title: Stereochemistry of amino acid spacers determines the pharmacokinetics of (111)In-DOTA-minigastrin analogues for targeting the CCK2/gastrin receptor.
abstract: The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study.
authors.affiliation: †Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Kolenc Peitl
authors.affiliation: ‡Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: MariaLuisa
authors.initials: M
authors.lastname: Tamma
authors.affiliation: †Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Kroselj
authors.affiliation: §Department of Nuclear Medicine, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Braun
authors.affiliation: ∥Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, CH-3010 Berne, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.affiliation: ∥Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, CH-3010 Berne, Switzerland.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.affiliation: ⊥Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Marija
authors.initials: M
authors.lastname: Sollner Dolenc
authors.affiliation: ‡Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.|§Department of Nuclear Medicine, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.affiliation: ‡Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.|§Department of Nuclear Medicine, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Mansi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005755:Gastrins / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D009369:Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011917:Rats, Inbred Lew; D043887:Receptor, Cholecystokinin B / Q000378:metabolism* / Q000502:physiology*
chemical_list: D005755:Gastrins; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D043887:Receptor, Cholecystokinin B; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C008530:minigastrin