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US 6,713,042 B2Granted
Ascorbic acid analogs for metalloradiopharmaceuticals
AssigneeBristol-Myers Squibb Pharma Company
InventorShuang Liu
Life of this patent
Estimating the term…
Abstract
The invention relates to the use of ascorbic acid analogs as buffering reagents and chelating agents for the preparation of metalloradiopharmaceuticals. Also, invention relates to the use of ascorbic acid as a buffering reagent, a chelating agent, and a stabilizer for the preparation and stabilization of radiopharmaceuticals and processes for making and using the same.
Claims45
A radiopharmaceutical composition comprising a radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m;
- and an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- M is a metallic radioisotope;
- Ch is a metal chelator;
- Ln is an optional linking group;
- BM is a biomolecule;
- m is 1 to about 10;
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- and
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount of the compound of formula (I) is effective to:
- (1) stabilize the radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m against radiation induced degradation and to at least one of (2) control the pH of the radiopharmaceutical composition and (3) reduce radiometal colloid formation.
17 more elements
A radiopharmaceutical composition comprising a radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m;
- and a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- M is a metallic radioisotope;
- Ch is a metal chelator;
- Ln is an optional linking group;
- BM is a biomolecule;
- m is 1 to about 10;
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- provided the radiopharmaceutical composition does not comprise an additional buffering agent or an additional chelating agent.
15 more elements
A method for buffering a radiopharmaceutical comprising contacting the radiopharmaceutical with an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O, NR1, or CUR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount is effective to control the pH of the radiopharmaceutical.
9 more elements
A method for chelating a radiopharmaceutical comprising contacting the radiopharmaceutical with an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount is effective to reduce radiometal colloid formation.
9 more elements
A method for stabilizing a radiopharmaceutical against radiation induced degradation and at least one of (1) controlling the pH of the radiopharmaceutical and (2) reducing radiometal colloid formation;
- comprising contacting the radiopharmaceutical with an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount is effective to:
- (1) stabilize the radiopharmaceutical against radiation induced degradation and to at least one of (2) control the pH of the radiopharmaceutical and (3) reduce radiometal colloid formation.
11 more elements
A method for preparing a stable radiopharmaceutical composition comprising contacting a radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m and an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- M is a metallic radioisotope;
- Ch is a metal chelator;
- Ln is an optional linking group;
- BM is a biomolecule;
- m is 1 to about 10;
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- and
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount of the compound of formula (I) is effective to:
- (1) stabilize the radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m against radiation induced degradation and to at least one of (2) control the pH of the radiopharmaceutical composition and (3) reduce radiometal colloid formation.
16 more elements
A kit comprising a sealed vial comprising a predetermined quantity of a radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m, and an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- M is a metallic radioisotope;
- Ch is a metal chelator;
- Ln is an optional linking group;
- BM is a biomolecule;
- m is 1 to about 10;
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, (C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- and
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- wherein the concentration of the compound of formula (I) in an pharmaceutically acceptable carrier or diluent is about 2 mg/mL to about 200 mg/mL;
- and
- wherein the amount of the compound of formula (I) is effective to:
- (1) stabilize the radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m against radiation induced degradation and to at least one of (2) control the pH of the radiopharmaceutical composition and (3) reduce radiometal colloid formation.
16 more elements
A kit comprising
- (a) a first vial comprising a predetermined quantity of a radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m;
- and an amount of a compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- M is a metallic radioisotope;
- Ch is a metal chelator;
- Ln is an optional linking group;
- BM is a biomolecule;
- m is 1 to about 10;
- X is O, NR1, or CHR1;
- Y is O or S;
- Z is hydroxyl or halogen;
- R1 is selected from:
- (C1-C10) alkyl substituted with 0-5 R2, C3-C10) cycloalkyl substituted with 0-5 R2, (C2-C10) alkenyl substituted with 0-5 R2, and aryl substituted with 0-5 R2;
- and
- R2 is independently selected at each occurrence from:
- NH2, OH, CO2H, C(═O)NH2, NHC(═NH)NH2, PO3H2, and SO3H;
- and
- wherein the amount of the compound of formula (I) is effective to:
- (1) stabilize the radiolabeled chelator-biomolecule conjugate of the formula M-Ch-Ln-(BM)m against radiation induced degradation and to at least one of (2) control the pH of the radiopharmaceutical composition and (3) reduce radiometal colloid formation;
- and
- (b) a second vial comprising a pharmaceutically acceptable carrier or diluent;
- wherein the compound of formula (I) is present in an amount sufficient to provide a concentration of about 2 mg/mL to about 200 mg/mL in the pharmaceutically acceptable carrier or diluent.
20 more elements
Dependencies are inferred from the claim text.