Modular PET Agent Construction Strategy through Strain-Promoted Double-Click Reagent with Efficient Photoclick Step

An efficient modular strategy for rapid assembly of positron emission tomography (PET) agents has been developed. The use of a sequential, rapid, and selective double-click reaction allows for a combinatorial approach to the cross-linking of positron emitter-bearing prosthetic groups with various ligands. The strain-promoted azide alkyne cyclization (SPAAC) coupling of 18F-labeled azide synthon with MC-DIBOD, a cyclooctadiyne with one of the triple bonds caged as a cyclopropenone moiety, produces a stable intermediate. A brief exposure of the latter to 350-420 nm light removes protection of the second triple bond allowing for the addition of an azide-tagged biomolecule. The utility of this strategy has been demonstrated by the construction of several PET agents. The value of modularity was demonstrated in the preparation of PSMA PET agents, where the hydrophilicity was easily modified to improve tumor to background contrast.

Automated summary

An efficient modular strategy for rapid assembly of PET agents has been developed, which allows for a combinatorial approach to cross-linking of positron emitter-bearing prosthetic groups with various ligands. The strategy utilizes a sequential and selective double-click reaction, specifically the strain-promoted azide alkyne cyclization (SPAAC) coupling, to produce a stable intermediate that can be modified with azide-tagged biomolecules. Several PET agents have been successfully constructed using this strategy, and the modularity of the approach has been demonstrated in the preparation of PSMA PET agents, where the hydrophilicity can be easily modified to improve tumor to background contrast.