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

IF 3.1 3区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

EJNMMI Research Pub Date : 2024-09-03 DOI:10.1186/s13550-024-01136-z

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

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引用次数: 0

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.

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猕猴黑质的神经黑素靶向 18 F-P3BZA PET/MR 成像。

背景：神经褐蛋白主要位于黑质（SN）的多巴胺能神经元中，可通过磁共振成像（MRI）检测到。它是一种很有前景的神经系统疾病成像基础生物标记物。我们之前开发了一种黑色素特异性探针 N-(2-(二乙基氨基)-乙基)-18F-5-氟吡啶戈啉酰胺（18F-P3BZA），该探针最初是为黑色素瘤成像而开发的。18F-P3BZA 在体外和体内都能与黑色素高度结合，并具有高保留率和良好的药代动力学特性。本研究进一步探讨了 18F-P3BZA 是否可用于定量检测健康猕猴鼻窦中的神经黑色素：18F-P3BZA 表现出理想的疏水性，估计对数 Know 为 5.08，对数 D7.4 为 1.68。18F-P3BZA 很容易通过血脑屏障，脑转运系数 (Kin) 为 40 ± 8 µL g-1s-1。18F-P3BZA 在神经黑色素 PC12 细胞、富含黑色素的黑色素瘤细胞和黑色素瘤异种移植物中特异性蓄积。在 60 分钟内，18F-P3BZA 与 B16F10 细胞的结合率（6.17 ± 0.53%IA 和 0.24 ± 0.05%IA ）远高于与 SKOV3 细胞的结合率（6.17 ± 0.53%IA 和 0.24 ± 0.05%IA ）。在生物分布研究中，18F-P3BZA 在 B16F10 肿瘤中的蓄积量（6.31 ± 0.99%IA/g）高于在 SKOV3 肿瘤中的蓄积量（0.25 ± 0.09%IA/g）。同时，过量的冷 19F-P3BZA 可以阻断 B16F10 肿瘤对 18F-P3BZA 的摄取（0.81 ± 0.02%IA/g, 抑制率为 88%）。注射后 30 分钟和 60 分钟，SN 与小脑的比率分别为 2.7 倍和 2.4 倍。结论：18F-P3BZA PET/MRI 能清晰显示神经络氨酸在神经元SN中的图像，有助于早期诊断与神经络氨酸表达异常相关的神经系统疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-

CiteScore

5.90

自引率

3.10%

发文量

审稿时长

13 weeks

期刊介绍： EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.