Rapid incorporation of bromine-76 utilizing organotrifluoroborate precursors

Abstract

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Objectives: Organotrifluoroborates have proven to be versatile intermediates in organic synthesis. Interestingly, they are crystalline ionic solids that are stable to both air and water for extended periods, and they are readily prepared from the corresponding boronic acids. Yet, trifluoroborates salts have proven to be as chemically reactive as boronic acids in radioiodination reactions and are far simpler to remove from reaction mixtures due to their ionic nature. We evaluated the use of organotrifluoroborate reagents in the preparation of bromine-76 labeled aryl, vinyl, and alkynyl substrates.

Methods: NH₄⁷⁶Br was obtained from Washington University School of Medicine. All the reactions were carried out using dry solvents under an inert atmosphere. Analyses of the products was performed by reversed-phase HPLC. Identification of all radioactive products was confirmed by co-elution with the corresponding non radioactive bromide compound. The radiosynthesis of 1-[⁷⁶Br]bromo-2-phenylethyne is representative of the reaction sequence. NH₄⁷⁶Br was placed in a Wheaton vial containing the trifluoroborate precursor in 50% aqueous tetrahydrofuran. To this was added peracetic acid in methanol. The mixture stirred for 10 min at room temperature. The radiobrominated product was isolated by passing the mixture through two dry Sep-pak cartridges (one silica and one alumina) to remove ionic material using hexane. The radiochemical yield was 80% and radiochemical purity of the 1-[⁷⁶Br]bromo-2-phenylethyne was >98% .

Results: A number of bromine-76 labeled aryl, vinyl and alkynyl bromides were prepared from the corresponding trifluoroborate salts. Bromination of vinyl trifluoroborates was found to proceed with retention of configuration. The radiochemical purity of the products typically exceed 98% and the overall radiochemical yields were very good (70–90 %). It is noteworthy that these purities are achieved by simply passing the reaction mixture through two Sep-pak cartridges. The simple isolation procedure is a consequence of the fact that the trifluoroborate starting materials are ionic and the products are lipophilic.

Conclusions: A convenient, high yield radiobromination procedure for preparing bromine-76 labeled aryl, vinyl, and alkynyl bromides has been developed. Because of the stability of the precursor trifluoroborates, the procedure is well suited for nuclear medicine imaging applications.

Research Support (if any): DOE Grant No. DE-FG02-04ER63895; NCI Grant No. R24-CA86307; the Robert H. Cole Foundation.