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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

ABSTRACT: While [¹⁸F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of 'off-target' [¹⁸F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [¹⁸F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson's disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [¹⁸F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [¹⁸F]-AV-1451 binding between Parkinson's disease and controls. Substantia nigra [¹⁸F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society-Unified Parkinson's Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson's disease groups. Despite the reduction of substantia nigra [¹⁸F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [¹⁸F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson's disease. Further investigations in longitudinal cohorts are warranted.

SUBMITTER: Mak E

PROVIDER: S-EPMC8410984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuromelanin 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.Results18F-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.Conclusion18F-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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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

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[18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.