RESUMO
Positron emission tomography (PET) studies of the monoamine neurotransmitter systems in the human brain employ a variety of radiotracers targeting the many receptors, transporters, and enzymes present in monoaminergic neurons. One of these is the vesicular monoamine transporter 2 (VMAT2), the protein responsible for the energy-dependent accumulation of monoamines into synaptic vesicles. The development of in vivo imaging radiotracers for VMAT2 is a story of starting with a well-characterized clinically used drug (tetrabenazine) which had a pharmacologically active metabolite: that metabolite that was in stepwise fashion refined and modified to provide both carbon-11 and fluorine-18 labeled VMAT2 radiotracers that are now used for human PET studies of neurodegenerative and psychiatric diseases. The design approach taken, which involved understanding the metabolism of the radiotracers and identification of the optimal ligand stereochemistry, are representative of important steps in the general concepts behind successful in vivo radiotracer design for brain imaging agents.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neuroimagem/métodos , Ensaio Radioligante/métodos , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Radioisótopos de Carbono/análise , Radioisótopos de Carbono/metabolismo , Radioisótopos de Flúor/análise , Radioisótopos de Flúor/metabolismo , Humanos , Tomografia por Emissão de Pósitrons/métodos , Proteínas Vesiculares de Transporte de Monoamina/análiseRESUMO
Recent experimental studies revealed that dopamine neuron dysfunction in chronic manganism may be due to a reduced capacity of dopamine release in the striatum. The findings imposed further difficulty in the differential diagnosis between manganism and IPD. We conducted a long-term clinical follow-up study of 4 manganism patients, applying a new tracer (18)F-9-fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) with positron emission tomography (PET). Twenty age-matched subjects including 4 manganism patients, 8 idiopathic Parkinson's disease (IPD) patients, and 8 healthy controls were enrolled for comparison. Volumes of interest of the bilateral putamen, caudate nuclei and occipital cortex as the reference region were delineated from individual magnetic resonance images. The clinical features of the manganism patients still progressed, with increased scores on the Unified Parkinson Disease Rating Scale. The (18)F-AV-133 uptake in the IPD patients decreased at the bilateral striatum, compared with the healthy controls. In the manganism patients, there was no decreased uptake of radioactivity involving the bilateral striatum, except Patient 4, who had a stroke with decreased uptake in the right posterior putamen. The (18)F-AV-133 PET finding reveals that nigrostriatum neurons are not degenerated in chronic manganism and can provide a useful neuroimage biomarker in the differential diagnosis.
Assuntos
Inibidores da Captação Adrenérgica/farmacocinética , Encéfalo/diagnóstico por imagem , Intoxicação por Manganês/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tetrabenazina/análogos & derivados , Idoso , Encéfalo/efeitos dos fármacos , Estudos de Casos e Controles , Dopamina/metabolismo , Feminino , Radioisótopos de Flúor/farmacocinética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Taiwan , Tetrabenazina/farmacocinética , Tomógrafos ComputadorizadosRESUMO
INTRODUCTION: 9-[(18)F]Fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the preparation of [(18)F]AV-133 and to make it more widely available, a simple and rapid purification method using solid-phase extraction (SPE) instead of high-pressure liquid chromatography (HPLC) was developed. The SPE method produced doses containing the non-radioactive pseudo-carrier 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [(18)F]AV-133 in the brains of mice. METHODS: The mice were injected with a bolus including [(18)F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amounts of AV-149 on [(18)F]AV-133 was evaluated by quantifying the brain distribution of radiolabelled tracer [(18)F]AV-133. The concentrations of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. RESULTS: The concentrations of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calculated ED50 value was 8.165mg/kg. The brain biodistribution and regional selectivity of [(18)F]AV-133 had no obvious differences at AV-149 doses lower than 0.1mg/kg. With increasing doses of AV-149, the brain biodistribution of [(18)F]AV-133 changed significantly. CONCLUSION: The results are important to further support that the improved radiolabelling procedure of [(18)F]AV-133 using an SPE method may be suitable for routine clinical application.
Assuntos
Encéfalo/metabolismo , Tetrabenazina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/farmacocinética , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Camundongos , Especificidade de Órgãos , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tetrabenazina/síntese química , Tetrabenazina/farmacocinética , Distribuição TecidualRESUMO
UNLABELLED: (99m)Tc-TRODAT-1 is the first clinical routine (99m)Tc radiopharmaceutical to evaluate dopamine neurons loss in Parkinson's disease (PD). (18)F-AV-133 is a novel PET radiotracer targeting the vesicular monoamine transporter type 2 (VMAT2) to detect monoaminergic terminal reduction in PD patients. The aim of this study is to compare both images in the same health control (HC) and PD subjects. METHODS: Eighteen subjects (8 HC and 10 PD) were recruited for (99m)Tc-TRODAT-1 SPECT, (18)F-AV-133 PET and MRI scans within two weeks. The SPECT images were performed at 4-h post-injection for 45 min, and the PET images were performed at 90 min post-injection for 10 min. Each PET and SPECT image was normalized into Montreal Neurological Institute template aided from individual MRI for comparison. For regional analysis, volume of interest (VOIs) of bilateral caudate nuclei, anterior, posterior putamen and occipital cortex (as reference region) were delineated from the normalized MRI. The specific uptake ratio (SUR) was calculated as (regional mean counts/reference mean counts-1). The nonparametric Mann-Whitney U test was used to evaluate the power of differentiating control from PD subjects for both image modalities. The correlations of the SURs to the clinical parameters were examined. For voxelwise analysis, two-sample t-test for group comparison between HC and PD was computed in both image modalities. RESULTS: The SURs of caudate nucleus and putamen correlated well between two image modalities (r = 0.81, p<0.001), and showed significant different between HC and PD subjects. Of note, the (18)F-AV-133 SUR displayed a better correlation to PD clinical laterality index as compared to (99m)Tc-TRODAT-1 (r = 0.73 vs. r = 0.33). Voxelwise analysis showed more lesions for PD subjects from (18)F-AV-133 image as compared to (99m)Tc-TRODAT-1 especially at the substantia nigra region. CONCLUSION: (18)F-AV-133 PET demonstrated similar performance in differentiation PD from control, and a better correlation to clinical characteristics than that of (99m)Tc-TRODAT-1 SPECT. (18)F-AV-133 PET also showed additional information in substantia nigra integrity in PD subjects by voxelwise analysis. Collectively, (18)F-AV-133 could be a promising and better tracer for clinical use to detect monoaminergic terminal reduction in PD patients.
Assuntos
Compostos de Organotecnécio , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tetrabenazina/análogos & derivados , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tropanos , Idoso , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-IdadeRESUMO
The early detection and monitoring of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, dementia with Lewy bodies and other dementias, and movement disorders, represent a significant unmet medical need. Tools for accurate and early differential diagnosis are necessary to determine the appropriate treatment for patients and to minimize inappropriate use of potentially harmful treatments. Such diagnostic imaging tools are expected to permit monitoring of disease progression and will thus accelerate testing and development of disease-modifying drugs. The new imaging tests may be useful as prognostic tools by identifying humans with neurodegenerative diseases before the clinical manifestations become evident.