Stabilization of neurotensin analogues: effect on peptide catabolism, biodistribution and tumor binding.
Neurotensin (NT) receptors in pancreatic and other neuroendocrine tumors are promising targets for imaging and therapeutic purposes. Here, we report on the effect of distinct changes in the peptide chain on catabolism in vitro for five radiolabeled [99mTc] neurotensin analogues having high affinity for neurotensin receptors. Substitution of NT(1-7) by (NalphaHis)Ac--the Tc-binding moiety--combined with a reduced bond 8-9 (CH2NH), N-methylation of peptide bonds or replacement of Ile(12) by tertiary leucin (Tle) led to peptide stabilization of various degrees. Biodistribution studies in nude mice bearing HT29 xenografts showed higher tumor uptake with more stable peptides, yielding high tumor to blood ratios of up to 70.
Bruehlmeier
Matthias
M
Paul Scherrer Institute, Center for Radiopharmaceutical Science, CH-5232 PSI, Villigen, Switzerland. peter.blaeuenstein@psi.ch
Garayoa
Elisa García
EG
Blanc
Alain
A
Holzer
Barbara
B
Gergely
Suzanne
S
Tourwé
Dirk
D
Schubiger
Pius August
PA
Bläuenstein
Peter
P
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D010455:Peptides; D019275:Radiopharmaceuticals; D009496:Neurotensin