Dataset Information

Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue.

ABSTRACT:

Background

Brown adipose tissue research is in the focus in the field of endocrinology. We designed a dual-modal fluorescent/PET fatty acid based tracer on commercially available Bodipy-C16, which can be synthesized to its corresponding triglyceride and which combines the benefits of fluorescent and PET imaging.

Methods

Bodipy-C16 was coupled to 1,3-diolein resulting in Bodipy-triglyceride. Bodipy-C16 and Bodipy-triglyceride compounds were radiolabeled with 18F using an 18F/19F exchange reaction to yield a dual-modal imaging molecule. Uptake of radiolabeled and non-labeled Bodipy-C16 and Bodipy-triglyceride was analyzed by fluorescence imaging and radioactive uptake in cultured adipocytes derived from human brown adipose tissue and white adipose tissue.

Results

Bodipy-C16 and Bodipy-triglyceride were successfully radiolabeled and Bodipy-C16 showed high shelf life and blood plasma stability (99% from 0-4 h). The uptake of Bodipy-C16 increased over time in cultured adipocytes, which was further enhanced after beta-adrenergic stimulation with norepinephrine. The uptake of Bodipy-C16 was inhibited by oleic acid and CD36 inhibitor sulfosuccinimidyl-oleate. The poor solubility of Bodipy-triglyceride did not allow stability or in vitro experiments.

Conclusion

The new developed dual modal fatty acid based tracers Bodipy-C16 and Bodipy-triglyceride showed promising results to stimulate further in vivo evaluation and will help to understand brown adipose tissues role in whole body energy expenditure.

SUBMITTER: Paulus A

PROVIDER: S-EPMC5560730 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue.

Paulus Andreas A Maenen Marco M Drude Natascha N Nascimento Emmani B M EBM van Marken Lichtenbelt Wouter D WD Mottaghy Felix M FM Bauwens Matthias M

PloS one 20170817 8

<h4>Background</h4>Brown adipose tissue research is in the focus in the field of endocrinology. We designed a dual-modal fluorescent/PET fatty acid based tracer on commercially available Bodipy-C16, which can be synthesized to its corresponding triglyceride and which combines the benefits of fluorescent and PET imaging.<h4>Methods</h4>Bodipy-C16 was coupled to 1,3-diolein resulting in Bodipy-triglyceride. Bodipy-C16 and Bodipy-triglyceride compounds were radiolabeled with 18F using an 18F/19F ex ...[more]

PMID: 28817670

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Project description:IntroductionBrown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [18F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume.ObjectiveWe aimed to identify metabolites in serum that are associated with BAT volume and activity in men.MethodsWe assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7-26.6) years, BMI 22.1 (20.5-23.4) kg/m2) who subsequently underwent a cold-induced [18F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort.ResultsAfter correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (β= 116 (85-148) mL, R2 = 0.81, p = 4.6 × 10-7; β = 79 (93-119) mL, R2 = 0.57, p = 5.9 × 10-4 and β= 91 (40-141) mL, R2 = 0.52, p = 1.0 × 10-3, respectively) as well as with BAT activity (β= 0.20 (0.11-0.29) g/mL, R2 = 0.59, p = 1.9 × 10-4; β = 0.15 (0.06-0.23) g/mL, R2 = 0.47, p = 2.0 × 10-3 and β= 0.13 (0.01-0.25) g/mL, R2 = 0.28, p = 0.04, respectively). When tested in three independent replication cohorts (total n = 37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (β= 0.15 (0.07-0.23) g/mL, R2 = 0.08, p = 4.2 × 10-4).ConclusionsLysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant.

Project description:INTRODUCTION:Our previous work demonstrated that the 99mTc renal tracer, 99mTc(CO)3(FEDA) (99mTc-1), has a rapid clearance comparable in rats to that of 131I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99mTc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18F renal imaging agent, Re(CO)3([18F]FEDA) (18F-1). Our goal was to develop an efficient one-step method for the preparation of 18F-1 and to compare its pharmacokinetic properties with those of 131I-OIH in rats. METHODS:18F-1 was prepared by the nucleophilic 18F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites. RESULTS:18F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [18F]fluoride. CONCLUSIONS:18F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131I-OIH and high in vivo radiochemical stability. Not only is 18F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18F/99mTc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

Project description:BACKGROUND:Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected 18F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal 18F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity. METHODS:Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75?MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated. RESULTS:The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions. CONCLUSIONS:This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected 18F-FDG tracer dose can be reduced to approximately 19?MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4?mSv to 0.36?mSv.

Project description:BACKGROUND:Several studies have explored the role of human brown adipose tissue (BAT) in energy expenditure. However, the link between BAT and appetite regulation needs to be more rigorously examined. OBJECTIVES:We aimed to investigate the associations of BAT volume and 18F-fluordeoxyglucose (18F-FDG) uptake after a personalized cold exposure with energy intake and appetite-related sensations in young healthy humans. METHODS:A total of 102 young adults (65 women; age: 22.08 ± 2.17 y; BMI: 25.05 ± 4.93 kg/m 2) took part in this cross-sectional study. BAT volume, BAT 18F-FDG uptake, and skeletal muscle 18F-FDG uptake were assessed by means of static 18F-FDG positron-emission tomography and computed tomography scans after a 2-h personalized exposure to cold. Energy intake was estimated via an objectively measured ad libitum meal and three nonconsecutive 24-h dietary recalls. Appetite-related sensations (i.e., hunger and fullness) were recorded by visual analog scales before and after a standardized breakfast (energy content = 50% of basal metabolic rate) and the ad libitum meal. Body composition was assessed by a whole-body DXA scan. RESULTS:BAT volume and 18F-FDG uptake were not associated with quantified ad libitum energy intake (all P > 0.088), nor with habitual energy intake estimated from the 24-h dietary recalls (all P > 0.683). Lean mass was positively associated with both the energy intake from the ad libitum meal (β: 17.612, R2 = 0.213; P < 0.001) and the habitual energy intake (β: 16.052, R2 = 0.123; P = 0.001). Neither the interaction BAT volume × time elapsed after meal consumption nor that of BAT 18F-FDG uptake × time elapsed after meal consumption had any significant influence on appetite-related sensations after breakfast or after meal consumption (all P > 0.3). CONCLUSIONS:Neither BAT volume, nor BAT 18F-FDG uptake after cold stimulation, are related to appetite regulation in young adults. These results suggest BAT plays no important role in the regulation of energy intake in humans.This trial was registered at clinicaltrials.gov as NCT02365129.

Dataset Information

Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue.

Background

Methods

Results

Conclusion

Publications

Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue.

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