Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor.

Abstract

We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [111In]XYIMSR-01 in 73.8-75.8% (n = 3) yield with specific radioactivities ranging from 118 - 1,021 GBq/μmol (3,200-27,600 Ci/mmol). Single photon emission computed tomography of [111In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 ± 145.4, 68.4 ± 29.0 and 1.7 ± 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX.

• Authors: Xing Yang, Il Minn, Steven P Rowe, Sangeeta Ray Banerjee, Michael A Gorin, Mary Brummet, Hye Soo Lee, Soo Min Koo, Polina Sysa-Shah, Ronnie C Mease, Sridhar Nimmagadda, Mohamad E Allaf, Martin G Pomper
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 33733-42 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26418876 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Neoplasm
• Enzyme Inhibitors
• Indium Radioisotopes
• Ligands
• Radiopharmaceuticals
• Recombinant Proteins
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases
• Fluorescein-5-isothiocyanate

Topics

• Animals
• Antigens, Neoplasm (chemistry)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (chemistry)
• Carcinoma, Renal Cell (diagnostic imaging, pathology)
• Cell Separation
• Enzyme Inhibitors (chemistry)
• Female
• Flow Cytometry
• Fluorescein-5-isothiocyanate
• Humans
• Indium Radioisotopes (chemistry)
• Kidney Neoplasms (diagnostic imaging, pathology)
• Ligands
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microscopy, Fluorescence (methods)
• Molecular Weight
• Neoplasm Transplantation
• Radiopharmaceuticals (chemistry)
• Recombinant Proteins (chemistry)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon