Synthesis and evaluation of <sup>18</sup>F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography

Pan, Jinhe; Lau, Joseph; Mesak, Felix; Hundal, Navjit; Pourghiasian, Maral; Liu, Zhibo; Bénard, François; Dedhar, Shoukat; Supuran, Claudiu T.; Lin, Kuo-Chi

doi:10.3109/14756366.2013.773994

Cited by 66 publications

(48 citation statements)

References 43 publications

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“…Tracers showed limited retention in tumors (#0.5 % ID/g at 0.5-4 h after injection) with low contrast (#1.0 tumor-toblood ratio). Our research group evaluated 18 F-labeled U-104 (compound H) (21), FEC (7-(2-fluoroethoxy)coumarin, compound N) (21), and tertiary-substituted benzenesulfonamides (compound K) Preinjection significantly reduced uptake of same organ/ratio (P , 0.05).…”

Section: Discussionmentioning

confidence: 99%

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Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

et al. 2015

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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 18 F 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 (AmBF 3 ) to generate monovalent or trivalent enzyme inhibitors. Binding affinity to CA-IX and other CA isoforms was determined via a stopped-flow, CA-catalyzed CO 2 hydration assay. Tracers were radiolabeled via 18 F-19 F isotope exchange reactions. Imaging/biodistribution studies were performed using HT-29 tumor-bearing immunocompromised mice. Results: Monomeric AmBF 3 -AEBS and AmBF 3 -ABS were obtained in 41% and 40% yields, whereas trimeric AmBF 3 -(AEBS) 3 and AmBF 3 -(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). 18 F-labeled sulfonamides were obtained in 16.3%-36.8% non-decay-corrected radiochemical yields, with 40-207 GBq/ mmol 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 18 F-AmBF 3 -(ABS) 3 . Preblocking with acetazolamide reduced more than 80% uptake of 18 F-AmBF 3 -(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.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, one coumarin and several sulfonamides have been radiolabeled for targeting CA-IX ( Fig. 1) (16)(17)(18)(19)(20)(21)(22)(23)(24). Although these tracers are potent CA-IX inhibitors, those that were evaluated in vivo (18)(19)(20)(21) suffered from low tumor uptake, selectivity, or stability (Table 1).…”

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confidence: 99%

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

et al. 2015

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“…We also showed that PPIs have a clear cytotoxic anti-tumor effect when used at high dosages as single agent 29,30 . It is demonstrated that CA IX represents a valuable antitumor target [51][52][53][54][55][56][57][58][59] . In fact, CA IX has been shown to be upregulated in a number of human cancer tissues as a consequence of either hypoxia-induced or constitutive hypoxia-inducible factor-1 activation, whereas it is not expressed in their normal counterparts, except for gastric mucosa 60 .…”

Section: Discussionmentioning

confidence: 99%

Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells

Federici¹,

Lugini²,

Marino³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Results: The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells. Discussion: These results represent the first successful attempt in combining two different proton exchanger inhibitors. Conclusion: This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alternative strategy against tumors.

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“…Initial efforts were hampered by the lack of target specificity, poor pharmacokinetics, and/or tracer instability 24,25 . Subsequently, our group and others have leveraged a radiometal-based approach to develop cell-impermeable tracers targeting CA-IX in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…CA-IX inhibitors have also been used as delivery vectors of cytotoxic payloads to target tumor cells within hypoxic niches [16][17][18] . Complementing these therapeutic efforts has been the development of CA-IX radiotracers derived from inhibitors for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications [19][20][21][22][23][24][25][26][27][28][29][30][31] . PET and SPECT can generate images of high resolution and sensitivity, while providing quantitative information on drug target expression.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Zhang

Lau

Zhang

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 lM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with 18 F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/lmol specific activity and >98% radiochemical purity.18 F-labeled 2 was stable in mouse plasma at 37 C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model.18 F-labeled 2 cleared through hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 ± 0.06% ID/g, with a tumor-to-muscle ratio of 1.99 ± 0.25. Subsequently, tumor xenografts were visualized with moderate contrast. This study demonstrates the use of a cationic motif for conferring isoform selectively for CA-IX imaging agents. ARTICLE HISTORY

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Synthesis and evaluation of ¹⁸F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography

Cited by 66 publications

References 43 publications

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells

Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

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Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography

Cited by 66 publications

References 43 publications

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells

Design, synthesis and evaluation of18F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

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Synthesis and evaluation of ¹⁸F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography

Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging