177Lu-AMBA: Synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer.

Abstract

UNLABELLED:

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%.

CONCLUSION:

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: Laura E Lantry, Enrico Cappelletti, Mary Ellen Maddalena, Jaclyn S Fox, Weiwei Feng, Jianqing Chen, Regi Thomas, Stephen M Eaton, Nancy J Bogdan, Thangavel Arunachalam, Jean Claude Reubi, Natarajan Raju, Edmund C Metcalfe, Luciano Lattuada, Karen E Linder, Rolf E Swenson, Michael F Tweedle, Adrian D Nunn
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 47 Issue 7 Pg. 1144-52 (Jul 2006) ISSN: 0161-5505 [Print] United States
• PMID: 16818949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2
• Oligopeptides
• Peptides
• Radioisotopes
• Receptors, Bombesin
• Lutetium
• Bombesin

Topics

• Animals
• Binding, Competitive
• Bombesin (chemistry)
• Cell Line, Tumor
• Disease Progression
• Gene Expression Regulation
• Humans
• Lutetium (pharmacology)
• Male
• Mice
• Mice, Nude
• Oligopeptides (chemistry, pharmacology)
• Peptides (chemistry)
• Prostatic Neoplasms (radiotherapy)
• Radioisotopes (pharmacology)
• Receptors, Bombesin (agonists, biosynthesis)