Imaging agents and methods of use

Patent metadata

Field	Value
Publication number	US-2021361784-A1
Application number	US-202117205628-A
Country	US
Kind code	A1
Filing date	Mar 18, 2021
Priority date	Dec 2, 2016
Publication date	Nov 25, 2021
Grant date	—

Abstract

An imaging agent and a method of its use for imaging a necrosis in a tissue of a subject. The imaging method may be positron emission tomography (PET). In at least one embodiment the imaging agent comprises 2-deoxy-2-[18F]fluoroglucaric acid (18F-FGA), or a pharmaceutically-acceptable salt thereof. The imaging agent may be disposed in a pharmaceutically-acceptable excipient, carrier, diluent, or vehicle. The imaging agent may be contained within a kit. The disclosure includes in at least one embodiment a method of preparing a radiopharmaceutical such as 18F-FGA for use in imaging. The 18F-FGA binds preferentially to necrotic cells versus living cells.

First claim

What is claimed is:

1 . An imaging agent comprising 2-deoxy-2-[ 18 F]fluoroglucaric acid ( 18 F-FGA), or a pharmaceutically-acceptable salt thereof, and wherein the binding affinity of 18 F-FGA for living cells is 50% or less of the binding affinity of 99m Tc-glucarate for living cells.

2 . The imaging agent of claim 1 disposed in a pharmaceutically-acceptable carrier, diluent, vehicle, or excipient.

3 . The imaging agent of claim 1 , produced by the method of combining:
(1) 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 F-FDG); (2) an oxidizing agent selected from the group consisting of 4-hydroxy-TEMPO, TEMPO methacrylate, 4-oxo-TEMPO, 4-amino-TEMPO, 4-acetamido-TEMPO, 4-carboxy-TEMPO, 4-hydroxy-TEMPO benzoate, 4-(2-iodoacetamido)-TEMPO, 4-maleimido-TEMPO, 4-isothiocyanato-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-methoxy-TEMPO, 4-cyano-TEMPO, 4-amino-4-carboxy-TEMPO, 4-phosphonooxy-TEMPO hydrate, 2,2,6,6-tetramethyl-4-(methylsulfonyloxy)-1-piperidinooxy, hydrogen peroxide, sodium hypochlorite, calcium hypochlorite, ozone, nitric acid, permanganate compounds, halogens, metal-catalyzed oxidation agents, gold nanoparticles, nanoparticles which mimic peroxidase activity-mimicking nanoparticles, glucose oxidase, and glucose-oxidizing enzymes or compounds; (3) a reaction accelerator selected from the group consisting of sodium bromide and potassium bromide; (4) a bicarbonate buffer, and (5) a reaction initiator selected from the group consisting of sodium hypochlorite and calcium hypochlorite.

4 . The imaging agent of claim 3 , wherein the bicarbonate buffer comprises sodium bicarbonate.

5 . The imaging agent of claim 3 , comprising a dosage that delivers a dose of radiation in a range of from 1 mCi to 50 mCi.

6 . A method of imaging a necrotic tissue in a subject via positron emission tomography (PET), comprising:
preparing an imaging agent comprising 2-deoxy-2-[ 18 F]fluoroglucaric acid ( 18 F-FGA), or a pharmaceutically-acceptable salt thereof, from a quantity of 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 F-FDG,; administering to the subject a dosage of the imaging agent pharmaceutically-acceptable salt thereof within about 3 hours after preparing the 18 F-FGA, wherein the dosage delivers a dose of radiation in a range of from 1 mCi to 50 mCi, and wherein the 18 F-FGA substantially localizes only in necrotic cells; allowing the 18 F-FGA to penetrate into the necrotic tissue of the subject; and collecting a PET image of the necrotic tissue.

7 . The method of claim 6 , wherein accumulation of the 18 F-FGA in the blood is less than 0.5% of the injected dose/gram after 3 hours.

8 . The method of claim 6 , wherein the subject is suspected of having tissue damage due to a cancer, brain stroke, traumatic brain injury, or myocardial infarction.

9 . The method of claim 6 , wherein the necrotic tissue is selected from a group consisting of tissues of the myocardium, brain, breast, prostate, colon, kidney, spleen, limb, and lung.

10 . A process for preparing a radiopharmaceutical composition, comprising:
combining a quantity of 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 F-FDG) with an oxidizing agent, a reaction accelerator, and an alkaline buffering agent to form a first mixture; adding a reaction initiator to the first mixture to form a reaction mixture; and incubating the reaction mixture, wherein substantially all of the 18 F-FDG is converted into 2-deoxy-2-[ 18 F]fluoroglucaric acid ( 18 F-FGA) after adding the reaction initiator, and wherein the conversion of 18 F-FDG into 18 F-FGA occurs without adjusting the pH of the reaction mixture during the conversion reaction, thereby preparing the radiopharmaceutical composition and wherein, after conversion of the 18 F-FDG into 18 F-FGA, the pH of the reaction mixture is adjusted to a pH in a range of about 6.5 to about 7.5.

11 . The process of claim 10 , wherein the oxidizing agent is selected from the group consisting of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 4-hydroxy-TEMPO, TEMPO methacrylate, 4-oxo-TEMPO, 4-amino-TEMPO, 4-acetamido-TEMPO, 4-carboxy-TEMPO, 4-hydroxy-TEMPO benzoate, 4-(2-iodoacetamido)-TEMPO, 4-maleimido-TEMPO, 4-isothiocyanato-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-methoxy-TEMPO, 4-cyano-TEMPO, 4-amino-4-carboxy-TEMPO, 4-phosphonooxy-TEMPO hydrate, 2,2,6,6-tetramethyl-4-(methylsulfonyloxy)-1-piperidinooxy, hydrogen peroxide, sodium hypochlorite, calcium hypochlorite, ozone, nitric acid, permanganate compounds, halogens, metal-catalyzed oxidation agents, gold nanoparticles, nanoparticles which mimic peroxidase activity-mimicking nanoparticles, glucose oxidase, and glucose-oxidizing enzymes or compounds.

12 . The process of claim 10 , wherein the alkaline buffering agent has a buffering capacity in a pH range of about 9 to about 12.

13 . The process of claim 10 , wherein the incubating step occurs at a reaction temperature in a range of about 0° C. to about 25° C.

14 . The process of claim 10 , wherein the oxidizing agent is a free compound, or is linked to a bead, resin, or polymer.

15 . The process of claim 10 , wherein the reaction initiator is selected from the group consisting of sodium hypochlorite and calcium hypochlorite and the reaction accelerator is selected from the group consisting of sodium bromide and potassium bromide.

16 . The process of claim 10 , wherein the alkaline buffering agent is a bicarbonate buffer.

17 . The process of claim 16 , wherein the bicarbonate buffer is sodium bicarbonate.

18 . A kit for producing a radiopharmaceutical, the kit comprising: (1) an oxidizing agent, (2) a reaction accelerator, (3) an alkaline buffering agent combined in a first container, and (4) a reaction initiator in a second container; and instructions for making 2-deoxy-2-[ 18 F]fluoroglucaric acid ( 18 F-FGA), wherein the instructions instruct a user of the kit to inject a quantity of 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 F-FDG) into the first container, then to inject the reaction initiator of the second container into the first container to form a reaction mixture, wherein upon combination of (1)-(4) with the 18 F-FDG, substantially all of the 18 F-FDG in the reaction mixture is converted into 18 F-FGA in less than about 10 minutes, and wherein the conversion of the 18 F-FDG into 18 F-FGA occurs without monitoring and adjusting the pH of the reaction mixture, the kit optionally comprising a container containing the 18 F-FDG and/or a container comprising an acid.

19 . The kit of claim 18 , wherein the oxidizing agent is selected from the group consisting of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 4-hydroxy-TEMPO, TEMPO methacrylate, 4-oxo-TEMPO, 4-amino-TEMPO, 4-acetamido-TEMPO, 4-carboxy-TEMPO, 4-hydroxy-TEMPO benzoate, 4-(2-iodoacetamido)-TEMPO, 4-maleimido-TEMPO, 4-isothiocyanato-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-methoxy-TEMPO, 4-cyano-TEMPO, 4-amino-4-carboxy-TEMPO, 4-phosphonooxy-TEMPO hydrate, 2,2,6,6-tetramethyl-4-(methylsulfonyloxy)-1-piperidinooxy, hydrogen peroxide, sodium hypochlorite, calcium hypochlorite, ozone, nitric acid, permanganate compounds, halogens, metal-catalyzed oxidation agents, gold nanoparticles, nanoparticles which mimic peroxidase activity-mimicking nanoparticles, glucose oxidase, and glucose-oxidizing enzymes or compounds.

20 . The kit of claim 18 , wherein the reaction initiator is selected from the group consisting of sodium hypochlorite and calcium hypochlorite and the reaction accelerator is selected from the group consisting of sodium bromide and potassium bromide.

Assignees

• Univ Oklahoma

Inventors

• Awasthi Vibhudutta
• Houson Hailey
• Nkepang Gregory

Classifications

• A61K51/0491 Primary

  Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K51/0402 Primary

  carboxylic acid carriers, fatty acids (amino acids A61K51/0406) · CPC title