In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass

Eriksson, Olof; Jahan, Mahabuba; Johnström, Peter; Korsgren, Olle; Sundín, Anders; Halldin, Christer; Johansson, Lars

doi:10.1016/j.nucmedbio.2009.12.004

Cited by 55 publications

(34 citation statements)

References 13 publications

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“…It is possible that, despite expressing tracer concentration in terms of BP, residual non-specific binding occurs [28,37]. However, a recent study in baboons showed that such nonspecific [ 18 F]FP-DTBZ binding was negligible in the pancreas [38].…”

Section: Results Of Clinical Trials With Radiotracers Vmat2mentioning

confidence: 99%

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In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

et al. 2016

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Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.

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Section: Results Of Clinical Trials With Radiotracers Vmat2mentioning

confidence: 99%

“…In that case, autoradiography in combination with immunohistochemistry would be needed to demonstrate specificity. Pig models of diabetes have shown conflicting results for [ 18 F]FP-DTBZ and labelled exendin-4, possibly because of model differences in pancreatic target expression [20,28].…”

Section: Preclinical Evaluation Of Beta-cell-selective Agentsmentioning

confidence: 99%

In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

et al. 2016

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“…Several analogues of DTBZ are currently being explored as putative positron-emission tomography [PET] tracers for the quantification of BCM, including [ 11 C]DTBZ [4-6], [ 18 F]fluoroethyl [FE]-DTBZ [7], and [ 18 F]FP-DTBZ [8-10]. Finding an ideal biomarker to quantify BCM is a big challenge as beta cells are low in abundance (1% to 2%) and dispersed all over the pancreas.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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BackgroundFluorine-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 (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 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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“…[ 11 C]-dihydrotetrabenazine (DTBZ) and the 18 F-labeled DTBZ analog FP-(+)-DTBZ have been shown to have high affinity for the type 2 vesicular acetylcholine transporter (VMAT2), which is expressed on the surface of rodent β-cells but appears to be entirely absent from pancreatic exocrine tissue (36–39). Unfortunately, primate models have shown very low pancreatic uptake of [ 11 C]-DTBZ, which suggests that the degree of VMAT2 expression is species dependent (40–42).…”

Section: Discussionmentioning

confidence: 99%

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

et al. 2017

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The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)–mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass.

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In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass

Cited by 55 publications

References 13 publications

In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

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

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

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