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.2023 Apr 21;14(5):636-644.
doi: 10.1021/acsmedchemlett.3c00057. eCollection 2023 May 11.

Modular One-Pot Strategy for the Synthesis of Heterobivalent Tracers

Affiliations

Modular One-Pot Strategy for the Synthesis of Heterobivalent Tracers

Thibaud Bailly et al. ACS Med Chem Lett..

Abstract

Bivalent ligands, i.e., molecules having two ligands covalently connected by a linker, have been gathering attention since the first description of their pharmacological potential in the early 80s. However, their synthesis, particularly of labeled heterobivalent ligands, can still be cumbersome and time-consuming. We herein report a straightforward procedure for the modular synthesis of labeled heterobivalent ligands (HBLs) using dual reactive 3,6-dichloro-1,2,4,5-tetrazine as a starting material and suitable partners for sequential SNAr and inverse electron-demand Diels-Alder (IEDDA) reactions. This assembly method conducted in a stepwise or in a sequential one-pot manner provides quick access to multiple HBLs. A conjugate combining ligands toward the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPR) was radiolabeled, and its biological activity was assessedin vitro andin vivo (receptor binding affinity, biodistribution, imaging) as an illustration that the assembly methodology preserves the tumor targeting properties of the ligands.

© 2023 American Chemical Society.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
General principleof the synthesis of heterobivalent ligands usingdichloro-s-tetrazine.
Figure 2
Figure 2
Structures of targeting moieties1,2, and3.
Figure 3
Figure 3
Structures of different spacers used in the synthesis.
Scheme 1
Scheme 1. Synthetic Reactions Used for the Preparation of Thiol- and Amino-Functionalized CXCR4, GRPR, and PSMA Ligands
Scheme 2
Scheme 2. General Synthetic Route toward HBL-Based Imaging Agents
Overall yields (withintermediatepurifications of13 and14) are indicatedin parentheses. TFA was used to deprotect compounds18,19,21, and22, whereasFA was preferred for compound20.
Figure 4
Figure 4
Representative chromatogramsof the crude mixture at differentsteps of the one-pot synthesis of18. (a) Chromatogramof9, (b) chromatogram of the crude mixture of the reactionof9 with dichlorotetrazine to provide13, (c) chromatogram of the crude mixture of13 aftera 2.5 h reaction with7 to yield15, (d)chromatogram of the one-pot synthesis of15 after a 20h reaction with BCN-NODAGA, (e) chromatogram of18 afterfinal purification. Vertical axis represents relative absorbance at260 nm with the exception of (a), which was recorded at 214 nm dueto the lack of absorbance of9 at 260 nm. SeeSupporting Information for detailed informationon the gradient and analytical system.
Figure 5
Figure 5
(A)The images show the maximum intensity projections recordedbetween 50 and 70 min p.i. of [68Ga]Ga-AMBA (A, left); [68Ga]Ga-PSMA11 (A, middle);and [68Ga]Ga-18 (A, right). (B) The imagesshow the axial images VOI analysis around both PC3 and 22Rv1 tumors,and the heart as a blood pool background. Signal seen on the headsof the mice is due to retro-orbital injection.
Figure 6
Figure 6
Biodistribution of [68Ga]Ga-18 at 2 h p.i.in nude mice xenografted with PC3 and 22Rv1 cells. Data points showmean ± SEMn = 2–5; for values of allcollected tissues and tumor-to-tissue ratios, see theSupporting Information.
See this image and copyright information in PMC

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