Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters

Goswami, Rajesh; Ponde, Datta E.; Kung, Mei Ping; Hou, Catherine; Kilbourn, M. R.; Kung, Hank F.

doi:10.1016/j.nucmedbio.2006.05.006

Cited by 74 publications

(67 citation statements)

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“…Optically pure 18 F-FP-DTBZ was prepared by an 18 F-fluoride displacement of the corresponding mesylate, and the product was purified by high-performance liquid chromatography as described previously (30,31). The radiochemical purity of 18 F-FP-(1)-DTBZ was greater than 95%, and the specific activity was 55,500-74,000 GBq (1,500-2,000 Ci)/mmol at the end of synthesis.…”

Section: Generalmentioning

confidence: 99%

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In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

et al. 2008

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Recent studies on gene expression of b-cell mass (BCM) in the pancreas showed that vesicular monoamine transporter 2 (VMAT2) is highly expressed in the BCM (mainly in the islets of Langerhans). Imaging pancreatic BCM may provide an important tool for understanding the relationship between loss of insulinsecreting b-cells and onset of diabetes mellitus. In this article, 9-fluoropropyl-(1)-dihydrotetrabenazine (FP-(1)-DTBZ), which is a VMAT2 imaging agent, was evaluated as a PET agent for estimating BCM in vivo. Methods: Organ biodistribution after an intravenous injection of 18 F-FP-(1)-DTBZ (active isomer) and 18 F-FP-(2)-DTBZ (inactive isomer) was evaluated in normal rats. The specificity of uptake of 18 F-FP-(1)-DTBZ was assessed by a pretreatment (3.8 mg of (1)-DTBZ per kilogram and 3.5 mg of FP-(1)-DTBZ per kilogram, intravenously, 5 min prior) or coadministration (2 mg of (1)-DTBZ per kilogram). PET studies were performed in normal rats. Results: The in vivo biodistribution of 18 F-FP-(1)-DTBZ in rats showed the highest uptake in the pancreas (5% dose/g at 30 min after injection), whereas 18 F-FP-(2)-DTBZ showed a very low pancreas uptake. Rats pretreated with FP-(1)-DTBZ displayed a 78% blockade of pancreas uptake. PET studies in normal rats demonstrated an avid pancreas uptake of 18 F-FP-(1)-DTBZ. Conclusion: The preliminary data obtained with 18 F-FP-(1)-DTBZ suggest that this fluorinated derivative of DTBZ shows good pancreas specificity and has the potential to be useful for quantitative measurement of VMAT2 binding sites reflecting BCM in the pancreas.

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Section: Generalmentioning

confidence: 99%

“…1), in rodents and nonhuman primates (30)(31)(32). It displayed excellent binding affinity (K i 5 0.11 nM) for VMAT2.…”

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In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

et al. 2008

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“…Multi-tracer PET imaging in a monkey model of PD induced by chronic MPTP treatment at a low dose shows progressive nigrostriatal dopaminergic neurodegeneration, and this results in a reduced storage capacity of VMAT2 and decreased uptake of [19] , suggesting that VMAT2 binding sites are AV-133) is a novel 18 F-labeled tetrabenazine derivative that selectively binds to VMAT2 with high affi nity [20,21] . [23] .…”

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confidence: 99%

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

et al. 2013

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The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson's disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[ 18 F] fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]AV-133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [ 18 F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These

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“…A novel 18 F-labeled tetrabenazine derivative, 18 F-(1)fluoropropyldihydrotetrabenazine ( 18 F-AV-133), that selectively binds with high affinity to VMAT2 has been developed to assess VMAT2 density in vivo with PET (11,12). To evaluate the utility of this novel tracer for assessing presynaptic neuronal integrity in PD, a PET study was performed to compare 18 F-AV-133 binding in PD patients and healthy controls (HCs).…”

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In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with ¹⁸F-AV-133

Okamura¹,

Villemagne²,

Drago³

et al. 2010

J Nucl Med

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PET provides a noninvasive means to evaluate the functional integrity of the presynaptic monoaminergic system in the living human brain. Methods: In this study, a novel 18 F-labeled tetrabenazine derivative, 18 F-(1)fluoropropyldihydrotetrabenazine ( 18 F-AV-133), was used for the noninvasive assessment of the vesicular monoamine transporters type 2 (VMAT2) in 17 Parkinson disease (PD) patients and 6 healthy controls. The binding potential (BP) of 18 F-AV-133 was calculated using Logan graphical analysis. Voxel-based and volume-of-interest-based analyses of BP images were performed to examine brain regional reductions in VMAT2 density in PD. Results: VMAT2 BP was decreased by 81% in the posterior putamen, 70% in the anterior putamen, and 48% in the caudate nucleus of PD patients. Voxelbased analysis demonstrated VMAT2 reductions in the striatum and mid brain of PD patients. Furthermore, VMAT2 BPs in the caudate nuclei significantly correlated with the clinical severity of PD. Conclusion: These findings indicate that the novel 18 Flabeled ligand 18 F-AV-133 can sensitively detect monoaminergic terminal reductions in PD patients. Studies with 18 F-AV-133 may allow the presymptomatic identification of individuals with disorders characterized by degeneration of dopaminergic nigrostriatal afferents.

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Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters

Cited by 74 publications

References 20 publications

In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with ¹⁸F-AV-133

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Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters

Cited by 74 publications

References 20 publications

In Vivo Imaging of β-Cell Mass in Rats Using 18F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

In Vivo Imaging of β-Cell Mass in Rats Using 18F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133

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In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with ¹⁸F-AV-133