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Tumor diagnosis with new 111In-radioligands based on truncated human gastrin releasing peptide sequences: synthesis and preclinical comparison.

Abstract
Radiolabeled analogs of the frog tetradecapeptide bombesin (BBN) have been proposed for diagnosis and therapy of gastrin releasing peptide receptor (GRPR)-expressing tumors. Following a different and yet unexplored approach, we have developed four novel (111)In-labeled truncated analogs of the human 27-mer GRP after conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) at the N-terminus of GRP(13/14/17/18-27) fragments. Analog affinities for the human GRPR determined against [(125)I-Tyr(4)]BBN were at the nanomolar level and dependent on truncation site. The respective (111)In radioligands specifically internalized in GRPR-expressing PC-3 cells. The shorter chain [(111)In-DOTA]GRP(17/18-27) analogs showed higher metabolic stability in mice. Radioligands specifically localized in human PC-3 xenografts in SCID mice, with [(111)In-DOTA]GRP(17-27) exhibiting the most favorable pharmacokinetic profile. This study has demonstrated the efficacy of human GRP-based radiopeptides to target GRPR-positive lesions in vivo and has revealed the impact of GRP chain length on key biological parameters of resulting radiotracers.
AuthorsPanteleimon J Marsouvanidis, Theodosia Maina, Werner Sallegger, Eric P Krenning, Marion de Jong, Berthold A Nock
JournalJournal of medicinal chemistry (J Med Chem) Vol. 56 Issue 21 Pg. 8579-87 (Nov 14 2013) ISSN: 1520-4804 [Electronic] United States
PMID24094035 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Heterocyclic Compounds, 1-Ring
  • Indium Radioisotopes
  • Receptors, Bombesin
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Topics
  • Animals
  • Cell Line, Tumor
  • Heterocyclic Compounds, 1-Ring (chemical synthesis, metabolism, pharmacokinetics)
  • Humans
  • Indium Radioisotopes
  • Mice
  • Mice, SCID
  • Molecular Structure
  • Neoplasms, Experimental (diagnosis)
  • Receptors, Bombesin (chemistry, metabolism)
  • Tissue Distribution

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