@article {Lau1434, author = {Joseph Lau and Zhibo Liu and Kuo-Shyan Lin and Jinhe Pan and Zhengxing Zhang and Daniela Vullo and Claudiu T. Supuran and David M. Perrin and Fran{\c c}ois B{\'e}nard}, title = {Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX{\textendash}Targeted PET Imaging}, volume = {56}, number = {9}, pages = {1434--1440}, year = {2015}, doi = {10.2967/jnumed.114.153288}, publisher = {Society of Nuclear Medicine}, abstract = {Carbonic anhydrase IX (CA-IX), a transmembrane enzyme, mediates cell survival under hypoxic conditions and is overexpressed in solid malignancies. In this study, we synthesized four 18F sulfonamide derivatives and evaluated their potential for imaging CA-IX expression with PET. Methods: Azide derivatives of 2 carbonic anhydrase inhibitors, 4-(2-aminoethyl)benzenesulfonamide (AEBS) and 4-aminobenzensulfonamide (ABS), were coupled to radiosynthons with either 1 or 3 alkynes and a pendent ammoniomethyltrifluoroborate (AmBF3) to generate monovalent or trivalent enzyme inhibitors. Binding affinity to CA-IX and other CA isoforms was determined via a stopped-flow, CA-catalyzed CO2 hydration assay. Tracers were radiolabeled via 18F-19F isotope exchange reactions. Imaging/biodistribution studies were performed using HT-29 tumor{\textendash}bearing immunocompromised mice. Results: Monomeric AmBF3-AEBS and AmBF3-ABS were obtained in 41\% and 40\% yields, whereas trimeric AmBF3-(AEBS)3 and AmBF3-(ABS)3 were obtained in 47\% and 55\% yields, respectively. Derivatives bound CA-I, -II, -IX, and -XII with good affinity (0.49{\textendash}100.3 nM). 18F-labeled sulfonamides were obtained in 16.3\%{\textendash}36.8\% non{\textendash}decay-corrected radiochemical yields, with 40{\textendash}207 GBq/μmol specific activity and greater than 95\% radiochemical purity. Biodistribution/imaging studies showed that the tracers were excreted through both renal and hepatobiliary pathways. At 1 h after injection, HT-29 tumor xenografts were clearly visualized in PET images with modest contrast for all 4 tracers. Tumor uptake was 2-fold higher for monovalent tracers (\~{}0.60 percentage injected dose per gram [\%ID/g]) than for trivalent tracers (\~{}0.30 \%ID/g); however, tumor-to-background ratios were significantly better for 18F-AmBF3-(ABS)3. Preblocking with acetazolamide reduced more than 80\% uptake of 18F-AmBF3-(ABS)3 in HT-29 tumors. Conclusion: Our data suggest that trimerization of an otherwise nonspecific CA inhibitor greatly enhances the selectivity for CA-IX in vivo and represents a promising strategy for creating multivalent enzyme inhibitors for selectively imaging extracellular enzyme activity by PET.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/56/9/1434}, eprint = {https://jnm.snmjournals.org/content/56/9/1434.full.pdf}, journal = {Journal of Nuclear Medicine} }