PT - JOURNAL ARTICLE AU - Lantry, Laura E. AU - Cappelletti, Enrico AU - Maddalena, Mary Ellen AU - Fox, Jaclyn S. AU - Feng, Weiwei AU - Chen, Jianqing AU - Thomas, Regi AU - Eaton, Stephen M. AU - Bogdan, Nancy J. AU - Arunachalam, Thangavel AU - Reubi, Jean Claude AU - Raju, Natarajan AU - Metcalfe, Edmund C. AU - Lattuada, Luciano AU - Linder, Karen E. AU - Swenson, Rolf E. AU - Tweedle, Michael F. AU - Nunn, Adrian D. TI - <sup>177</sup>Lu-AMBA: Synthesis and Characterization of a Selective <sup>177</sup>Lu-Labeled GRP-R Agonist for Systemic Radiotherapy of Prostate Cancer DP - 2006 Jul 01 TA - Journal of Nuclear Medicine PG - 1144--1152 VI - 47 IP - 7 4099 - http://jnm.snmjournals.org/content/47/7/1144.short 4100 - http://jnm.snmjournals.org/content/47/7/1144.full SO - J Nucl Med2006 Jul 01; 47 AB - 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/106 cells (2.5 × 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 (&gt;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 &lt; 0.001 and P &lt; 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.