Development and biological evaluation of 99mTc-sulfonamide derivatives for in vivo visualization of CA IX as surrogate tumor hypoxia markers

Akurathi, Vamsidhar; Dubois, Ludwig; Celen, Sofie; Lieuwes, Natasja G.; Chitneni, Satish K.; Cleynhens, Bernard; Innocenti, Alessio; Supuran, Claudiu T.; Verbruggen, Alfons; Lambin, Philippe; Bormans, Guy

doi:10.1016/j.ejmech.2013.10.027

Cited by 44 publications

(50 citation statements)

References 27 publications

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“…Starting with 23.3-38.5 GBq of 18 F-fluoride, 18 F-AmBF 3 -AEBS, 18 F-AmBF 3 -ABS, 18 F-AmBF 3 -(AEBS) 3 , and 18 F-AmBF 3 -(ABS) 3 were obtained in 24.8% 6 2.2%, 26.4% 6 10.2%, 28.0% 6 3.5%, and 26.9% 6 5.6% non-decay-corrected radiochemical yields (n 5 3) with corresponding specific activities of 185 6 22, 141 6 11, 66 6 9, and 49 6 12 GBq/mmol, respectively. After C18 Sep-Pak (Waters) purification, more than 95% radiochemical purity was obtained for all tracers based on high-performance liquid chromatography radiochromatograms.…”

Section: Chemistry and Radiochemistrymentioning

confidence: 99%

“…Nevertheless, the application of small-molecule inhibitors as PET tracers can be challenged by several effects such as nonspecific uptake in cells, poor clearance from blood (1), and rapid metabolic defluorination with accompanying bone uptake (2,3). In addition, 18 F labeling in high yield and at high specific activity often presents a significant challenge in the development of new PET tracers (4).…”

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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%

“…Extracellular targets are typically imaged with radiolabeled peptides, aptamers, and antibodies. Small molecules (e.g., 18 F-fluoromisonidazole, 18 F-fluorothymidine, and a host of others) have been used to probe enzymatic activity that may be associated within a given cell type. Nevertheless, the application of small-molecule inhibitors as PET tracers can be challenged by several effects such as nonspecific uptake in cells, poor clearance from blood (1), and rapid metabolic defluorination with accompanying bone uptake (2,3).…”

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confidence: 99%

“…We hypothesized that a multivalent enzyme inhibitor would restrict intracellular accumulation and enhance specific binding to an extracellular tumor target. To accomplish this, we used a radiosynthon that readily enables grafting of various ligands to a pentaerythritol core while allowing for facile radiolabeling at high specific activity with Curie levels of 18 F activity. Recently, we communicated this method for linking both peptides and small-molecule inhibitors in a trivalent motif (5).…”

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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: Chemistry and Radiochemistrymentioning

confidence: 99%

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confidence: 99%

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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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Synthesis of novel sulfonamides with anti‐Alzheimer and antioxidant capacities

Gök

Akıncıoğlu

Binici

et al. 2021

Archiv der Pharmazie

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A series of novel dopamine analogs incorporating urea and sulfonamide functional groups was synthesized from 3,4‐dimethoxyphenethylamine. The reaction of 3,4‐dimethoxyphenethylamine with N,N‐dimethylcarbamoyl chloride, followed by the sulfonyl chlorination of the urea derivative, gave benzene‐1‐sulfonyl chloride 9, which was reacted with NH3 (aq) or N‐alkyl amines to give related sulfonamides. The O‐demethylation reaction of the subsequent compounds with BBr3 afforded four novel phenolic dopamine analogs including sulfonamide and urea in the same structure. The anticholinergic and antioxidant effects of the synthesized compounds were examined. Compound 13 exhibited inhibition at the micromolar level for both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The IC50 value of 13 was calculated as 298 ± 43 µM for AChE and 321 ± 29 µM for BChE. The antioxidant and antiradical effects of the molecules were investigated by five different methods. Among the synthesized compounds 10–18, the best antioxidant and antiradical activities belong to the phenolic compounds 15–18. Compounds 16 and 18 have a higher reducing power than the standards used, that is, butylated hydroxytoluene, butylated hydroxyanisole, Trolox, and α‐tocopherol, for Fe3+–Fe2+ and Cu2+–Cu+ reducing activities. For the DPPH• radical scavenging method, compounds 16–18 have a much better scavenging power than the standard molecules. In addition, it has been determined by the induced‐fit docking method that compound 13 is well‐fitted in the active site of the enzymes. ADME studies reveal that the pharmacokinetic and physicochemical properties of all synthesized compounds are within an acceptable range.

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