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Title: The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution

The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper, and are therefore a promising option for labeling proteins with ⁶⁴Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.18-ΔC H2 (MW 120 kDa) with ⁶⁴Cu showed high tracer retention in the kidneys,(>38% injected dose per gram (ID/g) 48 h post-injection), presumably because the high local positive charge on the Cu II-SarAr moiety resulted in increased binding of the labeled protein to the negatively charged basal cells of the glomerulus. To test this hypothesis, ch14.18-ΔC H2 was conjugated with a series of Sar derivatives of decreasing positive charge and three commonly used macrocyclic polyaza polycarboxylate (PAC) BFCs. The immunoconjugates were labeled with ⁶⁴Cu and injected into mice, and PET/CT images were obtained at 24 and 48 h post injection (p.i.). At 48 h p.i., ex vivo biodistribution was carried out. In addition, to demonstrate the potential of metastasis detection using ⁶⁴Cu-labeled ch14.18-ΔC H2, a preclinical imaging study of intrahepatic neuroblastoma tumors was performed carried out. Reducing the positive charge on the Sar chelators decreased kidney uptakemore » of Cu-labeled ch14.18-ΔC H2 by more than 6-fold, from >45 ID/g to <6% ID/g, while the uptake in most other tissues, including liver, was relatively unchanged. However, despite this dramatic decrease, the renal uptake of the PAC BFCs was generally lower than that of the Sar derivatives, as was the liver uptake. Uptake of ⁶⁴Cu-labeled ch14.18-ΔC H2 in neuroblastoma hepatic metastases was detected using PET.« less
 [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [1] ;  [1] ;  [3] ;  [5] ;  [3] ;  [1]
  1. Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Univ. of Melbourne (Australia)
  4. Boston Children's Hospital, Boston, MA (United States)
  5. The Antibody Society & Huston BioConsulting LLC, Boston, MA (United States)
Publication Date:
Report Number(s):
Journal ID: ISSN 1043-1802; R&D Project: KBCH139; 00600; KB0202011
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Bioconjugate Chemistry
Additional Journal Information:
Journal Volume: 26; Journal Issue: 4; Journal ID: ISSN 1043-1802
American Chemical Society
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Nuclear Physics (NP) (SC-26)
Country of Publication:
United States
43 PARTICLE ACCELERATORS; bifunctional chelator; ΔCH2; sarcophagine; radioimmunoimaging; NOTA; ⁶⁴Cu
OSTI Identifier: