title: Synthesis and evaluation of intercalating somatostatin receptor binding peptide conjugates for endoradiotherapy.
abstract: OBJECTIVE
  Intercalators, planar aromatic compounds, are able to interact with DNA by sandwiching themselves between the stacked bases at right angles to the long axis of the helix. Under certain circumstances, Auger-electron-emitting radionuclides can be extremely radiotoxic and produce extensive DNA damage. Auger electron-emitting radioisotopes, are known to be highly cytotoxic when localized in cell nuclei due to highly localized energy deposition by low energy Auger electrons. In addition binding to the DNA might increase the retention in the receptor expressing tissues.
  
  
  METHODS
  In order to exploit the cytotoxic potential of intercalator-Auger-emitter conjugates, bis-benzimidazole dyes, Hoechst 33258 and 33342, were linked to a somatostatin receptor affine carrier peptide. For this purpose a bis-benzimidazole intercalating moiety was prepared using variations on the literature methods. The intercalating moieties were coupled under normal SPPS conditions to the carrier peptide, Tyr3-octreotate. To attach the chelating agent (DOTA) to the intercalating moiety, a free amine derivative was prepared and coupled in solution to DOTA tris-t-butyl ester. The resulting chelator-intercalator conjugate was then coupled to a Tyr3-octreotate carrying resin using SPPS.
  
  
  RESULTS
  The peptide conjugates were obtained in good yields after HPLC chromatography. The cellular uptake of the novel conjugates was determined using fluorescence microscopy. All intercalator-peptide conjugates revealed somatostatin receptor binding affinities in the nanomolar range.
  
  
  CONCLUSIONS
  The novel chelator-intercalator derivatives of the somatostatin receptor binding Tyr3-octreotate introduce a new scope to the range of tracers for therapeutic purposes.
authors: Universitätsklinikum Heidelberg, Department of Nuclear Medicine, 69120 Heidelberg, Germany.
authors: Keith
authors: K
authors: Graham
authors: Qin
authors: Q
authors: Wang
authors: Regine
authors: R
authors: Garcia Boy
authors: Michael
authors: M
authors: Eisenhut
authors: Uwe
authors: U
authors: Haberkorn
authors: Walter
authors: W
authors: Mier
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D006690:Bisbenzimidazole / Q000737:chemistry; D002462:Cell Membrane; D002540:Cerebral Cortex; D002851:Chromatography, High Pressure Liquid; D005456:Fluorescent Dyes / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D007364:Intercalating Agents; D008856:Microscopy, Fluorescence; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D011878:Radiotherapy; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D005456:Fluorescent Dyes; D006573:Heterocyclic Compounds, 1-Ring; D007364:Intercalating Agents; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride