title: Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy.
abstract: The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors.
  
  
  METHODS
  [DTPA-Pro(1),Tyr(4)]BN (A), [DOTA-Pro(1),Tyr(4)]BN (B), [DTPA-epsilon-Lys(3),Tyr(4)]BN (C), and [DOTA-epsilon-Lys(3),Tyr(4)]BN (D) (where DOTA is dodecanetetraacetic acid) were synthesized and studied for competition with binding of [(125)I-Tyr(4)]BN to the GRP receptor. The (111)In-labeled BN analogs were studied in vitro for binding and internalization by GRP receptor-expressing CA20948 and AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats. Specific tissue binding was tested by coinjection of 0.1 mg [Tyr(4)]BN.
  
  
  RESULTS
  All BN analogs competitively inhibited the binding of [(125)I-Tyr(4)]BN to the GRP receptor with 50% inhibitory concentration values in the range of 2-9 nmol/L. All (111)In-labeled analogs showed high and specific time- and temperature-dependent binding and internalization by CA20948 and AR42J cells. In in vivo studies, high and specific binding was found in GRP receptor-positive tissues such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for A-D, respectively). In a rat model, the AR42J tumor could clearly be visualized by scintigraphy using [(111)In-DTPA-Pro(1),Tyr(4)]BN as the radioligand. Although [(111)In-DOTA-Pro(1),Tyr(4)]BN showed the highest uptake of radioactivity in GRP receptor-positive tissues as well as higher target-to-blood ratios, [(111)In-DTPA-Pro(1),Tyr(4)]BN was easier to handle and is more practical to use. Therefore, we decided to start phase I studies with this DTPA-conjugated radioligand.
  
  
  CONCLUSIONS
  [(111)In-DTPA-Pro(1),Tyr(4)]BN is a promising radioligand for scintigraphy of GRP receptor-expressing tumors. We are currently performing a phase I study on patients with invasive prostate carcinoma.
authors.affiliation: Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands. breeman@nuge.azr.nl
authors.forename: Wouter A P
authors.initials: WA
authors.lastname: Breeman
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Jack L
authors.initials: JL
authors.lastname: Erion
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Bugaj
authors.forename: Ananth
authors.initials: A
authors.lastname: Srinivasan
authors.forename: Bert F
authors.initials: BF
authors.lastname: Bernard
authors.forename: Dik J
authors.initials: DJ
authors.lastname: Kwekkeboom
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives*; D007205:Indium Radioisotopes / Q000627:therapeutic use; D008297:Male; D008969:Molecular Sequence Data; D004369:Pentetic Acid; D019275:Radiopharmaceuticals; D051381:Rats; D018004:Receptors, Bombesin / Q000032:analysis*; D014018:Tissue Distribution
chemical_list: C400044:DTPA-Pro(1),Tyr(4)bombesin; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D004369:Pentetic Acid; D001839:Bombesin