Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods are needed to accommodate the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions enable rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and radiolabeling precursors’ instability can limit the applications of CMRH approaches. Methods: A series of aryl-boronic acids were converted into their corresponding aryl-boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl-boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. General protocols for the preparation of ¹⁸F-labeled and ¹²³I-labeled arenes utilizing CMRH of these substrates were developed and applied. The radiochemical conversions (RCC) were determined by radio-(U)HPLC. Results: Both ArB(Epin)s and ArB(Ppin)s-based radiolabeling precursors were prepared in a one-step synthesis with chemical yields of 49–99%. Radiolabeling of the aryl-boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7–99% and 10–99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically relevant PET tracers. Conclusions: This approach enables the synthesis of stable radiolabeling precursors and thus provides increased versatility in the application of CMRH, thereby supporting the development of novel PET and SPECT radiotracers.

Clinically used imaging modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) are highly sensitive non-invasive imaging modalities utilized in combination with magnetic resonance imaging (MRI) or computed tomography (CT) for the diagnosis of a multitude of disorders. Efficient and robust radiolabeling methods are needed to accommodate for the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions have been reported for the rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and instability of corresponding radiolabeling precursors can limit the applications of CMRH radiolabeling approaches. In this work, a general protocol for the preparation of 18F-labeled and 123I-labeled arenes applying CMRH of stable aryl boronate substrates is reported. The method utilizes aryl boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. Both ArB(Epin)s and ArB(Ppin)s based radiolabeling precursors were prepared in a one-step synthesis from the corresponding aryl boronic acids with chemical yields of 49-99%. Radiolabeling of the aryl boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7-99% and 10-99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically-relevant PET tracers.