title: An efficient bioorthogonal strategy using CuAAC click chemistry for radiofluorinations of SNEW peptides and the role of copper depletion.
abstract: The EphB2 receptor is known to be overexpressed in various types of cancer and is therefore a promising target for tumor cell imaging by positron emission tomography (PET). In this regard, imaging could facilitate the early detection of EphB2-overexpressing tumors, monitoring responses to therapy directed toward EphB2, and thus improvement in patient outcomes. We report the synthesis and evaluation of several fluorine-18-labeled peptides containing the SNEW amino acid motif, with high affinity for the EphB2 receptor, for their potential as radiotracers in the non-invasive imaging of cancer using PET. For the purposes of radiofluorination, EphB2-antagonistic SNEW peptides were varied at the C terminus by the introduction of L-cysteine, and further by alkyne- or azide-modified amino acids. In addition, two novel bifunctional and bioorthogonal labeling building blocks [(18)F]AFP and [(18)F]BFP were applied, and their capacity to introduce fluorine-18 was compared with that of the established building block [(18)F]FBAM. Copper-assisted Huisgen 1,3-dipolar cycloaddition, which belongs to the set of bioorthogonal click chemistry reactions, was used to introduce both novel building blocks into azide- or alkyne-modified SNEW peptides under mild conditions. Finally, the depletion of copper immediately after radiolabeling is a highly important step of this novel methodology.
authors.affiliation: Institut für Radiopharmazeutische Krebsforschung, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Pretze
authors.forename: Manuela
authors.initials: M
authors.lastname: Kuchar
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Constantin
authors.initials: C
authors.lastname: Mamat
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001386:Azides / Q000737:chemistry; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D005462:Fluorine Radioisotopes / Q000737:chemistry; D008297:Male; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D036183:Receptor, EphB2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000596:Amino Acids; D001386:Azides; D005462:Fluorine Radioisotopes; D009942:Organometallic Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D003300:Copper; D036183:Receptor, EphB2