A technetium 99m-labeled ligand of carbonic anhydrase IX selectively targets renal cell carcinoma in vivo

Small organic ligands, selective for tumor-associated antigens, are increasingly being considered as alternatives to monoclonal antibodies for the targeted delivery of diagnostic and therapeutic payloads such as radionuclides and drugs into neoplastic masses.

We have previously described a novel acetazolamide derivative, a carbonic anhydrase ligand with high affinity for the tumor-associated isoform IX (CAIX), which can transport highly potent cytotoxic drugs into CAIX-expressing solid tumors. The aim of the present study was to quantitatively investigate the biodistribution properties of said ligand and understand if acetazolamide conjugates merit further development as drug carriers and radioimaging agents.

METHODS - The conjugate described in this study consisting of a derivative of acetazolamide, a spacer and a peptidic (99m)Tc chelator was labeled using sodium pertechnetate under reducing conditions and injected intravenously into CAIX-expressing SKRC52 xenograft bearing mice. Animals were sacrificed and organ uptake as percent of injected activity (% IA/g) of radiolabeled ligand per gram of tissue evaluated between 10 min and 24 h. Additionally, post-mortem imaging by single photon emission computed tomography was performed.

RESULTS - The acetazolamide conjugate described in this study could be labeled to high radiochemical purity (> 95%, 2.2-4.5 MBq/nmol). Analysis of organ uptake at various time points revealed that the ligand displayed a maximal tumor accumulation three hours after intravenous injection (22% IA /g), with an excellent tumor:blood ratio of 70:1 at the same time point. The ligand accumulation in the tumor was more efficient than in any other organ, but a residual uptake in kidney, lung and stomach (9, 16 and 10 %IA/g respectively) was also observed in line with patterns of carbonic anhydrase isoform expression in those tissues. Interestingly, tumor:organ ratios improved upon administration of higher doses of radiolabeled ligand, suggesting that certain binding sites in normal organs can be saturated in vivo.

CONCLUSIONS - The (99m)Tc-labeled acetazolamide conjugate exhibits high tumor uptake and very favorable tumor:kidney ratios of up to 3 that may allow imaging of tumors in kidney and distant sites at earlier time points than commonly possible with antibody-based products. These data suggest that the described molecule merit further development as a radioimaging agent for CAIX-expressing renal cell carcinoma.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 Feb 18 [Epub ahead of print]

Nikolaus Krall, Francesca Pretto, Martin Mattarella, Cristina Müller, Dario Neri

ETH Zurich, Switzerland;, Philochem AG;, Philochem AG;, Paul Scherrer Institute., ETH Zurich, Switzerland;

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