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.
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Authors | Panteleimon J Marsouvanidis, Theodosia Maina, Werner Sallegger, Eric P Krenning, Marion de Jong, Berthold A Nock |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 56
Issue 21
Pg. 8579-87
(Nov 14 2013)
ISSN: 1520-4804 [Electronic] United States |
PMID | 24094035
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Heterocyclic Compounds, 1-Ring
- Indium Radioisotopes
- Receptors, Bombesin
- 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
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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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