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Stabilization of neurotensin analogues: effect on peptide catabolism, biodistribution and tumor binding

2002; Elsevier BV; Volume: 29; Issue: 3 Linguagem: Inglês

10.1016/s0969-8051(01)00304-3

1872-9614

Matthias Bruehlmeier, Elisa Garcı́a Garayoa, Alain Blanc, Barbara Holzer, Suzanne Gergely, Dirk Tourwé, P. August Schubiger, Peter Bläuenstein,

Peptidase Inhibition and Analysis

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 (NαHis)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.