Document Detail


Pharmacological properties of hydrophilic and lipophilic derivatives of octreotate.
MedLine Citation:
PMID:  14741567     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Derivatives of somatostatin (SST) represent the most important peptides for receptor targeting in oncological applications. Whereas the pharmacophor in somatostatin receptor-affine substances has been thoroughly investigated, the influence of modifications at the N-terminal has not yet been systematically studied. In order to investigate the influence of hydrophilic versus lipophilic modifications at the N-terminal end, a series of homologous derivatives of Tyr3-octreotate modified with oligomers of ethylene glycol or fatty acids were synthesized. For this purpose, Tyr3-octreotate was assembled using solid phase peptide synthesis and the fatty acids or oligomers of ethylene glycol were conjugated to the N-terminal end. The oligomers of ethylene glycol were activated by 4-nitrophenylchloroformate to obtain carbamate-linked hydrophilic compounds. The receptor affinities of these compounds were determined by competition experiments with [125I]Tyr3-octreotide on rat cortex membranes. The hydrophilic derivatives and the short chain lipophilic derivatives revealed IC50 values between 0.66 +/- 0.02 nM and 2.16 +/- 0.31 nM respectively. After labeling with (125)I the organ distribution of selected derivatives was investigated in Lewis rats bearing the rat pancreatic tumor CA20948. All of the compounds showed high tumor uptake. The peptides conjugated to oligomers of ethylene glycol showed low uptake into the liver and kidneys. Increasing the length of the fatty acids resulted in a remarkable decrease in kidney uptake. In conclusion, the systematic modifications at the N-terminal result in a low effect on the receptor affinity but allow the modulation of the pharmacokinetic properties of octreotide derivatives.
Authors:
Qin Wang; Keith Graham; Thomas Schauer; Thomas Fietz; Ashour Mohammed; Xiuxin Liu; Johannes Hoffend; Uwe Haberkorn; Michael Eisenhut; Walter Mier
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Publication Detail:
Type:  Comparative Study; Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nuclear medicine and biology     Volume:  31     ISSN:  0969-8051     ISO Abbreviation:  Nucl. Med. Biol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-26     Completed Date:  2004-09-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9304420     Medline TA:  Nucl Med Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  21-30     Citation Subset:  IM    
Affiliation:
Department of Nuclear Medicine, University Clinics, Heidelberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Iodine Radioisotopes / chemistry,  diagnostic use,  pharmacokinetics
Isotope Labeling / methods
Male
Metabolic Clearance Rate
Organ Specificity
Pancreatic Neoplasms / metabolism*,  radionuclide imaging
Peptides, Cyclic / chemistry,  diagnostic use,  pharmacokinetics*
Radiopharmaceuticals / chemistry,  diagnostic use,  pharmacokinetics
Rats
Rats, Inbred Lew
Receptors, Somatostatin / chemistry,  metabolism*
Tissue Distribution
Chemical
Reg. No./Substance:
0/Iodine Radioisotopes; 0/Peptides, Cyclic; 0/Radiopharmaceuticals; 0/Receptors, Somatostatin; 0/octreotate, Tyr(3)-

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