title: Pharmacological properties of hydrophilic and lipophilic derivatives of octreotate.
abstract: 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.affiliation: Department of Nuclear Medicine, University Clinics, Heidelberg, Germany.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Keith
authors.initials: K
authors.lastname: Graham
authors.forename: Thomas
authors.initials: T
authors.lastname: Schauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Fietz
authors.forename: Ashour
authors.initials: A
authors.lastname: Mohammed
authors.forename: Xiuxin
authors.initials: X
authors.lastname: Liu
authors.forename: Johannes
authors.initials: J
authors.lastname: Hoffend
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.forename: Michael
authors.initials: M
authors.lastname: Eisenhut
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-