Radiosynthesis of a 18F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo

Knieß, Torsten; Laube, Markus; Bergmann, Ralf; Sehn, Fabian; Graf, Franziska; Steinbach, J.; Wuest, Frank; Pietzsch, Jens

doi:10.1016/j.bmc.2012.04.022

Cited by 48 publications

(82 citation statements)

References 31 publications

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“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 in the following tumor cell models using a protocol published elsewhere with some modifications. 55 …”

Section: -(14-dioxa-8-azaspiro[45]decan-8-ylmethyl)phenol (13)mentioning

confidence: 99%

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

et al. 2015

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We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K(i) = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [(18)F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25-45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [(18)F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.

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Section: -(14-dioxa-8-azaspiro[45]decan-8-ylmethyl)phenol (13)mentioning

confidence: 99%

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

et al. 2015

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“…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). 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%

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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“…With their vital role in pharmacology, they have been utilized in many fields, such as medicinal, bioorganic, and pharmaceutical chemistry [2][3][4][5][6][7]. The substructure of indole is a key structural motif in a variety of bioactive compounds [8,9].…”

Section: Introductionmentioning

confidence: 99%

Lipase-Catalyzed Synthesis of Indolyl 4H-Chromenes via a Multicomponent Reaction in Ionic Liquid

et al. 2017

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Radiosynthesis of a 18F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo

Cited by 48 publications

References 31 publications

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

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

Lipase-Catalyzed Synthesis of Indolyl 4H-Chromenes via a Multicomponent Reaction in Ionic Liquid

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Radiosynthesis of a 18F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo

Cited by 48 publications

References 31 publications

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

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

Lipase-Catalyzed Synthesis of Indolyl 4H-Chromenes via a Multicomponent Reaction in Ionic Liquid

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¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent