Versatile Bispidine‐Based Bifunctional Chelators for 64CuII‐Labelling of Biomolecules

Bifunctional chelators as parts of modular metal‐based radiopharmaceuticals are responsible for stable complexation of the radiometal ion and for covalent linkage between the complex and the targeting vector. To avoid loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups. The C9 position of the very stable CuII chelator 3,7‐diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisation does not disturb the metal binding centre. We describe the preparation and characterisation of a set of novel bispidine derivatives equipped with suitable functional groups for diverse bioconjugation reactions, including common amine coupling strategies (bispidine‐isothiocyanate) and the Cu‐free strain‐promoted alkyne–azide cycloaddition. We demonstrate their functionality and versatility in an exemplary way by conjugation to an antibody‐based biomolecule and validate the obtained conjugate in vitro and in vivo.
Ready for bioconjugation: Modification of the bispidine backbone at the C9‐position via an ether linkage provides a set of suitable bifunctional chelators ready for incorporating into targeting moieties and 64CuII‐labelling. The usefulness of these bifunctional chelators for targeted positron emission tomography (PET) imaging is demonstrated in vivo.