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Review
, 24 (19)

Recent Advances in Bioorthogonal Click Chemistry for Efficient Synthesis of Radiotracers and Radiopharmaceuticals

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Review

Recent Advances in Bioorthogonal Click Chemistry for Efficient Synthesis of Radiotracers and Radiopharmaceuticals

Sajid Mushtaq et al. Molecules.

Abstract

In recent years, several catalyst-free site-specific reactions have been investigated for the efficient conjugation of biomolecules, nanomaterials, and living cells. Representative functional group pairs for these reactions include the following: (1) azide and cyclooctyne for strain-promoted cycloaddition reaction, (2) tetrazine and trans-alkene for inverse-electron-demand-Diels-Alder reaction, and (3) electrophilic heterocycles and cysteine for rapid condensation/addition reaction. Due to their excellent specificities and high reaction rates, these conjugation methods have been utilized for the labeling of radioisotopes (e.g., radiohalogens, radiometals) to various target molecules. The radiolabeled products prepared by these methods have been applied to preclinical research, such as in vivo molecular imaging, pharmacokinetic studies, and radiation therapy of cancer cells. In this review, we explain the basics of these chemical reactions and introduce their recent applications in the field of radiopharmacy and chemical biology. In addition, we discuss the significance, current challenges, and prospects of using bioorthogonal conjugation reactions.

Keywords: bioorthogonal reaction; click chemistry; molecular imaging; radioisotopes; radiolabeling; radiopharmaceuticals; site-specific reaction.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Selected bioorthogonal conjugation reactions. (1) Copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC); (2) strain-promoted azide-alkyne cycloaddition reaction (SPAAC); (3) tetrazine and trans-alkene substrates for inverse electron-demand-Diels–Alder reaction (IEDDA); (4) condensation reaction between 2-cyanobenzothiazole (CBT) and 1,2-aminothiol (N-terminal cysteine).
Figure 2
Figure 2
18F-radiolabeling of bombesin derivative using SPAAC: a) human plasma or dimethyl sulfoxide (DMSO), room temperature, 15 min. R = Pyr-Gln, Pyr = pyroglutamic acid, R1 = Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, RCY = radiochemical yield.
Figure 3
Figure 3
Radiolabeling of peptides or proteins using 18F-labeled ODIBO.
Figure 4
Figure 4
18F-radiolabeling of DBCO-modified cRGD dimer using 18F-labeled azide precursor and polystyrene-supported azide-modified resin for purification of unreacted substrate.
Figure 5
Figure 5
Radiolabeling of DBCO-conjugated cRGD peptide using 125I-labeled azide tracers.
Figure 6
Figure 6
Reaction of azide-conjugated Cetuximab antibody with DBCO-conjugated crossed bridged macrocyclic CB-TE1K1P chelator for 64Cu radiolabeling.
Figure 7
Figure 7
Preparation of 89Zr-labeled multifunctional nanoprobes using SPAAC ligation.
Figure 8
Figure 8
SPAAC for 99mTc-based radiolabeling of human serum protein.
Figure 9
Figure 9
Radiolabeling of tetrazine conjugated cRGD peptide using 18F-labeled TCO; a) DMSO, 10 s, room temperature.
Figure 10
Figure 10
IEDDA-mediated radiolabeling of trastuzumab.
Figure 11
Figure 11
IEDDA-mediated synthesis of 225Ac-labeled monoclonal antibody.
Figure 12
Figure 12
Synthesis of 68Ga-labeled microbubble using IEDDA.
Figure 13
Figure 13
General strategy for pre-targeted imaging and therapy using IEDDA.
Figure 14
Figure 14
A modified strategy using tetrazine-bearing clearing agent.
Figure 15
Figure 15
Radiosynthesis of 18F-labeled TCO.
Figure 16
Figure 16
Two-step pre-targeting strategy using 18F-labeled TCO.
Figure 17
Figure 17
11C-labeled tetrazine tracers for in vivo IEDDA reaction, (a) from ref [111], (b) from ref [112].
Figure 18
Figure 18
Pre-targeted IEDDA ligation between TCO-bisphosphonate and radiolabeled tetrazine in bone tissue.
Figure 19
Figure 19
[3+2] cycloaddition reaction using 18F-labeled nitriloxides or N-hydroxyimidoyl chloride.
Figure 20
Figure 20
Radiolabeling of biomolecules using sulfo-click chemistry.
Figure 21
Figure 21
Radiolabeling of antibodies using photochemical conjugation reaction.

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