Dataset Information

Imaging adipose tissue browning using the TSPO-18kDa tracer [¹⁸F]FEPPA.

ABSTRACT:

Objectives

The browning of white adipose tissue (WAT) into beige has been proposed as a strategy to enhance energy expenditure to combat the growing epidemic of obesity. Research into browning strategies are hampered by the lack of sensitive, translatable, imaging tools capable of detecting beige fat mass non-invasively. [¹⁸F]FDG is able to detect activated beige fat but provides little information on unstimulated beige fat mass. We have assessed the use of [¹⁸F]FEPPA, a tracer for the TSPO-18KDa found on the outer mitochondrial membrane, as an alternative imaging agent capable of detecting unstimulated brown fat (BAT) and beige fat.

Methods

Female Balb/c mice (n = 5) were treated for 7 days with the ?3 adrenergic agonist CL-316,243 to induce the browning of inguinal WAT (beige fat). Animals were imaged longitudinally with [¹⁸F]FDG and [¹⁸F]FEPPA and uptake in interscapular BAT and inguinal WAT assessed. The browning of inguinal WAT was confirmed using H&E and immunohistochemical detection of UCP-1 and TSPO.

Results

Repeated dosing with ?3-adrenergic agonist CL-316,243 caused a significant increase in [¹⁸F]FDG uptake in both interscapular BAT and inguinal WAT associated with the increased metabolic activity of brown and beige adipocytes respectively. [¹⁸F]FEPPA uptake was likewise increased in inguinal WAT but showed no increase in BAT uptake due to stimulation over the same time course. Furthermore, inguinal WAT uptake was unaffected by pharmacological blockade, indicating that [¹⁸F]FEPPA uptake is associated with the expression of mitochondria in BAT and beige adipocytes and independent of activation.

Conclusion

These data show that [¹⁸F]FEPPA can detect BAT and newly formed beige fat under non-stimulated, thermoneutral conditions and that uptake after stimulation is linked to mitochondrial expression as opposed to activation.

SUBMITTER: Hartimath SV

PROVIDER: S-EPMC6601022 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Imaging adipose tissue browning using the TSPO-18kDa tracer [<sup>18</sup>F]FEPPA.

Hartimath S V SV Khanapur S S Boominathan R R Jiang L L Cheng P P Yong F F FF Tan P W PW Robins E G EG Goggi J L JL

Molecular metabolism 20190506

<h4>Objectives</h4>The browning of white adipose tissue (WAT) into beige has been proposed as a strategy to enhance energy expenditure to combat the growing epidemic of obesity. Research into browning strategies are hampered by the lack of sensitive, translatable, imaging tools capable of detecting beige fat mass non-invasively. [<sup>18</sup>F]FDG is able to detect activated beige fat but provides little information on unstimulated beige fat mass. We have assessed the use of [<sup>18</sup>F]FEP ...[more]

PMID: 31105057

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Project description:BackgroundExpression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1β, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain.ResultsThe fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1β and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice.ConclusionsBased on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.

Project description:PurposePositron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.ProceduresVUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D 1H-15N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [18F]VUIIS1009A and [18F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [18F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.ResultsBoth VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC50 values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [18F]VUIIS1009A and [18F]VUIIS1009B exhibited greater binding potential (k 3/k 4)in tumor tissue compared to [18F]DPA-714. Interestingly, [18F]VUIIS1009B exhibited significantly greater tumor uptake (V T) than [18F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.ConclusionsThe novel PET ligand [18F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [18F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [18F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

Dataset Information

Imaging adipose tissue browning using the TSPO-18kDa tracer [¹⁸F]FEPPA.

Objectives

Methods

Results

Conclusion

Publications

Imaging adipose tissue browning using the TSPO-18kDa tracer [<sup>18</sup>F]FEPPA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Imaging adipose tissue browning using the TSPO-18kDa tracer [18F]FEPPA.

Objectives

Methods

Results

Conclusion

Publications

Imaging adipose tissue browning using the TSPO-18kDa tracer [<sup>18</sup>F]FEPPA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Imaging adipose tissue browning using the TSPO-18kDa tracer [¹⁸F]FEPPA.