Feng Hongyan, Tu Ning, Wang Ke, Ma Xiaowei, Zhang Zhentao, Liu Zhongchun, Cheng Zhen, Bu Lihong
PET-CT/MRI Center, Renmin Hospital of Wuhan University, 95Zhangzhidong Road, Wuchang District, Wuhan, 430060, Hubei, China.
Department of Nuclear Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
EJNMMI Res. 2024 Sep 3;14(1):79. doi: 10.1186/s13550-024-01136-z.
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)-F-5-fluoropicolinamide (F-P3BZA), which was initially developed for the imaging of melanoma. 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 F-P3BZA could be used to quantitatively detect neuromelanin in the SN in healthy rhesus macaques.
F-P3BZA exhibited desired hydrophobicity with estimated log Know 5.08 and log D7.4 1.68. F-P3BZA readily crossed the blood-brain barrier with brain transport coefficients (Kin) of 40 ± 8 µL g-1s-1. F-P3BZA accumulated specifically in neuromelanotic PC12 cells, melanin-rich melanoma cells, and melanoma xenografts. Binding of F-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, 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, F-P3BZA uptake in B16F10 tumors could be blocked by excess cold F-P3BZA (0.81 ± 0.02%IA/g, 88% inhibition, p < 0.05). PET/MRI F-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 F-P3BZA exhibited high levels of binding to the SN, and almost no binding to surrounding midbrain tissues.
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.
神经黑色素主要位于黑质致密部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用于神经系统疾病的影像学生物标志物。我们之前开发了一种黑色素特异性探针N-(2-(二乙氨基)-乙基)-F-5-氟吡啶甲酰胺（F-P3BZA），该探针最初是为黑色素瘤成像而开发的。F-P3BZA在体外和体内均表现出与黑色素的高结合水平，具有高滞留率和良好的药代动力学特性。在本研究中，我们进一步研究了F-P3BZA是否可用于定量检测健康恒河猴黑质中的神经黑色素。
F-P3BZA表现出所需的疏水性，估计log Kow为5.08，log D7.4为1.68。F-P3BZA能够轻易穿过血脑屏障，脑转运系数（Kin）为40±8 μL g-1s-1。F-P3BZA特异性地积聚在富含神经黑色素的PC12细胞、富含黑色素的黑色素瘤细胞和黑色素瘤异种移植瘤中。在60分钟时，F-P3BZA与B16F10细胞的结合远高于与SKOV3细胞的结合（分别为6.17±0.53%IA和0.24±0.05%IA）。在生物分布研究中，F-P3BZA在B16F10肿瘤中的积聚量（6.31±0.99%IA/g）高于SKOV3肿瘤（0.25±0.09%IA/g）。同时，过量的冷F-P3BZA可阻断F-P3BZA在B16F10肿瘤中的摄取（0.81±0.02%IA/g，抑制率88%，p<0.05）。在健康猕猴注射后30 - 60分钟，PET/MRI F-P3BZA能清晰显示富含神经黑色素的黑质。注射后30分钟和60分钟时，黑质与小脑的比值分别高出2.7倍和2.4倍。在体外放射自显影研究中，F-P3BZA与黑质表现出高结合水平，而与周围中脑组织几乎无结合。
F-P3BZA PET/MRI能清晰成像黑质中的神经黑色素，可能有助于早期诊断与神经黑色素表达异常相关的神经系统疾病。
