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Positron emission tomography (PET) with radiolabelled peptide-based tracers has attracted great interest in oncology over the past decades. The success of imaging is closely related to sufficient uptake of the radiotracer in malignant tissue and for this sufficient biological half-life, particularly in the bloodstream, is mandatory. Fast enzymatic degradation during circulation leading to insufficient imaging abilities of peptide-based radioligands remains a major issue. The design of multimeric constructs, bearing multiple targeting moieties, has been widely applied to improve target interaction. This concept may also be applied to prolong the biological half-life of peptide-based radiopharmaceuticals as enzymatic degradation can result in formation of metabolites still capable to interact with the target binding site. In this study we aimed to identify such metabolites and therefore we utilized the siderophore-based bifunctional chelator fusarinine C (FSC) for the design of novel mono- and multimeric constructs, bearing minigastrin (MG) analogues as targeting moieties to address cholecystokinin-2 receptors (CCK2R) which are overexpressed in a variety of cancerous diseases and are well known for fast enzymatic degradation, particularly for truncated des-(Glu) 5 -MG members, such as MG11. FSC-based imaging probes were radiolabelled with gallium-68 and characterized  in vitro  (logD, protein binding, affinity and cell-uptake studies, stability and metabolite studies, as well as generation of corresponding metabolites by artificial enzymatic degradation) and  in vivo  (biodistribution in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice and stability in blood of living BALB/c mice and analysis of corresponding organ homogenates and urine to identify degradation products). In summary, multimerization was accompanied by partial improvement towards targeting abilities. Identified metabolites formed by artificial enzymatic cleavage of trimeric FSC-MG conjugates  in vitro  contained intact binding sequences for the receptor. Furthermore, the  68 Ga-labelled trimers exhibiting increasing uptake of radioligand in tumour tissue over time and improved  in vivo  stability in blood samples of living animals of the trimers compared to corresponding mono- and dimers, strongly supporting our hypothesis.

plos one

Multimerization results in formation of re-bindable metabolites: A proof of concept study with FSC-based minigastrin imaging probes targeting CCK2R expression