RT Journal Article
SR Electronic
T1 Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1434
OP 1440
DO 10.2967/jnumed.114.153288
VO 56
IS 9
A1 Joseph Lau
A1 Zhibo Liu
A1 Kuo-Shyan Lin
A1 Jinhe Pan
A1 Zhengxing Zhang
A1 Daniela Vullo
A1 Claudiu T. Supuran
A1 David M. Perrin
A1 François Bénard
YR 2015
UL http://jnm.snmjournals.org/content/56/9/1434.abstract
AB 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–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 (0.49–100.3 nM). 18F-labeled sulfonamides were obtained in 16.3%–36.8% non–decay-corrected radiochemical yields, with 40–207 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.