Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors.
Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. Four (111)In-labeled DTPA-chelated NT analogs and one (111)In-labeled DOTA-chelated NT analog were evaluated in NMRI nude mice bearing NT receptor-positive HT29 tumors. Experiments with a coinjection of unlabeled NT or lysine were performed to investigate receptor-mediated uptake and kidney protection, respectively. In addition, the in vivo serum stability of the most promising analog was analyzed. In the biodistribution study in mice, at 4 hours postinjection, a low percentage of the injected dose per gram (%ID/g) of tissue for all compounds was found in NT receptor-negative organs, such as the blood, spleen, pancreas, liver, muscle, and femur. A high uptake was found in the colon, intestine, kidneys, and in implanted HT29 tumors. The coinjection of excess unlabeled neurotensin significantly reduced tumor uptake, showing tumor uptake to be receptor-mediated. To a lesser extent, this was also observed for the colon, but not for other tissues. We concluded that DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH and the DOTA-linked counterpart have the most favorable biodistribution properties regarding tumor uptake.
Janssen
Paul J J M
PJ
Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands. p.janssen@erasmusmc.nl
de Visser
Moniaue
M
Verwijnen
Suzanne M
SM
Bernard
Bert F
BF
Srinivasan
Ananth
A
Erion
Jack L
JL
Breeman
Wouter A P
WA
Vulto
Arnold G
AG
Krenning
Eric P
EP
de Jong
Marion
M
D000704:Analysis of Variance; D000818:Animals; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects; D008239:Lysine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009842:Oligopeptides / Q000737:chemistry; D004369:Pentetic Acid; D011859:Radiography; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D007205:Indium Radioisotopes; D009842:Oligopeptides; D009496:Neurotensin; D004369:Pentetic Acid; D008239:Lysine