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Axitinib sulfoxide (also known as AG-028458; PF-03482595) is a primary and S-oxidized metabolite of Axitinib, an investigational anticancer drug. Axitinib (AG013736 and Inlyta) is a potent, orally bioavailable, small molecule and multi-targeted inhibitor TKI (tyrosine kinase inhibitor) that inhibits VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM in Porcine aorta endothelial cells, respectively.
| Targets |
Major metabolite of Axitinib; VEGFR
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|---|---|
| ln Vivo |
[(11)C]axitinib and [(11)C]nintedanib were successfully synthesized with 10.5±2.6% and 25.6±3.3% radiochemical yield (corrected for decay), respectively. Biodistribution studies only demonstrated tumor uptake of [(11)C]nintedanib in FaDu xenografts of 1.66±0.02% ID/g at 60min p.i. In vivo stability analysis of [(11)C]axitinib at 45min p.i. revealed the formation of predominantly non-polar metabolites (36.6±6.8% vs 47.1±8.4% of parent tracer and 16.3±2.1% of polar metabolites), while for [(11)C]nintedanib mostly polar metabolites were found (70.9±4.1 vs 26.7±3.9% of parent tracer and only 2.4±1.6 of a non-polar metabolites). No isomerization of [(11)C]axtinib was observed in vivo; however, a sulfoxide metabolite could be detected using LC-MS/MS. For [(11)C]nintedanib, LC-MS/MS revealed formation of the reported primary carboxylic acid metabolite when in vitro plasma incubations were performed, with large differences in plasmas from different species. In vivo metabolite analysis, however, did not demonstrate the presence of the carboxylic acid in plasma or tumor tissue.
Conclusions: Reliable syntheses of [(11)C]axitinib and [(11)C]nintedanib were successfully developed. Tumor uptake was observed for [(11)C]nintedanib, albeit modest. The metabolic profiles of the tracers suggest that rapid metabolism is partly responsible for the modest tumor targeting observed[1].
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| Animal Protocol |
Following successful tracer synthesis, biodistribution studies in VU-SCC-OE and FaDu xenograft bearing mice were performed. Furthermore, tracer stability studies in mice were performed employing (radio-)HPLC and LC-MS/MS techniques. For [(11)C]nintedanib an LC-MS/MS method was developed to detect the primary carboxylic acid metabolite, resulting from methylester cleavage, in plasma and tumors, because this metabolite is postulated to be important for nintedanib efficacy. LC-MS/MS was also explored to assess the metabolic fate of [(11)C]axitinib in vivo, since axitinib has an isomerizable double bond[1].
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| References | |
| Additional Infomation |
Tyrosine kinase inhibitors (TKIs) are very attractive targeted drugs, although a large portion of patients remains unresponsive. PET imaging with EGFR targeting TKIs ([(11)C]erlotinib and [(18)F]afatinib) showed promise in identifying treatment sensitive tumors. The aim of this study was to synthesize two anti-angiogenic TKI tracers, [(11)C]axitinib and [(11)C]nintedanib, and to evaluate their potential for PET.[1]
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| Molecular Formula |
C22H18N4O2S
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|---|---|
| Molecular Weight |
402.469
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| Exact Mass |
402.115
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| Elemental Analysis |
C, 65.65; H, 4.51; N, 13.92; O, 7.95; S, 7.97
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| CAS # |
1347304-18-0
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| PubChem CID |
86278350
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.748
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
628
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CNC(C1=CC=CC=C1S(C1C=CC2C(=NNC=2C=1)/C=C/C1=CC=CC=N1)=O)=O
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| InChi Key |
MAHSNFBPPYMWFB-FMIVXFBMSA-N
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| InChi Code |
InChI=1S/C22H18N4O2S/c1-23-22(27)18-7-2-3-8-21(18)29(28)16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+
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| Chemical Name |
N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfinyl]benzamide
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| Synonyms |
Axitinib sulfoxide; 1347304-18-0; Axitinib metabolite M12; AxitinibSulfoxide; AG-028458; 55P8GY3IEK; Benzamide, N-methyl-2-((3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)sulfinyl); PF-03482595;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4847 mL | 12.4233 mL | 24.8466 mL | |
| 5 mM | 0.4969 mL | 2.4847 mL | 4.9693 mL | |
| 10 mM | 0.2485 mL | 1.2423 mL | 2.4847 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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