PET imaging of insulin-like growth factor type 1 receptor expression with a 64Cu-labeled Affibody molecule.

Abstract

The insulin-like growth factor 1 receptor (IGF-1R) serves as an attractive target for cancer molecular imaging and therapy. Previous single photon emission computerized tomography (SPECT) studies showed that the IGF-1R-targeting Affibody molecules (99m)Tc-ZIGF1R:4551-GGGC, [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551 and (111)In-DOTA-ZIGF1R:4551 can discriminate between high and low IGF-1R-expression tumors and have the potential for patient selection for IGF-1R-targeted therapy. Compared with SPECT, positron emission tomography (PET) may improve imaging of IGF-1R-expression, because of its high sensitivity, high spatial resolution, strong quantification ability. The aim of the present study was to develop the (64)Cu-labeled NOTA-conjugated Affibody molecule ZIGF-1R:4:40 as a PET probe for imaging of IGF-1R-positive tumor. An Affibody analogue (Ac-Cys-ZIGF-1R:4:40) binding to IGF-1R was site-specifically conjugated with NOTA and labeled with (64)Cu. Binding affinity and specificity of (64)Cu-NOTA-ZIGF-1R:4:40 to IGF-1R were evaluated using human glioblastoma U87MG cells. Small-animal PET, biodistribution, and metabolic stability studies were conducted on mice bearing U87MG xenografts after the injection of (64)Cu-NOTA-ZIGF-1R:4:40 with or without co-injection of unlabeled Affibody proteins. The radiosynthesis of (64)Cu-NOTA-ZIGF-1R:4:40 was completed successfully within 60 min with a decay-corrected yield of 75 %. (64)Cu-NOTA-ZIGF-1R:4:40 bound to IGF-1R with low nanomolar affinity (K D = 28.55 ± 3.95 nM) in U87MG cells. (64)Cu-NOTA-ZIGF-1R:4:40 also displayed excellent in vitro and in vivo stability. In vivo biodistribution and PET studies demonstrated targeting of U87MG gliomas xenografts was IGF-1R specific. The tumor uptake was 5.08 ± 1.07 %ID/g, and the tumor to muscle ratio was 11.89 ± 2.16 at 24 h after injection. Small animal PET imaging studies revealed that (64)Cu-NOTA-ZIGF-1R:4:40 could clearly identify U87MG tumors with good contrast at 1-24 h after injection. This study demonstrates that (64)Cu-NOTA-ZIGF-1R:4:40 is a promising PET probe for imaging IGF-1R positive tumor.

• Authors: Xinhui Su, Kai Cheng, Yang Liu, Xiang Hu, Shuxian Meng, Zhen Cheng
• Journal: Amino acids (Amino Acids) Vol. 47 Issue 7 Pg. 1409-19 (Jul 2015) ISSN: 1438-2199 [Electronic] Austria
• PMID: 25854877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Biomarkers, Tumor
• Copper Radioisotopes
• Peptide Fragments
• Radiopharmaceuticals
• Recombinant Fusion Proteins
• Staphylococcal Protein A
• Receptor, IGF Type 1

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Copper Radioisotopes (pharmacokinetics)
• Glioblastoma (diagnostic imaging, metabolism)
• Humans
• Mice, Nude
• Neoplasm Transplantation
• Peptide Fragments (pharmacokinetics)
• Positron-Emission Tomography
• Radiopharmaceuticals (pharmacokinetics)
• Receptor, IGF Type 1 (metabolism)
• Recombinant Fusion Proteins
• Staphylococcal Protein A (chemistry)
• Tissue Distribution