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¹⁷⁷Lu-AMBA: Synthesis and Characterization of a Selective ¹⁷⁷Lu-Labeled GRP-R Agonist for Systemic Radiotherapy of Prostate Cancer

¹ Ernst Felder Laboratories, Bracco Research USA Inc., Princeton, New Jersey; ² Bracco Imaging S.p.A., Milan, Italy; and ³ Institute of Pathology, University of Bern, Bern, Switzerland

Correspondence: For correspondence or reprints contact: Laura E. Lantry, PhD, Discovery Biology, Ernst Felder Laboratories, Bracco Research USA Inc., 305 College Rd. East, Princeton, NJ 08540-6608. E-mail: Laura.Lantry{at}bru.bracco.com

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 (K_d), 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 (K_d, 1.02 nmol/L), with a maximum binding capacity (B_max) of 414 fmol/10⁶ cells (2.5 x 10⁵ 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.

Key Words: gastrin-releasing peptide • prostate cancer • experimental radiotherapeutics • ¹⁷⁷Lu • preclinical

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