Flurpiridaz F 18

Flurpiridaz F 18

WeightAverage: 367.84
Monoisotopic: 367.1328329

Chemical FormulaC₁₈H₂₂ClFN₂O₃

• 863887-89-2
• Bms 747158-02

2-tert-butyl-4-chloro-5-[[4-(2-(18F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one

• 2-tert-butyl-4-chloro-5-[[4-(2-(18F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one
• 2-TERT-BUTYL-4-CHLORO-5-((4-((2-(18F)FLUOROETHOXY)METHYL)PHENYL)METHOXY)PYRIDAZIN-3(2H)-ONE
• 3(2H)-PYRIDAZINONE, 4-CHLORO-2-(1,1-DIMETHYLETHYL)-5-((4-((2-(FLUORO-18F)ETHOXY)METHYL)PHENYL)METHOXY)-
• UNII-TY3V24C029

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

Chemistry

Synthesis of precursor of [¹⁸F]Flurpiridaz (7) [2-(4-((1-tert-Butyl-5-chloro-6-oxo-1,6-dihydropyridazine-4-yloxy)methyl)benzyloxy)ethyl-4- methylbenzensulfonate] (6)

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).

Synthesis of [¹⁸F]Flurpiridaz (7)

Preliminary studies & synthesis of [¹⁹F]Flurpiridaz (7) (Cold runs)

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.

Methods

Firstly, consecutive cold syntheses of [¹⁹F]Flurpiridaz (7) were performed using stable isotope fluorine-19 and optimum reaction parameters were tried to be determined.

Eluent solution-I (Kryptofix K2.2.2./K₂CO₃)

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

Medical uses

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]

History

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]

Society and culture

Legal status

Flurpiridaz (¹⁸F) was approved for medical use in the United States in September 2024.^[2][3]

Names

Flurpiridaz (¹⁸F) is the international nonproprietary name.^[8]

References

1. ^ “Flurpiridaz F 18”. AMA Finder. Retrieved 27 September 2024.
2. ^ Jump up to:^{a b c d e} “Flyrcado (flurpiridaz F 18) injection, for intravenous use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 27 September 2024.
3. ^ Jump up to:^{a b c d e f g h i j k} “FDA approves imaging drug for evaluation of myocardial ischemia”. U.S. Food and Drug Administration (FDA). 27 September 2024. Retrieved 27 September 2024.  This article incorporates text from this source, which is in the public domain.
4. ^ “Drug Approval Package: Flyrcado Injection”. U.S. Food and Drug Administration (FDA). 25 October 2024. Retrieved 21 January 2025.
5. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration. 1 October 2024. Retrieved 8 November 2024.
6. ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
7. ^ “Flurpiridaz F-18”. Inxight Drugs. Retrieved 27 September 2024.
8. ^ World Health Organization (2011). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 65”. WHO Drug Information. 25 (1). hdl:10665/74623.

Further reading

• Maddahi J, Agostini D, Bateman TM, Bax JJ, Beanlands RS, Berman DS, et al. (October 2023). “Flurpiridaz F-18 PET Myocardial Perfusion Imaging in Patients With Suspected Coronary Artery Disease”. Journal of the American College of Cardiology. 82 (16): 1598–1610. doi:10.1016/j.jacc.2023.08.016. PMID 37821170.
• Matsumoto N (2023). “Progress of 18F-flurpiridaz in Clinical Trials”. Annals of Nuclear Cardiology. 9 (1): 91–93. doi:10.17996/anc.23-00011. PMC 10696143. PMID 38058576.

External links

• Clinical trial number NCT03354273 for “An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz (18F) Injection PET MPI in the Detection of Coronary Artery Disease (CAD)” at ClinicalTrials.gov
• Clinical trial number NCT01347710 for “A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients With CAD” at ClinicalTrials.gov

1. Maddahi J, Agostini D, Bateman TM, Bax JJ, Beanlands RSB, Berman DS, Dorbala S, Garcia EV, Feldman J, Heller GV, Knuuti JM, Martinez-Clark P, Pelletier-Galarneau M, Shepple B, Tamaki N, Tranquart F, Udelson JE: Flurpiridaz F-18 PET Myocardial Perfusion Imaging in Patients With Suspected Coronary Artery Disease. J Am Coll Cardiol. 2023 Oct 17;82(16):1598-1610. doi: 10.1016/j.jacc.2023.08.016. [Article]
2. Berman DS, Maddahi J, Tamarappoo BK, Czernin J, Taillefer R, Udelson JE, Gibson CM, Devine M, Lazewatsky J, Bhat G, Washburn D: Phase II safety and clinical comparison with single-photon emission computed tomography myocardial perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission tomography. J Am Coll Cardiol. 2013 Jan 29;61(4):469-477. doi: 10.1016/j.jacc.2012.11.022. Epub 2012 Dec 19. [Article]
3. Maddahi J, Lazewatsky J, Udelson JE, Berman DS, Beanlands RSB, Heller GV, Bateman TM, Knuuti J, Orlandi C: Phase-III Clinical Trial of Fluorine-18 Flurpiridaz Positron Emission Tomography for Evaluation of Coronary Artery Disease. J Am Coll Cardiol. 2020 Jul 28;76(4):391-401. doi: 10.1016/j.jacc.2020.05.063. [Article]
4. Patel KK, Singh A, Bateman TM: The Potential of F-18 Flurpiridaz PET/CT Myocardial Perfusion Imaging for Precision Imaging. Curr Cardiol Rep. 2022 Aug;24(8):987-994. doi: 10.1007/s11886-022-01713-5. Epub 2022 May 26. [Article]
5. FDA Approved Drug Products: FLYRCADO (flurpiridaz F 18) injection, for intravenous use [Link]

/////////////Flurpiridaz F 18, Flyrcado, APPROVALS 2024, FDA 2024, Bms 747158-02, BMS 747158-02, BM-747158-02, BMS747158-02