The growing impact of bioorthogonal click chemistry on the development of radiopharmaceuticals

Abstract

Click chemistry has become a ubiquitous chemical tool with applications in nearly all areas of modern chemistry, including drug discovery, bioconjugation, and nanoscience. Radiochemistry is no exception, as the canonical Cu(I)-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, inverse electron demand Diels-Alder reaction, and other types of bioorthogonal click ligations have had a significant impact on the synthesis and development of radiopharmaceuticals. This review will focus on recent applications of click chemistry ligations in the preparation of imaging agents for SPECT and PET, including small molecules, peptides, and proteins labeled with radionuclides such as (18)F, (64)Cu, (111)In, and (99m)Tc.

Keywords: click chemistry; radiochemistry.

Figure 1

Synthetic schemes of click reactions: (A) CuAAC; (B) SPAAC; (C) Diels-Alder reaction; (D) Staudinger ligation; (E) Two variations on the ‘click-to-chelate’ radiolabeling methodology using CuAAC and ^99mTc(CO)₃

Figure 2

(A) Synthesis of ¹⁸F-RGD-K5; (B) Decay-corrected anterior maximum- intensity PET projections of a female volunteer injected with ¹⁸F-RGD- K5.

Figure 3

(A) The synthetic route to ¹⁸F-transcyclooctene; (B) the synthesis of the PARP-1 inhibitor ¹⁸F-AAZD2281 using inverse electron-demand Diels-Alder click chemistry; (C) schematic for a methodology for pretargeted ⁶⁴Cu-immunoPET imaging agent based on inverse electron Diels-Alder click chemistry.