</sup>F-P3BZA binding was significantly higher in B16F10 cells vs. amelanotic SKOV3 cells (6.17 ± 0.53%IA vs. 0.24 ± 0.05%IA) and in pigmented PC12 cells vs. non-pigmented PC12 cells(7.09 ± 0.15%IA and 0.29 ± 0.05%IA).In the biodistribution study, <sup>18</sup>F-P3BZA had higher accumulation in B16F10 tumors (6.31 ± 0.99%IA/g) than in SKOV3 tumors (0.25 ± 0.09%IA/g). Meanwhile, <sup>18</sup>F-P3BZA uptake in B16F10 tumors could be blocked by excess cold <sup>19</sup>F-P3BZA (0.81 ± 0.02%IA/g, 88% inhibition, <i>p</i> &lt; 0.05). PET/MRI <sup>18</sup>F-P3BZA provided clear visualization of neuromelanin-rich SN at 30–60&#xa0;min after injection in healthy macaques. The SN to cerebella ratios were 2.7 and 2.4 times higher at 30 and 60&#xa0;min after injection. In vitro autoradiography studies <sup>18</sup>F-P3BZA exhibited high levels of binding to the SN of healthy human and almost no binding to the SN of Parkinson’s disease patient.</p> Conclusion <p><sup>18</sup>F-P3BZA PET/MRI clearly images neuromelanin in the SN, and may assist in the early diagnosis of neurological diseases associated with abnormal neuromelanin expression.</p>

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Neuromelanin-targeted 18F-P3BZA PET/MR imaging of the substantia nigra in rhesus macaques

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  • 发表日期：

    2025年11月24日

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  • Hongyan Feng,
  • Ning Tu,
  • Ke Wang,
  • Xiaowei Ma,
  • Zhentao Zhang,
  • Zhongchun Liu,
  • Zhen Cheng,
  • Lihong Bu

摘要

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 K ow 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. 18F-P3BZA binding was significantly higher in B16F10 cells vs. amelanotic SKOV3 cells (6.17 ± 0.53%IA vs. 0.24 ± 0.05%IA) and in pigmented PC12 cells vs. non-pigmented PC12 cells(7.09 ± 0.15%IA and 0.29 ± 0.05%IA).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 vitro autoradiography studies 18F-P3BZA exhibited high levels of binding to the SN of healthy human and almost no binding to the SN of Parkinson’s disease patient.

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.