Toward Stable N4-modified Neurotensins for Nts1-receptor-targeted Tumor Imaging with 99mtc.
From: Institute of Radioisotopes - Radiodiagnostic Products, National Center for Scientific Research Demokritos, 15310 Athens, Greece.
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 15
- Pages: 4767-76
- Medium: Print
- Language: English
- Citation (JAMA): Nock Berthold A, Nikolopoulou Anastasia, Reubi Jean-Claude, et al. Toward Stable N4-modified Neurotensins for Nts1-receptor-targeted Tumor Imaging with 99mtc.. J. Med. Chem. Jul 2006;49:4767-76
Abstract
A series of Gly-neurotensin(8-13) analogues modified at the N-terminus by acyclic tetraamines (Demotensin 1-4) were obtained by solid-phase peptide synthesis techniques. Strategic replacement of amino acids and/or reduction of sensitive peptide bonds were performed to enhance conjugate resistance against proteolytic enzymes. During 99mTc-labeling, single species radiopeptides, [99mTc]Demotensin 1-4, were easily obtained in high yields and typical specific activities of 1 Ci/micromol. Peptide conjugates displayed a high affinity binding to the human neurotensin subtype 1 receptor (NTS1-R) expressed in colon adenocarcinoma HT-29 or WiDr cells and/or in human tumor sections. [99mTc]Demotensin 1-4 internalized very rapidly in HT-29 or WiDr cells by a NTS1-R-mediated process. [99mTc]Demotensin 3 and 4, which remained stable during 1 h incubation in murine plasma, were selectively studied in nude mice bearing human HT-29 and WiDr xenografts. After injection, [99mTc]Demotensin 3 and 4 effectively and specifically localized in the experimental tumors and were rapidly excreted via the kidneys into the urine, exhibiting overall biodistribution patterns favorable for NTS1-R-targeted tumor imaging in man.
Mesh Headings (Keywords): Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Drug Stability, Female, Humans, Male, Mice, Mice, Nude, Neoplasms, Neurotensin, Oligopeptides, Organotechnetium Compounds, Pancreatic Neoplasms, Radiopharmaceuticals, Receptors, Neurotensin, Structure-Activity Relationship, Tissue Distribution, Transplantation, Heterologous
Check for Full Text / PubMed Unique Identifier (PMID): 16854083
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