April 27, 2025 9:01 am
Flurpiridaz F 18
WeightAverage: 367.84
Monoisotopic: 367.1328329
Chemical FormulaC18H22ClFN2O3
2-tert-butyl-4-chloro-5-[[4-(2-(18F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one
FDA APPROVED 9/27/2024, Flyrcado, A radioactive diagnostic drug to evaluate for myocardial ischemia and infarction
Flurpiridaz (18F), sold under the brand name Flyrcado, is a cyclotron-produced radioactive diagnostic agent for use with positron emission tomography (PET) myocardial perfusion imaging under rest or stress (pharmacologic or exercise).[3] Flurpiridaz (18F) It is given by intravenous injection.[3]
The most common adverse reactions include dyspnea (shortness of breath), headache, angina pectoris (severe pain in the chest), chest pain, fatigue, ST segment changes, flushing, nausea, abdominal pain, dizziness, and arrhythmia (irregular heartbeat).[3]
Flurpiridaz (18F) was approved for medical use in the United States in September 2024.[3][4][5][6]
PATENT
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | |
|---|---|---|---|---|
| US9687571 | No | 2017-06-27 | 2032-11-01 |  |
| US9603951 | No | 2017-03-28 | 2031-05-02 | |
| US9161997 | No | 2015-10-20 | 2026-02-04 | |
| US8936777 | No | 2015-01-20 | 2031-06-30 | |
| US8226929 | No | 2012-07-24 | 2028-06-21 | |
| US7344702 | No | 2008-03-18 | 2026-05-26 | |
SYN
https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-022-00182-z
Precursor 6 was synthesized according to the literature procedures with few changes (Purohit et al. 2008; Nagel 2014) Briefly, to a mixture of mucochloric acid (1) (1.18 g, 6.98 mmol) and Na2CO3 (0.33 g, 3.11 mmol) in 15 ml of distilled water was added tert-butylhydrazine hydrochloride (0.86 g, 6.90 mmol) in ice-water bath and reaction mixture was stirred for about 4 h. White precipitate was washed by water and dried under reduced vacuum after filtration. Then, 13.2 ml of benzene and acetic acid (1.86 g, 30,95 mmol) were added and reaction was kept at 40 °C for 4 h. Organic phase was extracted with 10 ml of water and washed by 5 ml of 1.25 M NaOH(aq), 5 ml of 5 M HCl(aq) and 10 ml of water respectively. 0.83 g of DCP (2) was obtained as an orange solid. 1.0 g of DCP (2) (4,53 mmol) was dissolved in 15 ml of dry DMF, 1,4-phenylene dimethanol (3.2 g, 23.16 mmol) and Cs2CO3 (6.0 g, 18.41 mmol) were slowly added to the solution and reaction was stirred at 68 °C under nitrogen atmosphere for about 6 h and allowed to be cooled down to room temperature. Crude product was extracted with CHCl3/water several times and evaporated under vacuum. Residue was subjected to flash column chromatography (silica gel 40 g, EtOAc/Hexane 3:2) and 0.91 g of compound 3 was obtained as white solid. Then, 0.91 g of an alcoholic compound 3 was dissolved in 15 ml of freshly distilled dichloromethane and 0.14 ml of PBr3 was slowly added to the solution. The reaction was carried out at room temperature for about 2 h under nitrogen atmosphere. Crude product was extracted with 30 ml of water and dried under vacuum. White solid product 4 was successfully obtained in a quantitative yield without further purification for next step. KOtBu (0.28 g, 2.49 mmol) and 11.2 ml of ethylene glycol were stirred at room temperature under nitrogen atmosphere. Then, 0.95 g of bromide compound 4 dissolved in 8 ml of dry THF was added slowly into the reaction mixture and the reaction was stirred at 60 °C for overnight. After cooling to room temperature, THF was evaporated and residue was extracted with CHCl3/water several times. Organic phase was evaporated under vacuum and residue was submitted to flash column chromatograpy (silica gel 40 g, EtOAc/Hexane 2:1) and 0.86 g of compound 5 was obtained as colorless oil in quantitative yield. Finally, to a mixture of 0.85 g of compound 5 and tosyl chloride (690 mg, 3.62 mmol) in 6 ml of dry dichloromethane, 0.64 ml of DIPEA and 4-(dimethylamino) pyridine (445 mg, 3.64 mmol) were added and reaction was carried out at room temperature for 2.5 h under nitrogen atmosphere. Dichloromethane was evaporated and crude product was directly subjected to flash column chromatograpy (silica gel 45 g, EtOAc/Hexane 2:1). 0.9 g of pure tosylate 6 (precursor of [18F]Flurpiridaz) was obtained by recrystallisation in dichloromethane at + 4 °C. Tosylate 6 was further purified through semipreparative HPLC for an accurate spectroscopic characterization (Fig. 1). Anal. Calcd for C25H29ClN2O6S: C, 57.63; H, 5.61; Cl, 6.80; N, 5.38; S, 6.15. Found: C, 57.86; H, 5.84; Cl, 7.03; N, 5.66; S, 6.34.
1H NMR ((CDCl3, 400 MHz) δ (ppm)): 7,80 (d, J = 9.1 Hz, 2H); 7,73 (s, 1H); 7,39 (d, J = 9.1 Hz, 2H); 5,29 (s, 2H,); 4,49 (s, 2H,); 4,20–4,19 (m, 2H); 3,70–3,65 (m, 2H); 2,42 (s, 3H); 1,60 (s, 9H).
Materials KF, Ethanol, and Acetonitrile were obtained from Sigma Aldrich. Kryptofix K2.2.2./K2CO3 (22 mg Kryptofix K2.2.2., 7 mg K2CO3, 300 µl acetonitrile and 300 µl pure water), TBA-HCO3 (0.075 M) solution and QMA Cartridges were from ABX. Sep-Pak C18 Plus Light Cartridge was from Waters.
Firstly, consecutive cold syntheses of [19F]Flurpiridaz (7) were performed using stable isotope fluorine-19 and optimum reaction parameters were tried to be determined.
50 mg of KF was dissolved in 2 mL of ultrapure water and directly passed through the preconditioned QMA cartridge. The QMA cartridge was rinsed with 5 mL of ultrapure water and dried with N2. [19F]F trapped on the QMA cartridge was eluted into the reaction vial with 600 µL of Kryptofix K2.2.2./K2CO3 solution. Solvents in the reaction vial were removed at 100 °C, [19F]F and Kryptofix K2.2.2./K2CO3 were dried gently. Then, 10 mg of precursor 6 dissolved in 2 mL of anhydrous acetonitrile was added to the reaction vial and the mixture was sealed and heated at 95 °C for 10 min. The reaction solution was diluted with 5 ml of ultrapure water and directly passed through a preconditioned C-18 cartridge. C-18 cartridge was rinsed with 5 mL of ultrapure water and dried with air. Finally, C-18 cartridge was eluted with 5 mL of ethanol and transferred into the final product vial. The final product was diluted with 5 mL of ultrapure water (n = 3) and analyzed by HPLC (described in HPLC analysis of precursor 6) to determine its composition.
Chromatogram analysis indicated that four different separate peaks were observed. The unreacted precursor 6 was detected around 11.55 min. The other two peaks were detected between 8 and 9 min. Another major peak around 5.5 min was detected. It was concluded that the chemical yield of product 7 was low due to the majority of side-product formations
Flurpiridaz (18F) is indicated for positron emission tomography myocardial perfusion imaging under rest or stress (pharmacologic or exercise) in adults with known or suspected coronary artery disease to evaluate for myocardial ischemia and infarction.[2][3]
Flurpiridaz F-18 is a fluorine 18-labeled agent developed by Lantheus Medical Imaging for the diagnosis of coronary artery disease.[7]
The efficacy and safety of flurpiridaz (18F) were evaluated in two prospective, multicenter, open-label clinical studies in adults with either suspected CAD (Study 1: NCT03354273) or known or suspected CAD (Study 2: NCT01347710).[3] Study 1 evaluated the sensitivity (ability to designate an imaged patient with disease as positive) and specificity (ability to designate an imaged patient without disease as negative) of flurpiridaz (18F) for the detection of significant CAD in subjects with suspected CAD who were scheduled for invasive coronary angiography (ICA).[3] Across three flurpiridaz (18F) imaging readers, estimates of sensitivity ranged from 74% to 89% and estimates of specificity ranged from 53% to 70% for CAD defined as at least 50% narrowing of an artery.[3]
Study 2 evaluated the sensitivity and specificity of flurpiridaz (18F) for the detection of significant CAD in subjects with known or suspected CAD who had ICA without intervention within 60 days prior to imaging or were scheduled for ICA.[3] Across three flurpiridaz (18F) imaging readers, estimates of sensitivity ranged from 63% to 77% and estimates of specificity ranged from 66% to 86% for CAD defined as at least 50% narrowing of an artery.[3]
Flurpiridaz (18F) was approved for medical use in the United States in September 2024.[2][3]
Flurpiridaz (18F) is the international nonproprietary name.[8]
This article incorporates text from this source, which is in the public domain./////////////Flurpiridaz F 18, Flyrcado, APPROVALS 2024, FDA 2024, Bms 747158-02, BMS 747158-02, BM-747158-02, BMS747158-02
| Clinical data | |
|---|---|
| Trade names | Flyrcado |
| Other names | NMB58, BMS-747158-02, flurpiridaz F-18, flurpiridaz F 18[1] (USAN US) |
| AHFS/Drugs.com | Flyrcado |
| License data | US DailyMed: Flurpiridaz |
| Routes of administration | Intravenous |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[2] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 863887-89-2 |
| PubChem CID | 11405965 |
| DrugBank | DB18773 |
| ChemSpider | 9580860 |
| UNII | TY3V24C029 |
| KEGG | D10009 |
| CompTox Dashboard (EPA) | DTXSID00235517 |
| Chemical and physical data | |
| Formula | C18H22Cl[18F]N2O3[2] |
| Molar mass | 367.8 [2] |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
Posted by DR ANTHONY MELVIN CRASTO Ph.D
Categories: approvals 2024, FDA 2024
Tags: approvals 2024, BM-747158-02, Bms 747158-02, BMS747158-02, fda 2024, Flurpiridaz F 18, Flyrcado
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