Document Detail

Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting.
MedLine Citation:
PMID:  18543899     Owner:  NLM     Status:  MEDLINE    
Radiolabeled sst 2 and sst 3 antagonists are better candidates for tumor targeting than agonists with comparable binding characteristics (Ginj, M.; Zhang, H.; Waser, B.; Cescato, R.; Wild, D.; Erchegyi, J.; Rivier, J.; Mäcke, H. R.; Reubi, J. C. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16436-16441.). Because most of the neuroendocrine tumors express sst 2, we used the known antagonists acetyl- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 1) (Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1996, 50, 709-715. Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1997, 51, 170; Erratum.) and H-Cpa (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]-2Nal (15)-NH 2 ( 7) (Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.; Coy, D. H. J. Med. Chem. 1999, 42, 1863-1871.) as leads for analogues with increased sst 2 binding affinity and selectivity. Among the 32 analogues reported here, DOTA- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)- dTyr (15)-NH 2 ( 3) and DOTA-Cpa (2)- c[ dCys (3)-Aph (7)(Hor)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 31) had the highest sst 2 binding affinity and selectivity. All of the analogues tested kept their sst 2 antagonistic properties (i.e., did not affect calcium release in vitro and competitively antagonized the agonistic effect of [Tyr (3)]octreotide). Moreover, in an immunofluorescence-based internalization assay, the new analogues prevented sst 2 internalization induced by the sst 2 agonist [Tyr (3)]octreotide without being active by themselves. In conclusion, several analogues (in particular 3, 31, and 32) have outstanding sst 2 binding and functional antagonistic properties and, because of their DOTA moiety, are excellent candidates for in vivo targeting of sst 2-expressing cancers.
Renzo Cescato; Judith Erchegyi; Beatrice Waser; Véronique Piccand; Helmut R Maecke; Jean E Rivier; Jean Claude Reubi
Related Documents :
23143019 - Nitrosyl isomerism in amorphous mn(tpp)(no) solids.
25116899 - Trapping atmospheric co2 with gold.
23379369 - Synthesis, microwave spectrum, and conformational properties of 2-fluoroethylazide (fch...
3178219 - A molecular shape analysis and quantitative structure-activity relationship investigati...
10446289 - Trifluoromethyl ketones and methyl fluorophosphonates as inhibitors of group iv and vi ...
24598819 - Influence of intermolecular interactions on solid state luminescence of imidazopyridine...
19911789 - New synthetic procedures to catena-phosphorus cations: preparation and dissociation of ...
16592369 - On completeness of the bergman metric and its subordinate metric.
22719719 - 1-[bis(4-fluoro-phen-yl)meth-yl]-4-[2-(naphthalen-2-yl-oxy)eth-yl]piperazine.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-06-11
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  51     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-03     Completed Date:  2008-08-12     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4030-7     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Cell Line
Chemistry, Physical
Drug Design*
Physicochemical Phenomena
Radiopharmaceuticals / chemistry*,  pharmacology*
Somatostatin / antagonists & inhibitors*,  classification,  metabolism
Grant Support
Reg. No./Substance:
0/Radiopharmaceuticals; 51110-01-1/Somatostatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Formation of C7H7(+) from benzyl chloride and chlorotoluene molecular ions: a theoretical study.
Next Document:  Synthesis and pharmacological characterization of chiral pyrrolidinylfuran derivatives: the discover...