title: Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides.
abstract: OBJECTIVE
  G protein-coupled receptor agonists are being used as radiolabeled vectors for in vivo localization and therapy of tumors. Recently, somatostatin-based antagonists were shown to be superior to agonists. Here, we compare the new [111In/68Ga]-labeled bombesin-based antagonist RM1 with the agonist [111In]-AMBA for targeting the gastrin-releasing peptide receptor (GRPR).
  
  
  METHODS
  IC50, Kd values, and antagonist potency were determined using PC-3 and HEK-GRPR cells. Biodistribution and imaging studies were done in nude mice transplanted with the PC-3 tumor. The antagonist potency was assessed by evaluating the effects on calcium release and on receptor internalization monitored by immunofluorescence microscopy.
  
  
  RESULTS
  The IC50 value of [(nat)In]-RM1 was 14 +/- 3.4 nmol/L. [(nat/111)In]-RM1 was found to bind to the GRPR with a Kd of 8.5 +/- 2.7 nmol/L compared with a Kd of 0.6 +/- 0.3 nmol/L of [111In]-AMBA. A higher maximum number of binding site value was observed for [111In]-RM1 (2.4 +/- 0.2 nmol/L) compared with [111In]-AMBA (0.7 +/- 0.1 nmol/L). [(nat)Lu]-AMBA is a potent agonist in the immunofluorescence-based internalization assay, whereas [(nat)In]-RM1 is inactive alone but efficiently antagonizes the bombesin effect. These data are confirmed by the calcium release assay. The pharmacokinetics showed a superiority of the radioantagonist with regard to the high tumor uptake (13.4 +/- 0.8% IA/g versus 3.69 +/- 0.75% IA/g at 4 hours after injection. as well as to all tumor-to-normal tissue ratios.
  
  
  CONCLUSIONS
  Despite their relatively low GRPR affinity, the antagonists [111In/68Ga]-RM1 showed superior targeting properties compared with [111In]-AMBA. As found for somatostatin receptor-targeting radiopeptides, GRP-based radioantagonists seem to be superior to radioagonists for in vivo imaging and potentially also for targeted radiotherapy of GRPR-positive tumors.
authors: Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland.
authors: Rosalba
authors: R
authors: Mansi
authors: Xuejuan
authors: X
authors: Wang
authors: Flavio
authors: F
authors: Forrer
authors: Stefan
authors: S
authors: Kneifel
authors: Maria-Luisa
authors: ML
authors: Tamma
authors: Beatrice
authors: B
authors: Waser
authors: Renzo
authors: R
authors: Cescato
authors: Jean Claude
authors: JC
authors: Reubi
authors: Helmut R
authors: HR
authors: Maecke
mesh_terms: D000818:Animals; D001839:Bombesin / Q000737:chemistry*; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018004:Receptors, Bombesin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014183:Transplantation, Heterologous
chemical_list: C512446:DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D009842:Oligopeptides; D011868:Radioisotopes; D018004:Receptors, Bombesin; D043562:Receptors, G-Protein-Coupled; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001839:Bombesin