Flotufolastat F 18

• Flotufolastat F-18 Gallium
• POSLUMA
• CAS 2305081-64-3
• 18FrhPSMA-7.3
• 18F-rhPSMA-7.3
• 1537.3 g/mol
• C₆₃H₉₆FGaN₁₂O₂₅Si

gallium;2-[7-[(1S)-1-carboxy-4-[[(2R)-1-[[(1R)-1-carboxy-5-[[4-[[(4R)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]butanoyl]amino]butyl]amino]-4-oxobutanoyl]amino]pentyl]amino]-3-[[4-[ditert-butyl(fluoranyl)silyl]benzoyl]amino]-1-oxopropan-2-yl]amino]-4-oxobutyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate

WeightAverage: 1470.63
Monoisotopic: 1469.662295938

Chemical FormulaC₆₃H₉₉FN₁₂O₂₅Si

2639294-14-5 CAS

FDA 2023, Posluma, 5/25/2023, To use with positron emission tomography imaging in certain patients with prostate cancer
Drug Trials Snapshot

Flotufolastat (¹⁸F), sold under the brand name Posluma, is a radioactive diagnostic agent for use with positron emission tomography (PET) imaging for prostate cancer.^[1] The active ingredient is flotufolastat (¹⁸F).^[1]

Flotufolastat (¹⁸F) was approved for medical use in the United States in May 2023.^[1][2]

SYNTHESIS

Bejot, R., et al. (2022). Methods of preparation of 18F labelled silyl-fluoride compounds (WO 2023047138 A1). World Intellectual Property Organization. https://patents.google.com/patent/WO2023047138A1/en?oq=WO2023047138A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023047138&_cid=P12-MB54HA-36492-1

EXAMPLES

rhPMSA-7, rhPMSA-10 & 2C013

Synthesis protocols for the ¹⁹F compounds ¹⁹F-rhPSMA-7.1 , ¹⁹F-rhPSMA-7.2, ¹⁹F-rhPSMA-7.3, ¹⁹F-rhPSMA-7.4, ¹⁹F-rhPSMA-10.1 , ¹⁹F-rhPSMA-10.2 and ¹⁹F-2C013 (shown below) are provided in WO2019/020831 , W02020/157177, WO2020/157184 and EP21157154.2.

rhPMSA-7.1

rhPMSA-7.2

rhPMSA-7.4

2C013

¹⁸F-Fluorination of rhPSMA-7.3

Aqueous ¹⁸F’ was passed through a quaternary methyl ammonium carbonate anion exchange cartridge (Sep-Pak Accell Plus QMA Carbonate), which was preconditioned with 5 mL of water. ¹⁸F’ was eluted with a 15 mg/mL cryptand 222 and 2.0 mg/mL potassium carbonate solution in acetonitrile/water (9/1 v/v). The resulting [¹⁸F]fluoride, cryptand and potassium carbonate solution was then azeotropically dried by heating at approx. 100 °C. Before radiolabelling, a 160 mM solution of acetic acid in DMSO was used to dissolve 0.27 pmol of rhPSMA-7.3. The resulting rhPSMA-7.3 solution was added to azeotropically-dried [¹⁸F]fluoride and the reaction mixture was incubated for 5 minutes at room temperature. For purification, a solid-phase extraction cartridge containing a hydrophobic resin (Sep-Pak Plus Short tC18 cartridge), preconditioned with 5 mL EtOH, followed by 10 mL of H2O was used. The labelling mixture was diluted with 5 mL citrate buffer (pH 5) and passed through the cartridge followed by 24 mL of citrate buffer. The ¹⁸F-rhPSMA-7.3 was eluted with 3 mL of a 1 :1 mixture (v/v) of EtOH in water.

Previously the process made use of oxalic acid and the impact of oxalic acid content, with on-cartridge drying of alkaline [¹⁸F]fluoride/K222, on radionuclide incorporation with rhPSMA-7.3 and similar silicon-fluorine acceptors (Kostikov, A. P. et al. Bioconjugate Chem. 2012, 23, 106-114) was evaluated. Maximum ¹⁸F-radiolabelling was reached when using approx.

30 pmol oxalic acid for 90 pmol of potassium hydroxide (acid-base molar ratio -0.6:1) (Wurzer, A. et al. EJNMMI radiopharm. chem. 6, 4 (2021)).

Although used in a limited quantity, oxalic acid may be toxic. Hence further development was conducted to replace oxalic acid with acetic acid, a common excipient for parenteral administration. Therefore, oxalic acid (dicarboxylic acid, 30 pmol) was replaced with 2 molar equivalents of acetic acid (monocarboxylic acid 60 pmol) and was shown to yield ¹⁸F-rhPSMA- 7.3 successfully using the Scintomics GRP synthesis module.

Implementation of the process with azeotropic drying of [¹⁸F]fluoride requires inverse addition, i.e., addition of acidified precursor solution to alkaline [¹⁸F]fluoride/K222 instead of addition of alkaline [¹⁸F]fluoride/K222 to the acidic precursor solution. As shown in Figure 1 , a higher amount of acid was required to prevent isomerisation of ¹⁸F-rhPSMA-7.3 or ¹⁹F-rhPSMA-7.3 in the presence of carbonate to related Compound A shown below. A decrease of radiolabelling conversion was also observed with increasing acid content. The optimised acetic acid amount for each process is provided in Table 1.

Compound A

Table 1 : Nominal acetic acid amounts for ¹⁸F-radiolabelling

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : Impact of acetic acid content on isomerisation (formation of Related Compound A) and yield.

Medical uses

Flotufolastat (¹⁸F) is indicated for positron emission tomography of prostate-specific membrane antigen positive lesions in men with prostate cancer.^[1][3]

References

1. ^ Jump up to:^{a b c d e} “Posluma- flotufolastat f-18 injection”. DailyMed. 2 June 2023. Retrieved 25 June 2023.
2. ^ “U.S. FDA Approves Blue Earth Diagnostics’ Posluma (Flotufolastat F 18) Injection, First Radiohybrid PSMA-targeted PET Imaging Agent for Prostate Cancer” (Press release). Blue Earth Therapeutics. 30 May 2023. Retrieved 25 June 2023 – via Business Wire.
3. ^ Heo YA (September 2023). “Flotufolastat F 18: Diagnostic First Approval”. Molecular Diagnosis & Therapy. 27 (5): 631–636. doi:10.1007/s40291-023-00665-y. PMID 37439946. S2CID 259843992.

External links

• Clinical trial number NCT04186819 for “Imaging Study to Investigate the Safety and Diagnostic Performance of rhPSMA 7.3 (18F) in Newly Diagnosed Prostate Cancer (LIGHTHOUSE)” at ClinicalTrials.gov
• Clinical trial number NCT04186845 for “Imaging Study to Investigate Safety and Diagnostic Performance of rhPSMA 7.3 (18F) PET Ligand in Suspected Prostate Cancer Recurrence (SPOTLIGHT)” at ClinicalTrials.gov

Flotufolastat F-18 gallium
Clinical data
Trade names	Posluma
Other names	18F-rhPSMA-7.3, flotufolastat F18 (USAN US)
License data	US DailyMed: Flotufolastat f-18
Routes of administration	Intravenous
ATC code	V09IX18 (WHO)
Legal status
Legal status	US: ℞-only[1]
Identifiers
CAS Number	2639294-14-5
PubChem CID	166177191
DrugBank	DB17851
UNII	811W19E3OL
KEGG	D12606
Chemical and physical data
Formula	C63H9918FN12O25Si
Molar mass	1537.3 g·mol−1
3D model (JSmol)	Interactive imageInteractive image
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/////////Flotufolastat F 18, Posluma, FDA 2023, APPROVALS 2023, Flotufolastat F-18 Gallium, 18FrhPSMA-7.3, 18F-rhPSMA-7.3