Synthesis of ¹⁸F-labeled neurotensin(8-13) via copper-mediated 1,3-dipolar [3+2]cycloaddition reaction

Introduction:

Click chemistry is a generic term for a set of reactions, which make use of several selective and modular building blocks to create heteroatom C-X-C links. The copper(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes according to a 1,3-dipolar [3+2]cycloaddition is a particularly powerful linking reaction due to its high degree of specificity and the biocompatibility of the reactants. Recently the first application of click chemistry in 18F chemistry has been reported [1]. Herein we report an alternative click chemistry strategy suitable for 18F labeling reactions.

Experimental:

The labeling strategy was exemplified by the synthesis of 18F-labeled neuropeptide neurotensin NT(8-13) [18F]3 (Fig. 1).
Results and Discussion: 4-[18F]Fluoro-N-(prop-2-ynyl)benzamide [18F]2 as novel terminal alkyne building block was prepared in 90% radiochemical yield by the reaction of readily available N-succinimidyl-4-[18F]fluorobenzoate [18F]SFB with propargyl amine. Purification of [18F]2 was performed by solid phase extraction. Coupling of 18F-labeled terminal alkyne with azide-functionalized NT(8-13) 1 gave the corresponding 18F-labeled NT(8-13) derivative [18F]3 in 66% yield as determined by radio-HPLC. Receptor binding of NT(8-13) derivative [19F]3 was investigated using the human colon adenocarcinoma cell line HT-29. The peptides inhibited the binding of [3H]-NT, showing a typical sigmoid curve. The in vitro binding affinity of NT(8-13) derivative [19F]3 was determined to be 66 nM.

Conclusion:

In summary, the use of [18F]fluoro-N-(prop-2-ynyl)benzamide [18F]2 as suitable click chemistry building block allows the convenient radiolabeling of 18F-labeled small molecular weight compounds as well as peptides as exemplified for the synthesis of 18F-labeled NT(8-13) [18F]3. This offers the application of click chemistry to the synthesis of a broad array of novel 18F-labeled compounds.
References:
[1] J. Marik, J.L. Sutcliffe, Tetrahedron Lett. 47 (2006) 6681-6684.