Positron Emission Tomography Tracer Design of Targeted Synthetic Peptides via ¹⁸F-Sydnone Alkyne Cycloaddition

Abstract

Chemically synthesized, small peptides that bind with high affinity and specificity to CD8-expressing (CD8+) tumorinfiltrating T cells, yet retain the desirable characteristics of small molecules, hold valuable potential for diagnostic molecular imaging of immune response. Here, we report the development of 18 F-labeled peptides targeting human CD8α with nanomolar affinity via the strain-promoted sydnone−alkyne cycloaddition with 4-[ 18 F]fluorophenyl sydnone. The 18 F-sydnone is produced in one step, in high radiochemical yield, and the peptide labeling proceeds rapidly. A hydrophilic chemical linker results in a tracer with favorable pharmacokinetic properties and improved image contrast, as demonstrated by in vivo PET imaging studies.

Hetero-Diels–Alder click reaction of dithioesters for a catalyst-free indirect 18F-radiolabelling of peptides

“…The well-known copper-catalyzed reaction of an azide with an alkyne (CuAAC) was widely employed, however with the main drawbacks related to the use of copper (cytotoxicity, undesired oxidative side-reactions, use of large excess of peptide and catalyst, difficulty to remove copper, additional control quality analysis). 6 Some metal-free cycloadditions such as SPAAC (strain-promoted azide–alkyne cycloaddition), 7 SPSAC (strain-promoted sydnone–alkyne cycloaddition), 8 or IEDDA (inverse electron demand Diels–Alder) 9 reactions were also reported; however, the accessibility of the involved reagents represents a limitation. Therefore, the introduction of alternative click reactions in the toolbox of peptide radiofluorination still remains a challenging and attractive research area.…”

18F-Labeled brain-penetrant EGFR tyrosine kinase inhibitors for PET imaging of glioblastoma

“…14 a Our laboratory recently reported work involving a cyclic peptide-based radiotracer, sydnone-HEHE-peptide, which fails to cross the BBB. 17 Focusing on brain distribution, we compared the PET/CT images between mice that were administered either sydnone-HEHE-peptide or 18 F-JCN037 (Fig. 2B).…”

Recent Advances in Bioorthogonal Click Chemistry for Enhanced PET and SPECT Radiochemistry

“…Nearly simultaneously, some new click reactions for the construction and production of radiolabeled peptides have been developed. To create the 18 F-labeled peptide-based radioconjugate targeting human CD8, Agnew and colleagues utilized a new click reaction of strain-promoted sydnone-alkyne cycloaddition (SPSAC), which was similar to SPAAC . In addition to SPSAC, the photoclick reaction may be another fascinating method for the preparation of short-lived 18 F-labeled radiotracers because of its fast reaction rate .…”

“…To create the 18 F-labeled peptide-based radioconjugate targeting human CD8, Agnew and colleagues utilized a new click reaction of strain-promoted sydnonealkyne cycloaddition (SPSAC), which was similar to SPAAC. 100 In addition to SPSAC, the photoclick reaction may be another fascinating method for the preparation of short-lived 18 F-labeled radiotracers because of its fast reaction rate. 101 This developed photoclick methodology can make full use of 18 F-labeled prosthetic vinyl ethers ([ 18 F]VE1 and [ 18 F]VE2) with high radiochemical yield (58% and 37%, respectively) to promote the photoclick cycloaddition with 9,10-phenanthrenequinones in 60 s under 395 nm light irradiation.…”