title: In vitro structure-activity relationship of Re-cyclized octreotide analogues.
abstract: BACKGROUND
  Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge.
  
  
  METHODS
  Various octreotide analogue sequences and coordination systems (e.g., S(2)N(2) and S(3)N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with (111)In-DOTA-Tyr(3)-octreotide in AR42J rat pancreatic tumor cells yielded IC(50) values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr(3)-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore.
  
  
  RESULTS
  Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr(3)-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids.
  
  
  CONCLUSIONS
  Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS(3) and N(2)S(2) coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of (99m)Tc-cyclized analogue 4.
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Shorouk F
authors.initials: SF
authors.lastname: Dannoon
authors.forename: Heather M
authors.initials: HM
authors.lastname: Bigott-Hennkens
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Jurisson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D004355:Drug Stability; D008958:Models, Molecular; D015282:Octreotide / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D017481:Receptors, Somatostatin; D012211:Rhenium; D015282:Octreotide