title: Biodistribution and catabolism of (18)F-labeled neurotensin(8-13) analogs.
abstract: 4-([(18)F]fluoro)benzoyl-neurotensin(8-13) ((18)FB-Arg(8)-Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 1) and two analogs stabilized in one and two positions ((18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 2, (18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)-Tle(12)-Leu(13)-OH, 3) were synthesized in a radiochemical yield of 25-36% and a specific activity of 5-15 GBq/mmol. The peptides were evaluated in vitro and in vivo for their potential to image tumors overexpressing neurotensin receptor 1 (NTR1) by positron emission tomography (PET). All analogs exhibited in vitro binding affinity in the low nanomolar range to NTR1-expressing human tumors, measured by quantitative receptor autoradiography, HT-29 and WiDr cells, and to sections of tumors derived from these cell lines in mice. The radiotracers were internalized in the cells in vitro, and the fluorinated peptides were able to mobilize intracellular Ca(2+) of WiDr cells. In in vivo studies in rats and in mice bearing HT-29 cell tumors, only a moderate uptake of the radioligands into the studied tumors was observed, presumed to be due to degradation in vivo and fast elimination by the kidneys. In comparison with the other analogs, the specific tumor uptake expressed as tumor-to-muscle relation was highest for the radioligand 3. The blood clearance of 3 was reduced by co-injection of peptidase inhibitors. The catabolic pathways of the radiofluorinated peptides were elucidated. The results suggest that the high binding affinity to NTR1 and the stabilization against proteolytic degradation are not yet sufficient for tumor imaging by PET.
authors.affiliation: Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.forename: Christoph
authors.initials: C
authors.lastname: Heichert
authors.forename: Peter
authors.initials: P
authors.lastname: Mäding
authors.forename: Holm
authors.initials: H
authors.lastname: Wittrisch
authors.forename: Marion
authors.initials: M
authors.lastname: Kretzschmar
authors.forename: Heike
authors.initials: H
authors.lastname: Rodig
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Koen
authors.initials: K
authors.lastname: Iterbeke
authors.forename: Kris
authors.initials: K
authors.lastname: Chavatte
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Bernd
authors.initials: B
authors.lastname: Johannsen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D005462:Fluorine Radioisotopes; D019073:HT29 Cells / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D009496:Neurotensin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D051381:Rats; D017208:Rats, Wistar; D018028:Receptors, Neurotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C054381:neurotensin (8-13); D002118:Calcium