title: Radiolabeled bombesin analogs for prostate cancer diagnosis: preclinical studies.
abstract: BACKGROUND
  Radionuclide imaging can be a useful tool for the diagnosis of prostate cancer. Bombesin (BBN) is a molecule with high affinity for gastrin releasing peptide (GRP) receptors which are over-expressed in that tumor. This report compares (99m)Tc-HYNIC-betaAla-BBN(7-14)NH2 [(99m)Tc-HYNIC-BBN] and (99m)Tc identical withN(PNP6)-Cys-betaAla-BBN(7-14)NH2 [(99m)TcN(PNP6)-Cys-BBN] with regard to labeling procedures as well as in vitro and in vivo evaluation (biodistribution and scintigraphic imaging).
  
  
  METHODS
  Peptide synthesis was performed in an automated peptide synthesizer. HYNIC-BBN was radiolabeled with pertechnetate using tricine and ethylenediamine diacetic acid (EDDA) as coligands. Cys- BBN was radiolabeled in a two-step procedure with the preparation of the precursor (99m)Tc-Nitrido first and then introducing diphosphine (PNP6). Radiochemical evaluation of conjugates, as well as studies of stability, transchelation toward cysteine, and partition coefficient were done. Biological studies included internalization, biodistribution in healthy animals and in animals bearing PC3 cancer cells with acquisition of images from the tumor-bearing animals.
  
  
  RESULTS
  Both complexes showed a high radiochemical yield along with good stability. Biodistribution studies pointed out strong renal excretion for the former complex due to its hydrophilic profile and marked hepatobiliary excretion for the latter, corresponding to observed lipophilicity. Tumor uptake was higher for (99m)Tc-HYNIC-BBN and the same occurred with internalization findings, which exceeded those of (99m)TcN(PNP6)-BBN. Blocking studies in mice bearing PC-3 tumor cells revealed significantly reduced pancreas and tumor uptake, demonstrating receptor specificity of the conjugates.
  
  
  CONCLUSIONS
  The best radiotracer was (99m)Tc-HYNIC-BBN on the basis of high radiochemical yield, fast radiolabeling procedure without need for a purification step, and more consistent tumor uptake.
authors.affiliation: Radiopharmacy Center, Institute of Energetic and Nuclear Research, Sao Paulo, SP 05508-000, Brazil. blfaintuch@hotmail.com
authors.forename: Bluma Linkowski
authors.initials: BL
authors.lastname: Faintuch
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.forename: Adriano
authors.initials: A
authors.lastname: Duatti
authors.forename: Emiko
authors.initials: E
authors.lastname: Muramoto
authors.forename: Salomao
authors.initials: S
authors.lastname: Faintuch
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006834:Hydrazines / Q000737:chemistry / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D017672:Nitrogen Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D010179:Pancreas / Q000000981:diagnostic imaging; D010720:Phosphines / Q000737:chemistry / Q000493:pharmacokinetics; D011467:Prostate / Q000000981:diagnostic imaging / Q000473:pathology; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000032:analysis; D014018:Tissue Distribution
chemical_list: D006834:Hydrazines; D017672:Nitrogen Compounds; D015609:Organotechnetium Compounds; D010720:Phosphines; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C117288:hydrazino nicotinamide; C531054:technetium 99m HYNIC-bombesin; D009536:Niacinamide; C044646:phosphine; D003545:Cysteine; D001839:Bombesin