Copper-mediated radiochemistry: historical impact, current trends, and future possibilities

Abstract

Modern approaches to copper-mediated radiolabeling have proven an important addition to the radiochemical toolbox. Radiopharmaceuticals prepared using this methodology have been translated from preclinical PET studies into clinical trials, and it has been adapted for radionuclides beyond fluorine-18, enabling theranostic applications. The methodology is also beginning to benefit from AI-assisted radiochemistry development. This perspective discusses the history, state-of-the-art, and potential future impact of copper-mediated radiochemistry on radiopharmaceutical development.

Keywords: Chemistry; Molecular imaging; Positron-emission tomography; Radionuclide imaging.

Fig. 1. Copper-mediated radiofluorination reactions.

A–D Early examples of the copper-mediated radiofluorination reactions with various aryl precursors. E The proposed general mechanism of the copper-mediated radiofluorination of organoboron and tin reagents is analogous to the Chan-Lam coupling reaction.

Fig. 2. New developments in copper-mediated radiolabeling.

A Improved copper-mediators and solvents for CMRF. B The directed (DG: Directing Group) radiofluorination of aryl halides with a Cu-N-Heterocycle-carbene (Cu-NHC). C Improved CMRF conditions for the suppression of protodeborylated byproduct formation. D Aminoquinoline-directed CMRF of aromatic C-H bonds. E The CMRF of aryl C-H bonds via the in-situ formation of aryl iodonium salts. F Selective Sequential Ir/Cu-mediated radiofluorination of Ar C-H bonds.

Fig. 3. Several compounds that rely on copper-mediated radiochemistry for their production are currently under clinical evaluation.

A Clinically Validated CMRF synthesis of [¹⁸F]FDOPA. B Clinically Validated CMRF synthesis of [¹⁸F]Flumazinil. C Initial human imaging experience with [¹⁸F]TRACK – brain PET (left, reproduced from ref. with permission^©. American Chemical Society) and whole-body dosimetry (right, reproduced from ref. under a CC BY 4.0 license). D Human imaging with [¹⁸F]-SynVesT-1 (Left, coregistered parametric VT images of representative baseline scan, 120-min PET data) and [¹⁸F]-SynVesT-2 (Right, summed SUV PET images of representative baseline scan, 40 to 60 min post-injection). Reproduced from refs. ^, with permission^©. SNMMI. E Clinical imaging with [¹¹C]LY2795050 prepared via Cu-mediated radiocyanation (representative bolus + infusion equilibrium ratio (EQR) images on two planes in a normal control (peak EQR = 2.8; EQR = distribution volume ratio, under equilibrium conditions). Parametric EQR images are calculated from the average of frames from 40 to 80 min post-injection, normalized by the value in cerebellar gray matter). Images reproduced from ref. with permission^©. American Chemical Society. F Nonhuman primate imaging with [¹¹C]CN-Nociceptin prepared via Cu-mediated radiocyanation (summed SUV PET images 20–60 min post-injection). Images reproduced from ref. with permission^©. American Chemical Society.

Fig. 4. The role of copper-mediated radiolabeling in pretargeting.

A Schematic for in vivo pretargeting. Recreated from ref. (using https://BioRender.com) with permission^©, SNMMI. B The rapid biorthogonal inverse-electron-demand Diels–Alder (click) reaction between trans-cyclooctene and an aryl tetrazine serves as the chemical basis for some in vivo pretargeting approaches. C Copper-mediated Radiofluorination was successfully employed to radiolabel methyl-phenyl-tetrazine. Adapted from ref. under a Creative Commons Attribution 3.0 Unported Licence.

Fig. 5. Copper-mediated radiolabeling with other radionuclides.

A The copper-mediated radioiodination and radioastination of radiotheranostic PARP inhibitors. B The coppermediated radiobromination of a variety of small-molecule radiotheranostic agents.

Fig. 6. High-throughput approaches for radiochemistry.

Systematic approaches to radiosynthesis optimization that combine designed data collection, high-throughput experimentation, and data science techniques will drastically accelerate radiopharmaceutical development timelines.