title: Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor.
abstract: The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.
authors: Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors: Petra
authors: P
authors: Kolenc-Peitl
authors: Rosalba
authors: R
authors: Mansi
authors: MariaLuisa
authors: M
authors: Tamma
authors: Tanja
authors: T
authors: Gmeiner-Stopar
authors: Marija
authors: M
authors: Sollner-Dolenc
authors: Beatrice
authors: B
authors: Waser
authors: Richard P
authors: RP
authors: Baum
authors: Jean Claude
authors: JC
authors: Reubi
authors: Helmut R
authors: HR
authors: Maecke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002942:Circular Dichroism; D006207:Half-Life; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D043887:Receptor, Cholecystokinin B / Q000187:drug effects* / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D002118:Calcium