title: N-terminal sugar conjugation and C-terminal Thr-for-Thr(ol) exchange in radioiodinated Tyr3-octreotide: effect on cellular ligand trafficking in vitro and tumor accumulation in vivo.
abstract: For effective targeting of somatostatin receptor (sst) expressing tumors by radiolabeled octreotide analogues, high ligand uptake into sst-positive cells is mandatory. To optimize it, two modifications have been introduced into [(125)I]Tyr(3)-octreotide ([(125)I]TOC): C-terminal Thr-for-Thr(ol) exchange (leading to Tyr(3)-octreotate (TOCA)) and N-terminal derivatization with different carbohydrates. Both have significant impact on radioligand uptake into sst(2)-expressing cells in vitro and in vivo. Glucose conjugation via Amadori reaction by itself led to improved tumor uptake of [(123)I]Gluc-TOC in vivo, which is based on an enhancement of peptide internalization despite a reduction in receptor affinity. In the case of the doubly modified analogues [(123)I]Gluc-TOCA, [(123)I]Gluc-S-TOCA, and [(123)I]Gal-S-TOCA, a cumulative effect of both structural modifications was observed, leading up to a 5-fold increased uptake of these compounds in sst-expressing tumors compared to [(125)I]TOC. Thus, glycosylation with small carbohydrates was found to be a suitable tool to enhance receptor-mediated uptake of radiolabeled octreotide analogues into sst-positive malignancies, leading to tracers with excellent characteristics for in vivo sst-imaging applications.
authors.affiliation: Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany. M.Schottelius@lrz.tum.de
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Veronique
authors.initials: V
authors.lastname: Eltschinger
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005947:Glucose / Q000737:chemistry*; D006031:Glycosylation; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008320:Maltose / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017481:Receptors, Somatostatin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014312:Trisaccharides / Q000737:chemistry*
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D014312:Trisaccharides; C045210:3-Tyr-octreotide; C008317:maltotriose; D008320:Maltose; D005947:Glucose; D015282:Octreotide