Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells.

COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.

Access to 18 F-labelled isoxazoles by ruthenium-promoted 1,3-dipolar cycloaddition of 4-[18 F]fluoro-N-hydroxybenzimidoyl chloride with alkynes.

4-[18 F]Fluoro-N-hydroxybenzimidoyl chloride (18 FBIC), an 18 F-labelled aromatic nitrile oxide, was developed as building block for Ru-promoted 1,3-dipolar cycloaddition with alkynes. 18 FBIC is obtained in a one-pot synthesis in up to 84% radiochemical yield (RCY) starting from [18 F]fluoride with 4-[18 F]fluorobenzaldehyde (18 FBA) and 4-[18 F]fluorobenzaldehyde oxime (18 FBAO) as intermediates, by reaction of 18 FBAO with N-chlorosuccinimide (NCS). 18 FBIC was found to be a suitable and stable synthon to give access to 18 F-labelled 3,4-diarylsubstituted isoxazoles by [Cp*RuCl(cod)]-catalysed 1,3-dipolar cycloaddition with various alkynes. So the radiosynthesis of a fluorine-18-labelled COX-2 inhibitor [18 F]1b, a close derivative of valdecoxib, was performed with 18 FBIC and 1-ethynyl-4-(methylsulfonyl)benzene, providing [18 F]1b in up to 40% RCY after purification in 85 minutes. The application of 18 FBIC as a building block in the synthesis of 18 F-labelled heterocycles will generally extend the portfolio of available PET radiotracers.

Synthesis and preliminary radiopharmacological characterisation of an 11 C-labelled azadipeptide nitrile as potential PET tracer for imaging of cysteine cathepsins.

An O-methyltyrosine-containing azadipeptide nitrile was synthesised and investigated for its inhibitory activity towards cathepsins L, S, K, and B. Labelling with carbon-11 was accomplished by reaction of the corresponding phenolic precursor with [11 C]methyl iodide starting from cyclotron-produced [11 C]methane. Radiopharmacological evaluation of the resulting radiotracer in a mouse xenograft model derived from a mammary tumour cell line by small animal PET imaging indicates tumour targeting with complex pharmacokinetics. Radiotracer uptake in the tumour region was considerably lower under treatment with the nonradioactive reference compound and the epoxide-based irreversible cysteine cathepsin inhibitor E64. The in vivo behaviour observed for this radiotracer largely confirms that of the corresponding 18 F-fluoroethylated analogue and suggests the limited suitability of azadipeptide nitriles for the imaging of tumour-associated cysteine cathepsins despite target-mediated uptake is evidenced.

Synthesis and Cyclooxygenase Inhibition of Sulfonamide-Substituted (Dihydro)Pyrrolo[3,2,1-hi]indoles and Their Potential Prodrugs.

Non-invasive imaging of cyclooxygenase-2 (COX-2) by radiolabeled ligands is attractive for the diagnosis of cancer, and novel highly affine leads with optimized pharmacokinetic profile are of great interest for future developments. Recent findings have shown that methylsulfonyl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles represent highly potent and selective COX-2 inhibitors but possess unsuitable pharmacokinetic properties for radiotracer applications. Based on these results, we herein present the development and evaluation of a second series of sulfonamide-substituted (dihydro)pyrrolo[3,2,1-hi]indoles and their conversion into the respective more hydrophilic N-propionamide-substituted analogs. In comparison to the methylsulfonyl-substituted leads, COX inhibition potency and selectivity was retained in the sulfonamide-substituted compounds; however, the high lipophilicity might hinder their future use. The N-propionamide-substituted analogs showed a significantly decreased lipophilicity and, as expected, lower or no COX-inhibition potency. Hence, the N-(sulfonyl)propionamides can be regarded as potential prodrugs, which represents a potential approach for more sophisticated radiotracer developments.

Bridging from Brain to Tumor Imaging: (S)-(-)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice.

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(-)- and (R)-(+)-[18F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [18F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB).

Development of Fluorinated Non-Peptidic Ghrelin Receptor Ligands for Potential Use in Molecular Imaging.

The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S)-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one ((S)-9) has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds (S)-9, (R)-9, and (S)-16 as suitable parent molecules for 18F-labeled positron emission tomography (PET) radiotracers to enable future investigation of GhrR in the brain.

Optical imaging of COX-2: studies on an autofluorescent 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitor.

This study aimed at in vivo visualization of cyclooxygenase-2 (COX-2) by optical imaging using a representative compound of a class of autofluorescent 2,3-diaryl-substituted indole-based selective COX-2 inhibitors (2,3-diaryl-indole coxibs). COX-2 was successfully visualized in mice models with phorbol myristate ester (TPA)-induced inflammation or bearing xenografted human melanoma cells by 2-[4-(aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-1H-indole (C1). COX-2 protein expression in both TPA-induced inflammatory sites and human melanoma xenografts was confirmed by immunoblotting. Control experiments using surrogate markers, sham injections, and non-COX-2 expressing melanoma cells further confirmed specificity of tissue association of C1. The merging of therapeutic and diagnostic properties of 2,3-diaryl-indole coxibs may widen the range of applications of COX-2-targeted treatment, e.g., for in situ-guided surgery and ex vivo diagnostics.

Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure.

A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of (18)F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET).

Novel (pyrazolyl)benzenesulfonamides with a nitric oxide-releasing moiety as selective cyclooxygenase-2 inhibitors.

Inhibition of cyclooxygenase-2 (COX-2) is a promising anti-inflammatory therapeutic strategy, but long-term medication with COX-2-inhibitors (coxibs) may be associated with adverse cardiovascular effects. Functionalization of existing lead structures with nitric oxide (NO)-releasing moieties is an auspicious approach to minimize these effects. In this regard, an organic nitrate (-O-NO2) substituent was introduced at a (pyrazolyl)benzenesulfonamide lead structure. The novel NO-coxibs selectively inhibited COX-2 in a low micromolar range (IC50(COX-2): 0.22-1.27 µM) and are supposed to be promising anti-inflammatory compounds with, in parallel, positive effects on vascular homeostasis.

Visualization of cyclooxygenase-2 using a 2,3-diarylsubstituted indole-based inhibitor and confocal laser induced cryofluorescence microscopy at 20K in melanoma cells in vitro.

This study aimed at visualization of cyclooxygenase-2 (COX-2) protein expression in melanoma cells by confocal laser induced cryofluorescence microscopy using 4-(3-(4-methoxyphenyl)-1H-indol-2-yl)benzene-sulfonamide (C1) representative for a novel class of autofluorescent 2,3-diarylsubstituted indole-based selective COX-2 inhibitors. COX-2 expression was measured in human melanoma cell lines A2058 and MelJuso by immunocytochemistry and immunoblotting. Cellular uptake experiments using varying C1 concentrations down to 0.1 nM (with/without molar excess of celecoxib as control) were performed at 37 °C. Cryofluorescence microscopy was conducted at 20 K. COX-2 protein expression was successfully visualized by C1 in A2058 cells. COX-2-negative MelJuso cells showed no specific accumulation of C1. Control experiments using celecoxib and, additionally, implemented fluorescence spectroscopy confirmed specificity of both cellular uptake and intracellular association of C1. Cryofluorescence microscopy in combination with spectroscopy allowed for visualization of COX-2 protein expression in melanoma cells in vitro using a selective COX-2 inhibitor at very low concentrations.

Investigations into the synthesis, radiofluorination and conjugation of a new [¹8F]fluorocyclobutyl prosthetic group and its in vitro stability using a tyrosine model system.

The [(18)F]fluorocyclobutyl group has the potential to be a metabolically stable prosthetic group for PET tracers. The synthesis of the radiolabeling precursor cis-cyclobutane-1,3-diyl bis(toluene-4-sulfonate) 8 was obtained from epibromohydrin in 7 steps (2% overall yield). The radiolabeling of this precursor 8 and its conjugation to L-tyrosine as a model system was successfully achieved to give the new non-natural amino acid 3-[(18)F]fluorocyclobutyl-L-tyrosine (L-3-[(18)F]FCBT) [(18)F]17 in 8% decay-corrected yield from the non-carrier-added [(18)F]fluoride. L-3-[(18)F]FCBT was investigated in vitro in different cancer cell lines to determine the uptake and stability. The tracer [(18)F]17 showed a time dependent uptake into different tumor cell lines (A549, NCI-H460, DU145) with the best uptake of 5.8% injected dose per 5×10(5) cells after 30min in human lung carcinoma cells A549. The stability of L-3-[(18)F]FCBT in human and rat plasma and the stability of the non-radioactive L-3-FCBT in rat hepatocytes were both found to be excellent. These results show that the non-natural amino acid L-3-[(18)F]FCBT is a promising metabolically stable radiotracer for positron emission tomography.

Radiolabeled COX-2 inhibitors for non-invasive visualization of COX-2 expression and activity--a critical update.

Cyclooxygenase-2 (COX-2) is a key player in inflammation. Its overexpression is directly associated with various inflammatory diseases and, additionally, with several processes of carcinogenesis. The development of new selective COX-2 inhibitors (COXIBs) for use in cancer treatment is in the focus of the medicinal chemistry research field. For this purpose, a set of methods is available to determine COX-2 expression and activity in vitro and ex vivo but it is still a problem to functionally characterize COX-2 in vivo. This review focusses on imaging agents targeting COX-2 which have been developed for positron emission tomography (PET) and single photon emission computed tomography (SPECT) since 2005. The literature reveals that different radiochemical methods are available to synthesize COXIBs radiolabeled with fluorine-18, carbon-11, and isotopes of radioiodine. Unfortunately, most of the compounds tested did not show sufficient stability in vivo due to de[¹8F]fluorination or de[¹¹C]methylation or they failed to bind specifically in the target region. So, suitable stability in vivo, matching lipophilicity for the target compartment and both high affinity and selectivity for COX-2 were identified as prominent criteria for radiotracer development. Up to now, it is not clear what approach and which model is the most suited to evaluate COX-2 targeting imaging agents in vivo. However, for proof of principle it has been shown that some radiolabeled compounds can bind specifically in COX-2 overexpressing tissue which gives hope for future work in this field.

Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist's perspective.

BACKGROUND: [18F]fluoromisonidazole ([18F]FMISO, 1H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole) is a commonly used radiotracer for imaging hypoxic conditions in cells. Since hypoxia is prevalent in solid tumors, [18F]FMISO is in clinical application for decades to explore oxygen demand in cancer cells and the resulting impact on radiotherapy and chemotherapy. RESULTS: Since the introduction of [18F]FMISO as positron emission tomography imaging agent in 1986, a variety of radiosynthesis procedures for the production of this hypoxia tracer has been developed. This paper gives a brief overview on [18F]FMISO radiosyntheses published so far from its introduction until now. From a radiopharmaceutical chemist's perspective, different precursors, radiolabeling approaches and purification methods are discussed as well as used automated radiosynthesizers, including cassette-based and microfluidic systems. CONCLUSION: In a GMP compliant radiosynthesis using original cassettes for FASTlab we produced [18F]FMISO in 49% radiochemical yield within 48 min with radiochemical purities > 99% and molar activities > 500 GBq/µmol. In addition, we report an easy and efficient radiosynthesis of [18F]FMISO, based on in-house prepared FASTlab cassettes, providing the radiotracer for research and preclinical purposes in good radiochemical yields (39%), high radiochemical purities (> 99%) and high molar activity (> 500 GBq/µmol) in a well-priced option.

Cyclotron-Based Production of 67Cu for Radionuclide Theranostics via the 70Zn(p,α)67Cu Reaction.

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although 61Cu and 64Cu are slowly being established as diagnostic radionuclides for PET, the availability of the therapeutic counterpart 67Cu plays a key role for further radiopharmaceutical development in the future. Until now, the 67Cu shortage has not been solved; however, different production routes are being explored. This project aims at the production of no-carrier-added 67Cu with high radionuclidic purity with a medical 30MeV compact cyclotron via the 70Zn(p,α)67Cu reaction. With this purpose, proton irradiation of electrodeposited 70Zn targets was performed followed by two-step radiochemical separation based on solid-phase extraction. Activities of up to 600MBq 67Cu at end of bombardment, with radionuclidic purities over 99.5% and apparent molar activities of up to 80MBq/nmol, were quantified.

Site-selective radiolabeling of peptides by (18)F-fluorobenzoylation with [(18F)]SFB in solution and on solid phase: a comparative study.

Peptides labeled with short-lived positron-emitting radionuclides are of outstanding interest as probes for molecular imaging by positron emission tomography (PET). Herein, the site-selective incorporation of fluorine-18 into lysine-containing peptides using the prosthetic labeling agent N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) is described. The reaction of [(18)F]SFB with four biologically relevant resin-bound peptides was studied and optimized. For comparison, each peptide was 18F-fluorobenzoylated in solution under different conditions and the product distribution was analyzed confirming the advantages of the solid-phase approach. The method's feasibility for selective radiolabeling either at the N-terminus or at the lysine side chain was demonstrated. Labeling on solid phase with [(18)F]SFB resulted in crude (18)F-fluorobenzoylpeptides whose radiochemical purities were typically greater than 90% and that could be prepared in synthesis times from 65 to 76 min.

Radioiodinated sunitinib as a potential radiotracer for imaging angiogenesis-radiosynthesis and first radiopharmacological evaluation of 5-[125I]Iodo-sunitinib.

Sunitinib® (SU11248) is a highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR). Radiolabeled inhibitors of RTKs might be useful tools for monitoring RTKs levels in tumour tissue giving valuable information for anti-angiogenic therapy. We report here the synthesis of a (125)I-labeled derivative of sunitinib® and its first radiopharmaceutical characterization. The non-radioactive reference compound 5-iodo-sunitinib 4 was prepared by Knoevenagel condensation of 5-iodo-oxindole with the corresponding substituted 5-formyl-1H-pyrrole. In a competition binding assay against VEGFR-2 a binding constant (K(d)) of 16 nM for 4 was found. The ability of 4 to inhibit tyrosine kinase activity was demonstrated on RTK expressing cells suggesting this radiotracer as a useful tool for monitoring VEGFR expression. 5-[(125)I]lodo-sunitinib, [(125)I]-4 was obtained via destannylation of the corresponding tributylstannyl precursor with [(125)I]NaI in the presence of H(2)O(2) in high radiochemical yield (>95%) and radiochemical purity (<98%) after HPLC purification. Determination of human plasma protein binding at time intervals of 0; 1; 2; 4 and 24h suggested a low non-specific binding of 5-10%. Preliminary biodistribution studies of [(125)I]-4 in healthy CD-1 mice showed a relatively high uptake in VEGFR-2 rich tissues like kidney and lung followed by rapid washout (9.6 and 9.7; 4.5 and 3.8% ID/g of kidney and lung at 1 and 4h, respectively).

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.

The radiosynthesis of 3-(4-[(18)F]fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole [(18)F]-3 as potential PET radiotracer for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo is described. [(18)F]-3 was prepared by McMurry cyclization of a (18)F-labeled intermediate with low valent titanium and zinc via a two-step procedure in a remote controlled synthesizer unit including HPLC purification and solid phase extraction. In this way [(18)F]-3 was synthesized in 80 min synthesis time in 10% total decay corrected yield from [(18)F]fluoride in radiochemical purity >98% and a specific activity of 74-91 GBq/µmol (EOS). [(18)F]-3 was evaluated in vitro using pro-inflammatory stimulated THP-1 and COX-2 expressing tumor cell lines (FaDu, A2058, HT-29), where the radiotracer uptake was shown to be consistent with up regulated COX-2 expression. The stability of [(18)F]-3 was determined by incubation in rat whole blood and plasma in vitro and by metabolite analysis of arterial blood samples in vivo, showing with 75% of original compound after 60 min an acceptable high metabolic stability. However, no substantial tumor accumulation of [(18)F]-3 could be observed by dynamic small animal PET studies on HT-29 tumor-bearing mice in vivo. This may be due to the only moderate COX-1/COX-2 selectivity of 3 as demonstrated by both cellular and enzymatic cyclooxygenase inhibition assay in vitro. Nevertheless, the new approach first using McMurry cyclization in (18)F-chemistry gives access to (18)F-labeled diarylsubstituted heterocycles that hold promise as radiolabeled COX-2 inhibitors.

Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors.

A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a-e showed IC(50) values ranging from 0.42 to 8.1 mM for COX-1 and 2.0 to 200 µM for COX-2. Most potent compound 3c (IC(50) (COX-2)=2.0 µM) was further used in molecular modeling docking studies.

Deuteration versus ethylation - strategies to improve the metabolic fate of an 18F-labeled celecoxib derivative.

The inducible isoenzyme cyclooxygenase-2 (COX-2) is closely associated with chemo-/radioresistance and poor prognosis of solid tumors. Therefore, COX-2 represents an attractive target for functional characterization of tumors by positron emission tomography (PET). In this study, the celecoxib derivative 3-([18F]fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-5-(p-tolyl)-1H-pyrazole ([18F]5a) was chosen as a lead compound having a reported high COX-2 inhibitory potency and a potentially low carbonic anhydrase binding tendency. The respective deuterated analog [D2,18F]5a and the fluoroethyl-substituted derivative [18F]5b were selected to study the influence of these modifications with respect to COX inhibition potency in vitro and metabolic stability of the radiolabeled tracers in vivo. COX-2 inhibitory potency was found to be influenced by elongation of the side chain but, as expected, not by deuteration. An automated radiosynthesis comprising 18F-fluorination and purification under comparable conditions provided the radiotracers [18F]5a,b and [D2,18F]5a in good radiochemical yields (RCY) and high radiochemical purity (RCP). Biodistribution and PET studies comparing all three compounds revealed bone accumulation of 18F-activity to be lowest for the ethyl derivative [18F]5b. However, the deuterated analog [D2,18F]5a turned out to be the most stable compound of the three derivatives studied here. Time-dependent degradation of [18F]5a,b and [D2,18F]5a after incubation in murine liver microsomes was in accordance with the data on metabolism in vivo. Furthermore, metabolites were identified based on UPLC-MS/MS.

Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives.

A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe(2), 4-Cl, 4-F). All compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC(50)=0.03-0.36 microM) compared to their corresponding 1,3-diaryl-substituted counterparts (IC(50)=0.15 to >10.0 microM). In both series, compounds possessing an electron-withdrawing group (Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups (Me, OMe, NMe(2)). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors.