title: Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives.
abstract: BACKGROUND
  To probe the interplay between radiotracer stability and somatostatin receptor affinity, Tyr(3)-octreotate and six variations of its peptide sequence, for which the Re-cyclized products were previously reported, were radiolabeled with (99m)Tc and investigated for their in vitro stability.
  
  
  METHODS
  Radiolabeling of the peptides was effected by ligand exchange from (99m)Tc-glucoheptonate, and the desired products were purified by radio-RP-HPLC. The in vitro stability in phosphate buffered saline, mouse serum and cysteine solutions at physiological temperature and pH for all seven (99m)Tc-cyclized peptides was determined by radio-RP-HPLC and radio-TLC. Normal CF-1 mouse biodistribution studies were performed for three of the (99m)Tc-cyclized peptides.
  
  
  RESULTS
  Based on the fully characterized Re-cyclized peptide analogues, four (99m)Tc-coordination motifs were proposed for the (99m)Tc-cyclized peptides. Technetium-99m-cyclized Tyr(3)-octreotate derivatives with N(2)S(2) metal coordination modes and large metal ring sizes were susceptible to oxidation and loss of (99m)Tc in the form of (99m)TcO(4)(-), as evidenced by their instability in the various solutions under physiological conditions (15-58% intact at 24 h). As anticipated, the addition of a third cysteine to the sequence stabilized the (99m)Tc metal coordination, and peptides with NS(3) coordination modes remained >85% intact out to 24 h. No significant differences were observed in the biodistribution studies performed with three peptides of varying stabilities.
  
  
  CONCLUSIONS
  Improvements in stability were not sufficient to outweigh the low somatostatin receptor affinity for the peptides in this study. Further improvements in the peptide sequence and/or metal coordination are needed to result in a radiodiagnostic/radiotherapeutic pair for targeting the somatostatin receptor.
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Bigott-Hennkens
authors.forename: Shorouk F
authors.initials: SF
authors.lastname: Dannoon
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Noll
authors.forename: Varyanna C
authors.initials: VC
authors.lastname: Ruthengael
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Jurisson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D003500:Cyclization; D003545:Cysteine / Q000737:chemistry; D004355:Drug Stability; D005260:Female; D007553:Isotope Labeling / Q000379:methods*; D051379:Mice; D015609:Organotechnetium Compounds / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D017481:Receptors, Somatostatin / Q000378:metabolism
chemical_list: D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-; D003545:Cysteine