Abstract
BackgroundThe 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-[18F]fluoropropyl)sulfonyl)propoxy-derivative of the high-affinity FFA-1 agonist TAK-875 ([18F]7) was reported. Here we describe the preparation of this tracer in high molar activity using a purification method permitting separation of [18F]7 from a structurally-related by-product and evaluation of the tracer in rats as a potential FFA-1 PET imaging agent.ResultsThe 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 [18F]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 [18F]7 in high molar activity. A strong anion-exchange resin was used to reformulate [18F]7 in high concentration. Starting from 96 to 311 GBq of [18F]fluoride, 3.8–15.4 GBq of pure [18F]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.ConclusionsAnalysis 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 [18F]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 tracers should focus on reducing non-specific binding in the pancreatic tissue.
Highlights
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
To produce the non-radioactive standard 7, the compound 4 was treated with Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) followed by base-mediated ester hydrolysis, as described before (Bertrand et al 2016b)
The radiosynthesis of [18F]7 was performed with an automated one-pot, two-step procedure. [18F]fluoride nucleophilic displacement of the tosylate leaving group was followed by base-mediated hydrolysis of the methyl ester (Scheme 2)
Summary
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. Insulin-secreting β-cells are localized in small (20 to 600 μM in diameter) clusters of endocrine cells called the islets of Langerhans, which are dispersed throughout the pancreas and account for only 1 to 2% of the total pancreatic mass (Ionescu-Tirgoviste et al, 2015). The size of this anatomical structure and its placement deep within the body restricts potential imaging modalities to those with high sensitivity, spatial resolution, and penetration depth. Nuclear molecular imaging using techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) hold the most promise
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