Copper(I)-mediated ¹¹C-carboxylation of (hetero)arylstannanes: radiosynthesis of [¹¹C]bexarotene.

Objectives: [¹¹C]CO₂ fixation strategies have recently been applied for the synthesis of ¹¹C-carbonylated radiopharmaceuticals. Whereas ¹¹C-carbamates have been translated for human PET studies, the syntheses of ¹¹C-carboxylic acids via [¹¹C]CO₂ fixation has proven to be challenging. A novel copper-mediated carboxylation strategy of aryl- and heteroaryl-stannanes is described as a mild (i.e. 1 atm) carboxylation method using CO₂ and is transferable for carbon-11 labeled aromatic and heteroaromatic carboxylic acids using [¹¹C]CO₂. The methodology was applied to the radiosynthesis of a retinoid X receptor (RXR) agonist, [¹¹C]bexarotene.

Methods: Feasibility of the carboxylation reaction was first tested by reactions in a sealed vessel under an atmosphere of CO₂. Translation of the method for [¹¹C]CO₂ involved varying the reaction temperature, solvent, Cu(I) source, and base, using PhSnBu₃ as precursor. The preparation of [¹¹C]benzoic acid was optimized as follows: temperature: 100 °C; time: 5 minutes; solvent: DMF (600 μL); [PhSnBu₃] = 0.1 M; [CuTC] = 9.4 mM; and [TMEDA] = 1.3 M. Substrate scope was evaluated using tributyltin compounds substituted by para-substituted benzene derivatives (pMe, pMeO, pCl, and pCF₃), followed by compounds substituted with 2-furan, 2-thienyl, and N-heteroarenes (3-pyridyl, 2-pyrazyl, 2-pyrimidyl and 5-pyrimidyl). The new carboxylation method was applied in the fully automated radiosynthesis of [¹¹C]bexarotene using the TracerMaker (Scansys Laboratorieteknik, Denmark) synthesis module.

Results: [¹¹C]Benzoic acid was isolated in a decay-corrected RCY of 45% relative to starting [¹¹C]CO₂, with molar activity A_m = 9.3 GBq/µmol (250 mCi/µmol), and radiochemical purity >99%, in 29 min. Decay-corrected radiochemical yields (RCYs) of ca. 30-70% were obtained with arylstannanes (PhSnBu₃ and its corresponding pMe, pMeO and pCF₃ substituted derivatives). Formation of ¹¹C-carboxylic acids bearing 3-pyridyl, and 2-pyrazyl groups were successfully generated with RCYs between 32-34%, while yields for the transfer of electron-rich heteroarenes 2-furyl and 2-thienyl were generally lower (<3%). [¹¹C]Bexarotene was synthesized and formulated in a decay-corrected RCY of 32 ± 5% (n = 3), relative to starting [¹¹C]CO₂, with molar activity A_m = 38 ± 23 GBq/μmol (1.0 ± 0.6 Ci/μmol) and radiochemical purities >95% in 41 ± 4 minutes from EOB. Isolated formulations (10% ethanol/90% saline v/v) from scaled up reactions contained up to 5.74 GBq (155 mCi) of activity and high molar activity (A_m = 63 GBq/μmol; 1.7 Ci/μmol).

Conclusions: We have developed a novel copper-mediated carboxylation methodology for the preparation of (hetero)aryl carboxylic acids from organostannanes using a stoichiometric quantity of CO₂ under atmospheric pressure, as well as sub-stoichiometric quantities of [¹¹C]CO₂. The successful radiosynthesis, purification, and formulation of [¹¹C]bexarotene, using a fully automated commercial synthesis module, demonstrates feasibility of ¹¹C-carboxylation reactions in radiopharmaceutical production.

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