Cgmp-compliant automated [18f]fspg production for clinical examination
OwnerMai LIN, Henry Charles MANNINGinventors
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Abstract
According to various aspects of this disclosure, the present disclosure relates to an automated process for the radiosynthesis of [18F]FSPG, a positron emission tracer. The automated optimized process of the present invention enables the centralized and large-scale production of [18F]FSPG for commercial use.
Claims45
An automated process for the synthesis of (S)-4-(3-18F-fluoropropyl)-L-glutamic acid ([18F]FSPG) in a cassette, the method comprising:
- a. Dissolving a (S)-4-(3-18F-fluoropropyl)-L-glutamic acid precursor in anhydrous acetonitrile and adding the resulting solution to a reaction vessel comprising radiolabeled fluoride (18F);
- b. Heating the reaction vessel at 100° C. to 110° C. for 5 minutes to 15 minutes to provide a crude intermediate product;
- c. Adding a first aliquot of an acid to the reaction vessel and heating at 100° C. to 110° C. for 2 to 10 minutes followed by adding an aliquot of a base to the reaction vessel and heating at 60° C. to 80° C. for 5 to 15 minutes to remove protecting groups to provide a crude [18F]FSPG;
- d. Acidifying the crude [18F]FSPG;
- e. Loading the acidified crude 18F-FSPG onto one or more reverse-phase/cation exchange solid phase extraction cartridges;
- f. Eluting the [18F]FSPG off the one or more reverse-phase solid phase extraction cartridges;
- g. Purifying the [18F]FSPG through one or more carbon-phase/reverse-phase solid phase extraction cartridges;
- and
- wherein each of (a)-(g) are within the cassette.
The process according to any preceding claims, wherein the first aliquot of acid in step (c) is selected from the group consisting of sulfuric acid, hydrochloric acid, and trifluoroacetic acid.
The process according to any preceding claims, wherein the first aliquot of acid in step (c) is sulfuric acid.
The process according to any preceding claims, wherein the first aliquot of acid in step (c) is hydrochloric acid.
The process according to any preceding claims, wherein the base in step (c) is sodium hydroxide.
The process according to any preceding claims, wherein the base in step (c) is potassium hydroxide.
The process according to any preceding claim, wherein the one or more reverse-phase solid phase extraction cartridges are washed with water to remove side products before step (f).
The process according to any preceding claim, wherein the crude [18F]FSPG is acidified with a second aliquot of sulfuric acid in step (d).
The process according to any preceding claim, further comprising purifying the [18F]FSPG through one or more normal-phase solid phase extraction cartridges outside of the cassette.
The process according to any preceding claim, further comprising sterilizing the [18F]FSPG product through a sterilizing filter to produce a final [18F]FSPG composition.
The process according to any preceding claim, wherein the final purified [18F]FSPG has a greater than 90% radiochemical purity.
The process according to any preceding claim, wherein the final purified [18F]FSPG has a greater than 95% radiochemical purity.
The process according to any preceding claim, wherein the final purified [18F]FSPG has a greater than 96% radiochemical purity.
The process according to any preceding claim, wherein the final purified [18F]FSPG has a greater than 97% radiochemical purity.
The process according to any preceding claim, wherein the final purified [18F]FSPG has a greater than 98% radiochemical purity.
The process according to any preceding claim, wherein the process produces [18F]FSPG with a non-decay corrected radiochemical yield of at least 10%.
The process according to any preceding claim, wherein the reaction product is loaded onto the reverse-phase solid phase extraction with a flow rate of 8 ml/min to 20 ml/min and eluted off the reverse-phase solid phase extraction cartridge with a flow rate of 4 ml/min to 14 ml/min.
The process according to any preceding claim, wherein the one or more solid phase extraction cartridges in step (e) contain reverse-phase/cation exchange sorbents.
The process according to any preceding claim, wherein the [18F]FSPG is eluted off the reverse-phase solid phase extraction cartridge in the same direction as the crude [18F]FSPG was loaded.
The process according to any preceding claim, wherein the one or more reverse-phase solid extraction cartridges in step (f) comprise aluminum oxide.
The process according to any preceding claim, wherein the one or more carbon-phase/reverse-phase solid extraction cartridges in step (g) comprise a carbon sorbent.
The process according to any preceding claim, wherein the FSPG precursor has one of the following structure(s):
The process according to any preceding claim, wherein the [18F]FSPG has a starting activity of about 10 to 125 Gbq.
The process according to any preceding claim, wherein the final [18F]FSPG composition has a concentration of about 185 to 1850 MBq/ml.
The process according to any preceding claim, wherein the final [18F]FSPG composition is produced in less than 40 minutes from the start of synthesis.
The process according to any preceding claim, wherein the final [18F]FSPG composition has a pH of 6.5 to 7.5.
The process according to any preceding claim, wherein the radiolabeled fluoride is prepared by a method comprising:
- a. Irradiating 18O water to produce a solution of 18F in 18O water;
- b. Loading the 18F solution onto a quaternary ammonium anion exchange cartridge pre-conditioned with potassium bicarbonate;
- c. Eluting 18F from the cartridge into the reaction vessel with an eluent of potassium carbonate/4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane in 50% water/acetonitrile solution;
- and
- d. Heating the reaction vessel to remove water.
Dependencies are inferred from the claim text.