Development and application of new 18F-glycoconjugates for PET

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Positron emission tomography (PET) is established in clinical and experimental molecular imaging. However, so far there are only a few 18F-labeled peptide radiopharmaceuticals that are used in human PET studies and clinical trials. This is particularly ascribed to their time-consuming and demanding radiosyntheses. In the previous funding period glycosylazide precursors were successfully developed that are suitable for the efficient click chemistry-based strategy of concomitant 18F-labeling and glycosylation of alkynyl-functionalized peptides. Using this method, a variety of 18F- glycosylated biomolecules (e.g. avb3-affine RGD peptides, neurotensin peptoids, NPY derivatives, and also non-peptide ligands for the neurotensin receptor and the endothelin receptor-A) have been prepared and characterized in vitro and in vivo as highly affine and selective PET tracers. We could show that glycosylation itself and the position of the fluorine substitution in the glycosyl residues largely determined the biodistribution of glycoconjugates in vivo, as demonstrated on a series of glycosylated RGD peptides. Moreover, we showed that glycosylation has a positive influence on the in-vivo stability of a non-peptidic endothelin receptor ligand when compared to its fluoroethoxy analog. Further objectives of this project are: A) the application of successfully developed 18F-glycoconjugates for PET imaging of angiogenesis in the (radio)therapy monitoring in animal models, and B) the development of subtype-selective 18F-glycosylated radioligands for the neurotensin receptor-2. C) In addition, the developed 18F-fluoroglycosylation strategy should be adapted to the radiolabeling of cells. This aims to analyze immunological approaches to cancer therapy and rapid cell-cell recognition processes with PET imaging. For this purpose, selected [18F]fluorodeoxyglucosyl azide are used for click chemistry-based labeling of cells and subjected to cell-trafficking experiments using suitable animal models for the determination of the biokinetics of the cells and the quantification of PET imaging data. The 18F-fluoroglycosylation strategy developed in this project has already been proven suitable for tracer development projects and provides, in case of successful adaptation for cell trafficking studies with PET, also an additional potential for use in preclinical imaging studies.