Photocatalytic [¹¹C]CO₂ Fixation for Synthesis of α-Hydroxy ¹¹C-Carboxylic Acids

Abstract

Rapid synthesis is essential for carbon-11, a routinely used radioactive isotope with a physical half-life of 20.4 minutes. Typically, cyclotron production delivers the isotope as [¹¹C]CO₂ or [¹¹C]CH₄, which can be converted to secondary carbon-11 precursors ([¹¹C]CN, [¹¹C]CH₃I, etc.), although the transformations lead to loss of activity yields. Hence, direct fixation of [¹¹C]CO₂ into complex molecules is appealing for operational simplicity and time efficiency.

Photocatalysis unlocks rapid reactivity under mild conditions. Our lab has developed photocatalytic methods to prepare ¹¹C-amino acids and ¹¹C-phenylacetic acids from [¹¹C]CO₂. These functional groups are found in biochemicals and drug molecules, opening synthetic routes to novel radiopharmaceuticals.

We have developed a photocatalytic method to prepare ⍺-hydroxy ¹¹C-carboxylic acids, a functionality found in various metabolites and neuroactive drugs. This method leverages readily available ketone substrates as precursors for radiolabelling with [¹¹C]CO₂, assisted by an iridium-based photocatalyst. We have employed experimental design using Bayesian optimisation to improve the radiochemical yields of ¹¹C-⍺-hydroxy acids. Furthermore, we have developed conditions that efficiently extract [¹¹C]CO₂ into the reaction medium independent of the substrate structure, which overcomes a shortcoming of previously reported methods.

Subsequently, we have prepared a scope of ¹¹C-⍺-hydroxy acids to demonstrate the method’s versatility. Since characterization of ¹¹C-⍺-hydroxy acids requires their non-radioactive standards, we developed a metal-free photocatalysed synthesis of ⍺-hydroxy acids with stable CO₂. We were able to synthesize all requisite non-radioactive standards and, in the process, demonstrated the breadth of the metal-free method.