title: 177Lu-AMBA: Synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer.
abstract: Gastrin-releasing peptide receptors (GRP-R) are upregulated in many cancers, including prostate, breast, and lung. We describe a new radiolabeled bombesin (BBN) analog for imaging and systemic radiotherapy that has improved pharmacokinetics (PK) and better retention of radioactivity in the tumor.
  
  
  METHODS
  DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA) was synthesized and radiolabeled. The human prostate cancer cell line PC-3 was used to determine the binding (Kd), retention, and efflux of 177Lu-AMBA. Receptor specificity was determined by in vitro autoradiography in human tissues. PK and radiotherapy studies were performed in PC-3 tumor-bearing male nude mice.
  
  
  RESULTS
  177Lu-AMBA has a high affinity for the GRP-R (Kd, 1.02 nmol/L), with a maximum binding capacity (Bmax) of 414 fmol/10(6) cells (2.5 x 10(5) GRP-R/cell). Internalization was similar for 177Lu-AMBA (76.8%), 177Lu-BBN8 (72.9%), and 125I-[Tyr4]-BBN (74.9%). Efflux was markedly lower for 177Lu-AMBA (2.9%) compared with 177Lu-BBN8 (15.9%) and 125I-[Tyr4]-BBN (46.1%). By receptor autoradiography, Lu-AMBA binds specifically to GRP-R (0.8 nmol/L) and to the neuromedin B receptor (NMB-R) (0.9 nmol/L), with no affinity for the bb3 receptor (>1,000 nmol/L). 177Lu-AMBA was renally excreted (55 %ID 1 h [percentage injected dose at 1 h]); tumor uptake at 1 and 24 h was 6.35 %ID/g and 3.39 %ID/g, respectively. One or 2 doses of 177Lu-AMBA (27.75 MBq/dose) significantly prolonged the life span of PC-3 tumor-bearing mice (P < 0.001 and P < 0.0001, respectively) and decreased PC-3 tumor growth rate over controls. When compared using World Health Organization criteria, mice receiving 2 doses versus 1 dose of 177Lu-AMBA demonstrated a shift away from stable/progressive disease toward complete/partial response; by RECIST (Response Evaluation Criteria in Solid Tumors), median survival increased by 36% and time to progression/progression-free survival increased by 65%.
  
  
  CONCLUSIONS
  177Lu-AMBA binds with nanomolar affinity to GRP-R and NMB-R, has low retention of radioactivity in kidney, demonstrates a very favorable risk-benefit profile, and is in phase I clinical trials.
authors.affiliation: Ernst Felder Laboratories, Bracco Research USA Inc., Princeton, New Jersey 08540-6608, USA. Laura.Lantry@bru.bracco.com
authors.forename: Laura E
authors.initials: LE
authors.lastname: Lantry
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappelletti
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Maddalena
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Fox
authors.forename: Weiwei
authors.initials: W
authors.lastname: Feng
authors.forename: Jianqing
authors.initials: J
authors.lastname: Chen
authors.forename: Regi
authors.initials: R
authors.lastname: Thomas
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Eaton
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Bogdan
authors.forename: Thangavel
authors.initials: T
authors.lastname: Arunachalam
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Natarajan
authors.initials: N
authors.lastname: Raju
authors.forename: Edmund C
authors.initials: EC
authors.lastname: Metcalfe
authors.forename: Luciano
authors.initials: L
authors.lastname: Lattuada
authors.forename: Karen E
authors.initials: KE
authors.lastname: Linder
authors.forename: Rolf E
authors.initials: RE
authors.lastname: Swenson
authors.forename: Michael F
authors.initials: MF
authors.lastname: Tweedle
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Nunn
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000737:chemistry; D045744:Cell Line, Tumor; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D008187:Lutetium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011868:Radioisotopes / Q000494:pharmacology*; D018004:Receptors, Bombesin / Q000819:agonists / Q000096:biosynthesis*
chemical_list: C512446:DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2; D009842:Oligopeptides; D010455:Peptides; D011868:Radioisotopes; D018004:Receptors, Bombesin; D008187:Lutetium; D001839:Bombesin