RT Journal Article
SR Electronic
T1 <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
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1144
OP 1152
VO 47
IS 7
A1 Laura E. Lantry
A1 Enrico Cappelletti
A1 Mary Ellen Maddalena
A1 Jaclyn S. Fox
A1 Weiwei Feng
A1 Jianqing Chen
A1 Regi Thomas
A1 Stephen M. Eaton
A1 Nancy J. Bogdan
A1 Thangavel Arunachalam
A1 Jean Claude Reubi
A1 Natarajan Raju
A1 Edmund C. Metcalfe
A1 Luciano Lattuada
A1 Karen E. Linder
A1 Rolf E. Swenson
A1 Michael F. Tweedle
A1 Adrian D. Nunn
YR 2006
UL http://jnm.snmjournals.org/content/47/7/1144.abstract
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.