Synthesis of GPR40 targeting <sup>3</sup>H‐ and <sup>18</sup>F‐probes towards selective beta cell imaging

Bertrand, Romain; Hamp, Isabel; Brönstrup, Mark; Weck, Remo; Lukacevic, Mario; Polyák, András; Roß, Tobias L.; Gotthardt, Martin; Plettenburg, Oliver; Derdau, Volker

doi:10.1002/jlcr.3412

Cited by 13 publications

(13 citation statements)

References 16 publications

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“…Therefore, targeting FFAR1 with selective synthetic agonists has received considerable attention as a potential treatment option for type 2 diabetes averting the risk of hypoglycemia associated with other insulin‐secreting pathways as observed for sulphonyl urea . Numerous novel synthetic FFAR1 agonists have been developed and FFAR1 targeting probes are considered also for functional ß‐cell imaging …”

Section: Introductionmentioning

confidence: 99%

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

Ackerson

Amberg

Atzrodt

et al. 2019

J Biochem & Molecular Tox

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For fasiglifam (TAK875) and its metabolites the substance‐specific mechanisms of liver toxicity were studied. Metabolism studies were run to identify a putatively reactive acyl glucuronide metabolite. In vitro cytotoxicity and caspase 3/7 activation were assessed in primary human and dog hepatocytes in 2D and 3D cell culture. Involvement of glutathione (GSH) detoxication system in mediating cytotoxicity was determined by assessing potentiation of cytotoxicity in a GSH depleted in vitro system. In addition, potential mitochondrial liabilities of the compounds were assessed in a whole‐cell mitochondrial functional assay. Fasiglifam showed moderate cytotoxicity in human primary hepatocytes in the classical 2D cytotoxicity assays and also in the complex 3D human liver microtissue (hLiMT) after short‐term treatment (24 hours or 48 hours) with TC50 values of 56 to 68 µM (adenosine triphosphate endpoint). The long‐term treatment for 14 days in the hLiMT resulted in a slight TC50 shift over time of 2.7/3.6 fold lower vs 24‐hour treatment indicating possibly a higher risk for cytotoxicity during long‐term treatment. Cellular GSH depletion and impairment of mitochondrial function by TAK875 and its metabolites evaluated by Seahorse assay could not be found being involved in DILI reported for TAK875. The acyl glucuronide metabolites of TAK875 have been finally identified to be the dominant reason for liver toxicity.

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Section: Introductionmentioning

confidence: 99%

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

Ackerson

Amberg

Atzrodt

et al. 2019

J Biochem & Molecular Tox

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“…(S)-methyl-2-(6-((2′,6′-dimethyl-4′-(3-((3-fluoropropyl)sulfonyl)propoxy)-[1,1′-biphenyl] 3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (6). Product 6 was prepared as described previously (Bertrand et al 2016b). 50% Deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride) in THF (37 mg, 0.166 mmol, 1.65 equiv.)…”

Section: Methodsmentioning

confidence: 99%

“…These new probes were used to track specific labeling of cells overexpressing the FFA-1 receptor. Later in 2016, while we were working on the same tracer, Bertrand and coworkers published the radiosynthesis of the ((3-[ 18 F]fluoropropyl)sulfonyl)propoxy-derivative of TAK-875 ( [ 18 F]7) in 16.7% ± 5.7% radiochemical yield (RCY) in low molar activity (≥0.6 GBq/μmol) (Bertrand et al 2016b). We report here a fully automated process to produce [ 18 F]7 , including optimized HPLC purification and reformulation conditions allowing for removal of the elimination by-product to obtain a high purity, high molar activity, and concentrated formulation of [ 18 F]7 for in vivo evaluation in rats.…”

Section: Introductionmentioning

confidence: 99%

A high molar activity 18F-labeled TAK-875 derivative for PET imaging of pancreatic β-cells

Dornan

Petrenyov

Simard

et al. 2018

EJNMMI radiopharm. chem.

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Background The free-fatty acid receptor-1 (FFA-1) is expressed by β -cells and is a promising target for molecular imaging of functional β -cell mass. Recently, the ((3-[ 18 F]fluoropropyl)sulfonyl)propoxy-derivative of the high-affinity FFA-1 agonist TAK-875 ( [ 18 F]7 ) was reported. Here we describe the preparation of this tracer in high molar activity using a purification method permitting separation of [ 18 F]7 from a structurally-related by-product and evaluation of the tracer in rats as a potential FFA-1 PET imaging agent. Results The radiotracer was produced by nucleophilic radio-fluorination of the tosylate precursor and deprotection of the methyl ester. Semi-preparative HPLC with a C18 column revealed that [ 18 F]7 co-eluted with a non-radioactive impurity. Mass spectrometry identified the impurity as the alkene-containing elimination by-product. A pentafluorophenyl-functionalized HPLC column was found to separate the two compounds and allowed for purification of [ 18 F]7 in high molar activity. A strong anion-exchange resin was used to reformulate [ 18 F]7 in high concentration. Starting from 96 to 311 GBq of [ 18 F]fluoride, 3.8–15.4 GBq of pure [ 18 F]7 (end of synthesis (EOS)) was prepared (RCY 8.3% ± 1.1% decay-corrected, n = 4) in high molar activity (166–767 GBq/μmol at EOS). This PET agent was evaluated in rats using dynamic microPET/CT imaging, ex vivo biodistribution, and radio-metabolite studies. MicroPET/CT exhibited high uptake of the tracer in the abdominal area. There was no measurable decrease of the PET signal in the pancreatic area in rats pre-treated with saturating doses (30 mg/kg) of TAK-875. Biodistribution studies corroborated the microPET/CT results. Radiometabolism analyses revealed high compound stability with only the parent molecule detected in the pancreas. Conclusions Analysis of the crude reaction mixture and identification of the elimination by-product allowed for the development of a fully automated process to prepare the TAK-875-derived PET agent [ 18 F]7 in high purity and high molar activity. Even though the radiotracer exhibited high in vivo stability, microPET/CT and biodistribution results confirmed recent reports demonstrating that lipophilic analogs of TAK-875 display a high degree of non-specific binding, masking any specific binding to FFA-1 in pancreatic β -cells. Future development of TAK-875-derived PET t...

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“…Due to this relatively high expression of FFAR1 in islets, Bertrand et al modified the scaffold of the FFAR1 agonist TAK875 and then conjugated the compound with different fluorophores, of which probe 16 conjugated with Alexa488 maintained its agonistic properties and enhanced insulin secretion in a glucose-stimulated manner [145]. The same group further labeled derivatives of TAK875 with 18 F and yielded good radiochemical results [146]. Although further studies assessing the in vivo efficacy of these probes in imaging β-cells are still needed, these initial results represented the first important steps toward successful β-cell imaging by targeting FFAR1.…”

Section: Ffar1 Targeting Probementioning

confidence: 99%

Molecular imaging of β-cells: diabetes and beyond

Wei

Lan

Luo

et al. 2019

Advanced Drug Delivery Reviews

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Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic βcells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual βcells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Imaging and Therapy of Diabetes: State of the Art".

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Synthesis of GPR40 targeting ³H‐ and ¹⁸F‐probes towards selective beta cell imaging

Cited by 13 publications

References 16 publications

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

A high molar activity 18F-labeled TAK-875 derivative for PET imaging of pancreatic β-cells

Molecular imaging of β-cells: diabetes and beyond

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Synthesis of GPR40 targeting 3H‐ and 18F‐probes towards selective beta cell imaging

Cited by 13 publications

References 16 publications

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

A high molar activity 18F-labeled TAK-875 derivative for PET imaging of pancreatic β-cells

Molecular imaging of β-cells: diabetes and beyond

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Synthesis of GPR40 targeting ³H‐ and ¹⁸F‐probes towards selective beta cell imaging