General Carbon Isotopic Labeling of Bioactive Carboxylic Acids Enabled by Organic Photoredox Catalysis

Introduction: The application of molecular imaging has greatly advanced personalized medicine and has generated a profound impact on patient care. In particular, positron emission tomography (PET) is among the most widely used modalities, often requiring isotopic labeling of bioactive molecules to generate the desired imaging probes. Unfortunately, radiochemistry is often the bottleneck in the development of novel agents due to complicated synthesis and incompatibility with complex molecules. Considering the wide presence of carboxylic acids in drug/bioactive molecules, we developed a general and simple method to perform ¹¹C-labeling through carboxylic acid groups via organic photoredox reactions.

Methods: In order to develop an applicable method to label carboxylic acids in high yields and molar activity, we considered to convert the carboxylic acids to a labeled carboxylic acid derivative, in this case, nitriles via photoredox catalysis. The labeled nitriles can be separated from unreacted carboxylic acid, leading to labeled agents with high molar activity. After generating a carbon centered radical, labeled nitriles were obtained under either copper catalyzed radical cyanation pathway or through the conversion into carbon cation in the presence of an oxidant, followed by cyanide anion addition. In the presence of a photoredox catalyst and chiral ligands, asymmetric radiolabeling was also explored.

Results: A broad spectrum of carboxylic acid substrate was found to undergo radiocyanation in moderate to high yield. This simple method could be expanded bioactive ligands containing carboxylic acid, including flurbiprofen, ursodeoxycholic acid and enoxolone. When a chiral ligand was used, good radio chemical yield and enantioselectivity was obtained, which would be interesting to directly produce chiral PET agents through labeling. The method also successfully generated ¹¹C-labeled amino acids and peptides after introducing an aqueous buffer as base and K₂S₂O₈ as oxidant. The corresponding ¹¹C-labeled amino acids and peptides were observed with moderate to excellent yields.

Conclusions: Through organic photoredox catalysis, we introduce a versatile approach for achieving comprehensive isotopic labeling of carboxylic acids, encompassing natural amino acids and peptides. Using this approach, we have successfully obtained ¹¹C-labeled carboxylic acids and derivatives from ¹²C-carboxylic acids with moderate to excellent yields. These radiolabeled carboxylic acids with high molar activity could potentially serve as clinically relevant PET tracers without altering their structure.

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