title: (64)Cu labeled AmBaSar-RGD2 for micro-PET imaging of integrin αvβ3 expression.
abstract: Integrin αvβ3 plays a critical role in tumor-induced angiogenesis and metastasis. Previously, a 64Cu-AmBaSar- RGD monomer with high in vivo stability compared with 64Cu-DOTA-RGD was developed for integrin αvβ3 PET imaging. It has been established that dimeric RGD peptides have higher receptor-binding affinity and superior in vivo kinetics compared with monomeric RGD peptides due to the polyvalency effect. In this context, we synthesized and evaluated 64Cu-labeled AmBaSar dimeric RGD conjugates (64Cu-AmBaSar-RGD2) for PET imaging of integrin αvβ3 expression. The dimeric RGD peptide was conjugated with a cage-like chelator AmBaSar and labeled with 64Cu. Cell binding, microPET imaging, receptor blocking, and biodistribution studies of 64Cu-AmBaSar-RGD2 were conducted in the U87MG human glioblastoma xenograft model. AmBaSar-RGD2 conjugate was obtained in reasonable yield (45.0 ± 2.5%, n= 4) and the identity was confirmed by HPLC and MS (found 1779.8, calculated m/z for [M+H]+ M: C81H125N27O19 1779.9). 64Cu-AmBaSar-RGD2 was obtained with high radiochemical yield (92.0 ± 1.3%) and purity (≥ 98.0%) under mild conditions (pH 5.0~5.5, 23~37 °C) in 30 min. The specific activity of 64Cu-AmBaSar-RGD2 was estimated to be 15-22 GBq/µmol at the end of synthesis. Based on microPET imaging and biodistribution studies, 64Cu-AmBaSar-RGD2 has demonstrated higher tumor uptake at selected time points than 64Cu-AmBaSar-RGD. At 20 h p.i., the tumor uptake reached 0.65 ± 0.05 %ID/g for 64Cu-AmBaSar-RGD and 1.76 ± 0.38 %ID/g for 64Cu-AmBaSar-RGD2, respectively. The integrin αvβ3 targeting specificity was confirmed by blocking experiments. Therefore, the new tracer 64Cu-AmBaSar- RGD2 exhibited better tumor-targeting efficacy and more favorable in vivo pharmacokinetics than the 64Cu labeled RGD monomer due to the polyvalency effect.
authors.affiliation: Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Hancheng
authors.initials: H
authors.lastname: Cai
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.forename: Chiun-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Ryan
authors.initials: R
authors.lastname: Park
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D014183:Transplantation, Heterologous
chemical_list: C543149:4-((8-amino-3,6,10,13,16,19-hexaazabicyclo(6.6.6)icosane-1-ylamino)methyl)benzoic acid; C578842:64Cu-AmBaSar-RGD2; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D039302:Integrin alphaVbeta3; D010455:Peptides