Abstract | UNLABELLED: METHODS: LLP2A was conjugated to 1,4,8,11-tetraazacyclotetradecane-1-(methane phosphonic acid)-8-(methane carboxylic acid) (CB-TE1A1P) and 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid ( NODAGA) chelators for (68)Ga and (64)Cu labeling. The conjugates were synthesized by solid-phase peptide synthesis, purified by reversed-phase high-performance liquid chromatography, and verified by liquid chromatography mass spectrometry. Saturation and competitive binding assays with B16F10 melanoma cells determined the affinity of the compounds for VLA-4. The biodistributions of the LLP2A conjugates were evaluated in murine B16F10 subcutaneous tumor-bearing C57BL/6 mice. Melanoma metastasis was induced by intracardiac injection of B16F10 cells. PET/CT imaging was performed at 2, 4, and 24 h after injection for the (64)Cu tracers and 1 h after injection for the (68)Ga tracer. RESULTS: (64)Cu-labeled CB-TE1A1P-PEG4-LLP2A and NODAGA-PEG4-LLP2A showed high affinity to VLA-4, with a comparable dissociation constant (0.28 vs. 0.23 nM) and receptor concentration (296 vs. 243 fmol/mg). The tumor uptake at 2 h after injection was comparable for the 2 probes, but (64)Cu-CB-TE1A1P-PEG4-LLP2A trended toward higher uptake than (64)Cu-NODAGA-PEG4-LLP2A (16.9 ± 2.2 vs. 13.4 ± 1.7 percentage injected dose per gram, P = 0.07). Tumor-to-muscle and tumor-to-blood ratios from biodistribution and PET/CT images were significantly higher for (64)Cu-CB-TE1A1P-PEG4-LLP2A than (64)Cu-NODAGA-PEG4-LLP2A (all P values < 0.05). PET/CT imaging of metastatic melanoma with (68)Ga-NODAGA-PEG4-LLP2A and (64)Cu-NODAGA-PEG4-LLP2A showed high uptake of the probes at the site of metastasis, correlating with the bioluminescence imaging of the tumor. CONCLUSION: These data demonstrate that (64)Cu-labeled CB-TE1A1P/ NODAGA LLP2A conjugates and (68)Ga-labeled NODAGA-LLP2A are excellent imaging agents for melanoma and potentially other VLA-4-positive tumors. (64)Cu-CB-TE1A1P-PEG4-LLP2A had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a PET imaging agent for melanoma.
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Authors | Wissam Beaino, Carolyn J Anderson |
Journal | Journal of nuclear medicine : official publication, Society of Nuclear Medicine
(J Nucl Med)
Vol. 55
Issue 11
Pg. 1856-63
(Nov 2014)
ISSN: 1535-5667 [Electronic] United States |
PMID | 25256059
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc. |
Chemical References |
- 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methane carboxylic acid)
- 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
- Acetates
- Carboxylic Acids
- Chelating Agents
- Copper Radioisotopes
- Dipeptides
- Gallium Radioisotopes
- Heterocyclic Compounds, 1-Ring
- Heterocyclic Compounds, 2-Ring
- Integrin alpha4beta1
- LLP2A compound
- Organophosphonates
- Peptides
- Phenylurea Compounds
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Topics |
- Acetates
(chemistry)
- Animals
- Binding, Competitive
- Carboxylic Acids
(chemistry)
- Chelating Agents
(chemistry)
- Chromatography, High Pressure Liquid
- Chromatography, Liquid
- Copper Radioisotopes
(chemistry)
- Dipeptides
(chemistry)
- Gallium Radioisotopes
(chemistry)
- Heterocyclic Compounds, 1-Ring
(chemistry)
- Heterocyclic Compounds, 2-Ring
(chemistry)
- Integrin alpha4beta1
(metabolism)
- Mass Spectrometry
- Melanoma
(diagnostic imaging, metabolism)
- Melanoma, Experimental
- Mice
- Mice, Inbred C57BL
- Neoplasm Transplantation
- Organophosphonates
(chemistry)
- Peptides
(chemistry)
- Phenylurea Compounds
(chemistry)
- Positron-Emission Tomography
- Protein Binding
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