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EJNMMI Research

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Open Access 01-12-2011 | Original research

Decreased defluorination using the novel beta-cell imaging agent [¹⁸F]FE-DTBZ-d4 in pigs examined by PET

Authors: Mahabuba Jahan, Olof Eriksson, Peter Johnström, Olle Korsgren, Anders Sundin, Lars Johansson, Christer Halldin

Published in: EJNMMI Research | Issue 1/2011

Abstract

Background

Fluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [¹⁸F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [¹⁸F]FE-DTBZ.

Methods

[¹⁸F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [¹⁸F]FE bromide ([¹⁸F]FCD₂CD₂Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling.

Results

[¹⁸F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (k _{defluorination} = 0.0016 ± 0.0007 min^-1) compared to the non-deuterated analogue (k _{defluorination} = 0.012 ± 0.002 min^-1), resulting in a six fold increase in half-life stability.

Conclusions

[¹⁸F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [¹⁸F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [¹⁸F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.

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Title: Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
Authors: Mahabuba Jahan
Olof Eriksson
Peter Johnström
Olle Korsgren
Anders Sundin
Lars Johansson
Christer Halldin
Publication date: 01-12-2011
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2011
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/2191-219X-1-33

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Decreased defluorination using the novel beta-cell imaging agent [¹⁸F]FE-DTBZ-d4 in pigs examined by PET

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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