CA1070695A - Iminodiacetic acid pharmaceutical - Google Patents
Iminodiacetic acid pharmaceuticalInfo
- Publication number
- CA1070695A CA1070695A CA242,855A CA242855A CA1070695A CA 1070695 A CA1070695 A CA 1070695A CA 242855 A CA242855 A CA 242855A CA 1070695 A CA1070695 A CA 1070695A
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- CA
- Canada
- Prior art keywords
- gallium
- radio
- indium
- chelate
- technetium
- Prior art date
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
A chelate of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 or indium-113m and a substituted iminodiacetic acid or an 8-hydroxyquinoline useful as a radio-pharmaceutical external imaging agent.
The invention also includes prepara-tive methods therefor.
A chelate of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 or indium-113m and a substituted iminodiacetic acid or an 8-hydroxyquinoline useful as a radio-pharmaceutical external imaging agent.
The invention also includes prepara-tive methods therefor.
Description
~070695 BACKGROIJND OF THE INVENTION
.. . . Radiopharmaceutical imaging agents have been utilized heretofore for the external imaging of various portions of the anatomy. Only radiopharmaceuticals which emit gamma-photons ' are suitable for this utility. The field of application is ~; restricted due to the fact that of the radionuclides which emit gamma rays, very few meet the additional requirements imposed ; by the inherent limitations of exiting imaging systems and by -~ the necessity of keeping the radiation dose as low as possible.
`~ lO Among these requirements are the need for a simple gamma spectrum, a high yield of photons having an energy sufficiently low to permit effective collimation and efficient detection and i `~ a half-life sufficiently short to permit the administration of ~ .
,' millicurie quantities without an excessive post-test radiation dose.
.. . .
,' The usual method of external imaging generally com-~,. t prises labeling or tagging an organic compound suitable for ,'~ administration to a patient with a suitable radio-isotope.
~' More particularly, a biological agent known to localize in the . . .
particular organ or anatomical section to be imaged is labeled to a small extent with a radio-isotope. The thus labeled ' biological agent then permits external imaging of the desired ; !
organ utilizing conventional radio scanning technigues.
^ The problems associated with prior art attempts in : . .
;~ this direction center mainly on combining the requirements (1) , that the biological agent be specific to the organ to be imaged ;~ (2) that a suitable radionuclide be employed as the labeling ~, agent (3) that the labeled agent is sufficiently stable ln vivo to permit effective imaging and (4) that the labeled biological , 30 agent retains its organ specificity.
, . . .
.'~' . - .
.. . . Radiopharmaceutical imaging agents have been utilized heretofore for the external imaging of various portions of the anatomy. Only radiopharmaceuticals which emit gamma-photons ' are suitable for this utility. The field of application is ~; restricted due to the fact that of the radionuclides which emit gamma rays, very few meet the additional requirements imposed ; by the inherent limitations of exiting imaging systems and by -~ the necessity of keeping the radiation dose as low as possible.
`~ lO Among these requirements are the need for a simple gamma spectrum, a high yield of photons having an energy sufficiently low to permit effective collimation and efficient detection and i `~ a half-life sufficiently short to permit the administration of ~ .
,' millicurie quantities without an excessive post-test radiation dose.
.. . .
,' The usual method of external imaging generally com-~,. t prises labeling or tagging an organic compound suitable for ,'~ administration to a patient with a suitable radio-isotope.
~' More particularly, a biological agent known to localize in the . . .
particular organ or anatomical section to be imaged is labeled to a small extent with a radio-isotope. The thus labeled ' biological agent then permits external imaging of the desired ; !
organ utilizing conventional radio scanning technigues.
^ The problems associated with prior art attempts in : . .
;~ this direction center mainly on combining the requirements (1) , that the biological agent be specific to the organ to be imaged ;~ (2) that a suitable radionuclide be employed as the labeling ~, agent (3) that the labeled agent is sufficiently stable ln vivo to permit effective imaging and (4) that the labeled biological , 30 agent retains its organ specificity.
, . . .
.'~' . - .
-2 bm/~
- :
It is an object of the present invention to provide a ra~iolabeled biological agent having a hlgh degree of in vivo stability and which is highly organ-selective. It is a further `~ object of the invention to provide a method of external imaging employing said agent. It is still a further object of the invention to provide a method for the preparation of said agent.
.. SUM~5ARY OF THE INVE:NTION
.''~ .
` The above objects are achieved by providing a radio-. 10 labeled aiagnostic agent which combines the high target organ ;' specificity of various drugs and biochemicals with the excellent - .
nuclear imaging properties of the radiometals ~echnetium-99m, ~ cobalt-57, gallium-67, gallium-68, indium-lll or indium-113m.
-~ The invention is predicated on the discovery that chelates of the above radiometals with a substituted iminodiacetic acid or an 8-hydroxyquinoline have a high degree of in vivo stability, are highly specific to certain organs or anatomical sections and possess excellent nuclear imaging properties.
The above chelates may be prepared by reacting the , 20 desired radio-isotope with the chelating agent.
` DETAILED DESCRIPTION OF THE INVENTION
'.
Technetium-99m is commercially available either from an isotope generator as a daughter product of molybdenum-99 or as a direct product from a commercial supplier. It is also available as a solvent extraction product from molybdenum-99 solutions generally as alkali metal pertechnetate solutions at 5-100 mCi. A further discussion of preparative methods appears in U. S. Patents 3,468,808 and 3,382,152.
'' ' . ' ~ bm~
.:.: ~ ' ' ,,: ' ~ 1070695 '' ' ' .
The technetium-~99m chelate is most preferably prepared by reducing a solution of a pertechnetate, e.g., an alkali metal pertechnetate in the presence of the chelating agent. The reduction is preferably effected ;utilizing stannous chloride as a reducing agent. Any suitable reducing agent may be employed including other stannous salts such as stannous pyrophosphate.
j As a result of this reduction step, the product will also contain ' a significant proportion of the stannous chelate. It is to be understood that the present invention includes the product mixture containing both the radiometal chelate and the correspond-ing stannous chelate.
, Indeed, the composition of the invention is most ~ conveniently provided as a sterile kit consisting of non-radio-,' active chemicals for mixing with the radiometal source prior to use. The kit preferably contains a stannous salt solution, ~$;
~'~ chelating agent solution, pH buffer solution or combinations ?~ thereof. Using sterile reagents and aseptic techniques, the respective solutions would be mixed with each other in any desired order and then with the radiometal source solution. The resulting solution containing the radiometal chelate, the stannous chelate and any free chelate may then be employed directly for imaging purposes.
~; Generally, a solution adapted for intravenous administration containing up to 15 mCi of radioactivity is administered to the patient. Generally, this may be accomplished ~ by administering 0.2-1 ml of a solution containing from about 2 ,~' to about 100 mg of combined chelate product. Radioassay of the radio-isotope in the desired organ may be accomplished utilizing ~; conventional equipment, such as a scintillation camera, etc.
Organ specificity is determined by the particular .: .
bm/ ~
' chela~ing a~ent employed. ~ll of the chelates according to - th~ present invention, however, are cleared through either the kidneys or liver. Therefore, the chelates of the above radio-metals with most substituted iminodiacetic acids and 8-hydroxy-'. quinolines may be utilized for the imaging of these organs.
i~ Preferably, the chelating agents are of the formula .~
R - N or ~R
; H
- wherein R may be alkyl of up to about 24 carbon atoms preferably about 14 carbon atoms, alkenyl, aryl alkyl or cyclo-aliphatic groups substituted with halogen, hydroxy, carboxy, nitro, amino, keto or heterocyclic groups. The groups may be interrupted by ., ~ .
ether or thio-ether linkages.
The most preferred chelating agents are the substituted iminodiacetic acid and 8-hydroxyquinoline analogs of drugs and biochemicals whose organ specificity characteristics are known.
Other specific chelating agents suitable for use in the practice of the invention are N-methyl-iminodiacetic acid, N-(10-carboxydecyl) iminodiacetic acid, N-[N'-(2,6-dimethyl-phenyl) carbamoylmethyl] iminodiacetic acid, N-(o-bromobenzyl) iminodiacetic acid, N-[3-(1-naphthyloxy)-2-hydroxypropyl]
iminodiacetic acid, nitrilotriacetic acid, or 5,7-diiodo-8-hydroxyquinoline.
It is to be understood that the term "substituted iminodiacetic acid" is intended to include those compounds wherein R in the above structural f~rmula combines with each methylene group to form a heterocyclic ring. ~n example of such an-acid is 2,6-pyridinedicarboxylic acid.
.
bm/~
'~ 1070695 The gallium and indium chelates are pxepared b~ the addition of either GaC13 or indium chloride in ~05 M NCL to the appropriate chelating agent at pH 3.5. After a 25-minute incubation period, the pH is- raised to between 5 and 7.
The invention is illustrated by the following non-limiting examples.
2 grams (~01 moles) of a~pha-chloro-2,6-~cetylxylidide and 2 grams (0.01 moles) of iminodiacetic acid (disodium salt) were refluxed in 200 ml of a 3:1 ETOH/H2O mixture for 48 hours.
The mixture was evaporated to dryness to yield a yellow residue.
25 ~1 of H2O were added to the residue. That which failed to go into solution was collected by vacuum filtration. To the filtrate concentrated hydrochloric acid was added drop-wise and the pH
monitored. At pH 3 the clear solution became cloudy and was cooled overnight. An off-white precipitate was collected which was recrystallized from boiling water. The product was identified as N-[N'-(2,6-dimethylphenyl) carhamoylmethyl] iminodiacetic acid. m.p. 201 203. Percent yield 20~ of theoretical.
NMR:DMSO-d6 ~ = 7.11 (s,3, aromatic protons) = 3.63 (s,4,CH2-COO-) = 3.57 (s,2,-CH2-N =) ~ = 2.20 (s,6,CH3) CHN: 57.13 C 6.16 H 9.52N Theor 57.10 C 6.23 H 9.43N Exp The N-[N'-(2,6-dimethylphenyl) carbamoylmethyl]
iminodiacetic acid prepared according to Example 1 in an amount of 150 mg.(0.51 mmoles) was dissolved in 3 ml of 0.1 N NaOH.
.
bm/-~
~ .
The pH of the solution was adjusted to 3.5 with 1 N HCl.
Extra 0.lN NaOH was added thereto to compensate for the acidic SnC12 solution which follows. 0.3 cc o a solution of SnC12 (20 mg. 0.11 mmole in 10 ml oL 1 N HCl) was added.
After a five-minute wait 80 microcuries of technetium-99m as sodium pertechnetate was added. The product was chromato-graphed in saline and recorded on a radiochromatogram scanner.
The resulting graph showed a peak at the solvent front, Rf=l due to the chelated compound. There was little colloid for-mation. There was substantially no free tech~etium-99m (TRf=.75).
Methyl iminodiacetic acid in an amount of 150 mg was dissolved in 3 ml of 0.1 N NaOH. The pH of the solution was adjusted to 3.5 with 1 N HCl. Extra 0.1 N NaOH was added there-to to compensate for the acidic SnC12 solution which follows.
0.3 cc of a solution of SnC12 (20 mg. 0.11 mmole in 10 ml of 1 N HCl) was added. After a five-minute wait 80 microcuries of technetium-99m as sodium pertechnetate was added. The product was chromatographed in saline and recorded on a radiochromato-gram scanner. The resulting graph showed a peak at the solvent front, Rf=l due to the chelated compound. There was llttle colloid formation. There was substantially no free technetium-99m (TRf = .75).
2 ~ Ci (technetium-99m) of the product of Example 2 were injected intravenously into mice. The animals were sacrificed serially after injection and the activities in major organs were determined by counting multiple samples from each organ in a scintillation counter. The in vivo distribution of the product of Example 2 in the mice were plotted as a ~' - .
.. . .
. - bm~J - . '' ,- '' ,. ,. ' , : , , .
: . , , ,.. - :~ :-f' 1(~70695 function of time. See ~i~. 1.
The procedure of Example 4 was followed utilizing the product of Example 3. The in vlvo distribution of this product in mice as a function of time were plotted. See Fig.
2.
4 mCi (technetium-99m) of the product of Fxample 2 were intravenously injected into laboratory dogs. One animal was selected for imaging at various time intervals utilizing a scintillation camera. Camera images were obtained in multiple exposures and demonstrated the localization of technetium-99m in the liver. See Fig. 3, which depicts anterior imaging studies and demonstrates the rapid uptake by the liver which is clearly ' identified at 5 minutes. (Frame A). The gall bladder appears as a cold defect. Sequential images taken at 25, 40 and 50 ,` minutes are shown in Frames B, C, and D, in which clearance ; from the liver is demonstrated with progressive accumulation of the radiopharmaceutical in the gall b~adder. Less than 10~ and
- :
It is an object of the present invention to provide a ra~iolabeled biological agent having a hlgh degree of in vivo stability and which is highly organ-selective. It is a further `~ object of the invention to provide a method of external imaging employing said agent. It is still a further object of the invention to provide a method for the preparation of said agent.
.. SUM~5ARY OF THE INVE:NTION
.''~ .
` The above objects are achieved by providing a radio-. 10 labeled aiagnostic agent which combines the high target organ ;' specificity of various drugs and biochemicals with the excellent - .
nuclear imaging properties of the radiometals ~echnetium-99m, ~ cobalt-57, gallium-67, gallium-68, indium-lll or indium-113m.
-~ The invention is predicated on the discovery that chelates of the above radiometals with a substituted iminodiacetic acid or an 8-hydroxyquinoline have a high degree of in vivo stability, are highly specific to certain organs or anatomical sections and possess excellent nuclear imaging properties.
The above chelates may be prepared by reacting the , 20 desired radio-isotope with the chelating agent.
` DETAILED DESCRIPTION OF THE INVENTION
'.
Technetium-99m is commercially available either from an isotope generator as a daughter product of molybdenum-99 or as a direct product from a commercial supplier. It is also available as a solvent extraction product from molybdenum-99 solutions generally as alkali metal pertechnetate solutions at 5-100 mCi. A further discussion of preparative methods appears in U. S. Patents 3,468,808 and 3,382,152.
'' ' . ' ~ bm~
.:.: ~ ' ' ,,: ' ~ 1070695 '' ' ' .
The technetium-~99m chelate is most preferably prepared by reducing a solution of a pertechnetate, e.g., an alkali metal pertechnetate in the presence of the chelating agent. The reduction is preferably effected ;utilizing stannous chloride as a reducing agent. Any suitable reducing agent may be employed including other stannous salts such as stannous pyrophosphate.
j As a result of this reduction step, the product will also contain ' a significant proportion of the stannous chelate. It is to be understood that the present invention includes the product mixture containing both the radiometal chelate and the correspond-ing stannous chelate.
, Indeed, the composition of the invention is most ~ conveniently provided as a sterile kit consisting of non-radio-,' active chemicals for mixing with the radiometal source prior to use. The kit preferably contains a stannous salt solution, ~$;
~'~ chelating agent solution, pH buffer solution or combinations ?~ thereof. Using sterile reagents and aseptic techniques, the respective solutions would be mixed with each other in any desired order and then with the radiometal source solution. The resulting solution containing the radiometal chelate, the stannous chelate and any free chelate may then be employed directly for imaging purposes.
~; Generally, a solution adapted for intravenous administration containing up to 15 mCi of radioactivity is administered to the patient. Generally, this may be accomplished ~ by administering 0.2-1 ml of a solution containing from about 2 ,~' to about 100 mg of combined chelate product. Radioassay of the radio-isotope in the desired organ may be accomplished utilizing ~; conventional equipment, such as a scintillation camera, etc.
Organ specificity is determined by the particular .: .
bm/ ~
' chela~ing a~ent employed. ~ll of the chelates according to - th~ present invention, however, are cleared through either the kidneys or liver. Therefore, the chelates of the above radio-metals with most substituted iminodiacetic acids and 8-hydroxy-'. quinolines may be utilized for the imaging of these organs.
i~ Preferably, the chelating agents are of the formula .~
R - N or ~R
; H
- wherein R may be alkyl of up to about 24 carbon atoms preferably about 14 carbon atoms, alkenyl, aryl alkyl or cyclo-aliphatic groups substituted with halogen, hydroxy, carboxy, nitro, amino, keto or heterocyclic groups. The groups may be interrupted by ., ~ .
ether or thio-ether linkages.
The most preferred chelating agents are the substituted iminodiacetic acid and 8-hydroxyquinoline analogs of drugs and biochemicals whose organ specificity characteristics are known.
Other specific chelating agents suitable for use in the practice of the invention are N-methyl-iminodiacetic acid, N-(10-carboxydecyl) iminodiacetic acid, N-[N'-(2,6-dimethyl-phenyl) carbamoylmethyl] iminodiacetic acid, N-(o-bromobenzyl) iminodiacetic acid, N-[3-(1-naphthyloxy)-2-hydroxypropyl]
iminodiacetic acid, nitrilotriacetic acid, or 5,7-diiodo-8-hydroxyquinoline.
It is to be understood that the term "substituted iminodiacetic acid" is intended to include those compounds wherein R in the above structural f~rmula combines with each methylene group to form a heterocyclic ring. ~n example of such an-acid is 2,6-pyridinedicarboxylic acid.
.
bm/~
'~ 1070695 The gallium and indium chelates are pxepared b~ the addition of either GaC13 or indium chloride in ~05 M NCL to the appropriate chelating agent at pH 3.5. After a 25-minute incubation period, the pH is- raised to between 5 and 7.
The invention is illustrated by the following non-limiting examples.
2 grams (~01 moles) of a~pha-chloro-2,6-~cetylxylidide and 2 grams (0.01 moles) of iminodiacetic acid (disodium salt) were refluxed in 200 ml of a 3:1 ETOH/H2O mixture for 48 hours.
The mixture was evaporated to dryness to yield a yellow residue.
25 ~1 of H2O were added to the residue. That which failed to go into solution was collected by vacuum filtration. To the filtrate concentrated hydrochloric acid was added drop-wise and the pH
monitored. At pH 3 the clear solution became cloudy and was cooled overnight. An off-white precipitate was collected which was recrystallized from boiling water. The product was identified as N-[N'-(2,6-dimethylphenyl) carhamoylmethyl] iminodiacetic acid. m.p. 201 203. Percent yield 20~ of theoretical.
NMR:DMSO-d6 ~ = 7.11 (s,3, aromatic protons) = 3.63 (s,4,CH2-COO-) = 3.57 (s,2,-CH2-N =) ~ = 2.20 (s,6,CH3) CHN: 57.13 C 6.16 H 9.52N Theor 57.10 C 6.23 H 9.43N Exp The N-[N'-(2,6-dimethylphenyl) carbamoylmethyl]
iminodiacetic acid prepared according to Example 1 in an amount of 150 mg.(0.51 mmoles) was dissolved in 3 ml of 0.1 N NaOH.
.
bm/-~
~ .
The pH of the solution was adjusted to 3.5 with 1 N HCl.
Extra 0.lN NaOH was added thereto to compensate for the acidic SnC12 solution which follows. 0.3 cc o a solution of SnC12 (20 mg. 0.11 mmole in 10 ml oL 1 N HCl) was added.
After a five-minute wait 80 microcuries of technetium-99m as sodium pertechnetate was added. The product was chromato-graphed in saline and recorded on a radiochromatogram scanner.
The resulting graph showed a peak at the solvent front, Rf=l due to the chelated compound. There was little colloid for-mation. There was substantially no free tech~etium-99m (TRf=.75).
Methyl iminodiacetic acid in an amount of 150 mg was dissolved in 3 ml of 0.1 N NaOH. The pH of the solution was adjusted to 3.5 with 1 N HCl. Extra 0.1 N NaOH was added there-to to compensate for the acidic SnC12 solution which follows.
0.3 cc of a solution of SnC12 (20 mg. 0.11 mmole in 10 ml of 1 N HCl) was added. After a five-minute wait 80 microcuries of technetium-99m as sodium pertechnetate was added. The product was chromatographed in saline and recorded on a radiochromato-gram scanner. The resulting graph showed a peak at the solvent front, Rf=l due to the chelated compound. There was llttle colloid formation. There was substantially no free technetium-99m (TRf = .75).
2 ~ Ci (technetium-99m) of the product of Example 2 were injected intravenously into mice. The animals were sacrificed serially after injection and the activities in major organs were determined by counting multiple samples from each organ in a scintillation counter. The in vivo distribution of the product of Example 2 in the mice were plotted as a ~' - .
.. . .
. - bm~J - . '' ,- '' ,. ,. ' , : , , .
: . , , ,.. - :~ :-f' 1(~70695 function of time. See ~i~. 1.
The procedure of Example 4 was followed utilizing the product of Example 3. The in vlvo distribution of this product in mice as a function of time were plotted. See Fig.
2.
4 mCi (technetium-99m) of the product of Fxample 2 were intravenously injected into laboratory dogs. One animal was selected for imaging at various time intervals utilizing a scintillation camera. Camera images were obtained in multiple exposures and demonstrated the localization of technetium-99m in the liver. See Fig. 3, which depicts anterior imaging studies and demonstrates the rapid uptake by the liver which is clearly ' identified at 5 minutes. (Frame A). The gall bladder appears as a cold defect. Sequential images taken at 25, 40 and 50 ,` minutes are shown in Frames B, C, and D, in which clearance ; from the liver is demonstrated with progressive accumulation of the radiopharmaceutical in the gall b~adder. Less than 10~ and
3% of the injected dose remained in the blood at 10 minutes and 60 minutes, respectively. Sufficient cholecystokinin was in-jected into the dog intravenously to effect contraction of the gall bladder. Sequential studies revealed radiopharmaceutical activity progressing through the small intestines. See Fig. 4.
Within 1 minute of the injection of cholecystokinin the technetium-99m labeled product is seen leaving the gall bladder :, , (Frame E). Frames F, G and H taken at 5, 10 and 35 minutes show a bolus of activity moving progressively through a small intestine. The images were obtained using a gamma scintillation - 30 camera (Pho Gamma III) and a parallel hole high sensitivity .
;. . .
~ bm/~ -8-~070695 collimator.
The procedure o~ Example 6 was carried out and the results compared with those obtained following injection of the same dog at a later time with I-131 Rose Bengal. Both before and after plasma loading with bromosulphthalein (BSP) to simulate hyperbilirubinemia, BSP levels of 4-7 mg percent did not substantially alter the plasma clearance or imaging characteristics of the technetium-99m labeled product. These ; 10 images were of much better quality when compared to those ob-tained subsequently in the same dog using I-131 Rose Bengal.
See Fig. 5.
` EXAMPLE 8 The procedure of Examples 2 and 3 was followed to prepare the technetium-99m chelate of 8-hydroxyquinoline, employing a 7 m-molar solution of 8-hydroxyquinoline and an acidic stannous chloride reducing solution. The chelate was recovered by chloroform extraction at a yield greater than 90~. ' ., Biodistribution studies were undertaken utilizing the procedure of Example 4. 2 ~ Ci (technetium-99m) of the above i chelate were injected intravenously into 25 g mice. The ` animals were sacrificed after 60 minutes and the activities in , major organs were determined by counting multiple samples from :. .
each organ in a scintillation counter. It was determined that ~ on an average, 40% of the injected dose appeared in the liver ;l and 20~ in the intestines. -',: .
..
_9_ bm/~
. , .
~ ~070695 EXAMPL~ 9 The gallium-67 chelate of 8-hydroxy~uinoline was prepared by adding Ga67C13 in 0.05M I~Cl to an a~ueous 7 m-molar 8-hydroxyquinoline solution having a pH of 3.5.
~ollowing a 25 minute incubation period the pH is raised to 6.
Chloroform extraction of the reaction product produc~d a >90%
yield of the chelate. Biodistribution studies were undertaken according to the procedure outlined in Example 8. Following intravenous injection of the chelate into 25 g mice, 25% of the injected dose was found in the liver, 13% in the intestines and 20% in the blood after 60 minutes.
,~ , The technetium-99m chelate of nitrilotriacetic acid was prepared according to the stannous chloride reduction method outlined in Examples 2, 3 and 8. The chelate is water-soluble with >95% migration in saline employing paper chromato-graphy. Biodistribution studies were carried out according to the procedure outlined in Example 8. The chelate was found to rapidly clear through the kidneys to urine (40% eliminated in urine after 60 minutes) with less than 5% of the injected dose found in the liver and intestines.
The cobalt-57 chelate of N-[N'-(2,6-dimethylphenyl) carbamoylmethyl] iminodiacetic acid was prepared by heating ~-5 ~ Ci of Co C12 in the presence of 1 ml (20 mg~ml) of a solution of the compound (pH 4-5) for 1 hour at 100C. The chelate was chromatographed and biodistribution studies ., .
.
bm/~"~, . . .
- 10~70695 carried out using ~he procedure of Example 8. At 30 minutes, 28% of the injected dose appears in the liver and 12% in the intestines.
The technetium-99M chelate of 10-carboxydecylimino-diacetic acid was prepared according to the stannous chloride reduction method of Examples 2, 3 and 8. The product was chromatographed in saline. ~98~ the material had an Rf=1.
Biodistribution studies of the chelate accordiny to Example 8 : in ten 25 g mice showed rapid blood clearance with less than 6%
of the injected dose remaining in the blood at 60 minutes.
Radioactivity was eliminated through both kidneys and liver- with persistent activity noted in the liver and lungs.
The technetium-99m chelate of N-(o-bromobenzyl) iminodiacetic acid was prepared by the stannous chloride reduction method described in Examples 2, 3 and 8. The product was paper chromatographed in saline (98~ had an Rf=l.) Biodistribution studies carried out on twelve 25 g mice accord-ing to the procedure of Example 8 showed rapid blood clearance (less than 5% remaining at 60 ~inutes? with a high uptake in the liver (40~) and intestines (30%) at 30 minutes.
EX~MPLE 14 :.
The procedure of Example 11 was followed to prepare the cobalt-57 chelate o~ methyliminodiacetic acid.
bm/~
, - ~ 1070695 The procedure of Example 9 was followed to prepare the gallium-67 chelate of methyliminodlacetic acid.
Biodistribution studies carried out according to the procedure of Example 8 showed rapid renal clearance.
The stannous chloride reduction procedure of Examples 2, 3 and 8 was employed to prepare the technetium-99m chelate of 5,7-diiodo~8-hydroxyquinoline.
The stannous chloride reduction method of Examples 2, 3 and 8 was used to prepare the technetium-99m chelate of 2,6-pyridinedicarboxylic acid.
. . . .
, . ~ .
;:
' ' bm/J/~
~ ' .
Within 1 minute of the injection of cholecystokinin the technetium-99m labeled product is seen leaving the gall bladder :, , (Frame E). Frames F, G and H taken at 5, 10 and 35 minutes show a bolus of activity moving progressively through a small intestine. The images were obtained using a gamma scintillation - 30 camera (Pho Gamma III) and a parallel hole high sensitivity .
;. . .
~ bm/~ -8-~070695 collimator.
The procedure o~ Example 6 was carried out and the results compared with those obtained following injection of the same dog at a later time with I-131 Rose Bengal. Both before and after plasma loading with bromosulphthalein (BSP) to simulate hyperbilirubinemia, BSP levels of 4-7 mg percent did not substantially alter the plasma clearance or imaging characteristics of the technetium-99m labeled product. These ; 10 images were of much better quality when compared to those ob-tained subsequently in the same dog using I-131 Rose Bengal.
See Fig. 5.
` EXAMPLE 8 The procedure of Examples 2 and 3 was followed to prepare the technetium-99m chelate of 8-hydroxyquinoline, employing a 7 m-molar solution of 8-hydroxyquinoline and an acidic stannous chloride reducing solution. The chelate was recovered by chloroform extraction at a yield greater than 90~. ' ., Biodistribution studies were undertaken utilizing the procedure of Example 4. 2 ~ Ci (technetium-99m) of the above i chelate were injected intravenously into 25 g mice. The ` animals were sacrificed after 60 minutes and the activities in , major organs were determined by counting multiple samples from :. .
each organ in a scintillation counter. It was determined that ~ on an average, 40% of the injected dose appeared in the liver ;l and 20~ in the intestines. -',: .
..
_9_ bm/~
. , .
~ ~070695 EXAMPL~ 9 The gallium-67 chelate of 8-hydroxy~uinoline was prepared by adding Ga67C13 in 0.05M I~Cl to an a~ueous 7 m-molar 8-hydroxyquinoline solution having a pH of 3.5.
~ollowing a 25 minute incubation period the pH is raised to 6.
Chloroform extraction of the reaction product produc~d a >90%
yield of the chelate. Biodistribution studies were undertaken according to the procedure outlined in Example 8. Following intravenous injection of the chelate into 25 g mice, 25% of the injected dose was found in the liver, 13% in the intestines and 20% in the blood after 60 minutes.
,~ , The technetium-99m chelate of nitrilotriacetic acid was prepared according to the stannous chloride reduction method outlined in Examples 2, 3 and 8. The chelate is water-soluble with >95% migration in saline employing paper chromato-graphy. Biodistribution studies were carried out according to the procedure outlined in Example 8. The chelate was found to rapidly clear through the kidneys to urine (40% eliminated in urine after 60 minutes) with less than 5% of the injected dose found in the liver and intestines.
The cobalt-57 chelate of N-[N'-(2,6-dimethylphenyl) carbamoylmethyl] iminodiacetic acid was prepared by heating ~-5 ~ Ci of Co C12 in the presence of 1 ml (20 mg~ml) of a solution of the compound (pH 4-5) for 1 hour at 100C. The chelate was chromatographed and biodistribution studies ., .
.
bm/~"~, . . .
- 10~70695 carried out using ~he procedure of Example 8. At 30 minutes, 28% of the injected dose appears in the liver and 12% in the intestines.
The technetium-99M chelate of 10-carboxydecylimino-diacetic acid was prepared according to the stannous chloride reduction method of Examples 2, 3 and 8. The product was chromatographed in saline. ~98~ the material had an Rf=1.
Biodistribution studies of the chelate accordiny to Example 8 : in ten 25 g mice showed rapid blood clearance with less than 6%
of the injected dose remaining in the blood at 60 minutes.
Radioactivity was eliminated through both kidneys and liver- with persistent activity noted in the liver and lungs.
The technetium-99m chelate of N-(o-bromobenzyl) iminodiacetic acid was prepared by the stannous chloride reduction method described in Examples 2, 3 and 8. The product was paper chromatographed in saline (98~ had an Rf=l.) Biodistribution studies carried out on twelve 25 g mice accord-ing to the procedure of Example 8 showed rapid blood clearance (less than 5% remaining at 60 ~inutes? with a high uptake in the liver (40~) and intestines (30%) at 30 minutes.
EX~MPLE 14 :.
The procedure of Example 11 was followed to prepare the cobalt-57 chelate o~ methyliminodiacetic acid.
bm/~
, - ~ 1070695 The procedure of Example 9 was followed to prepare the gallium-67 chelate of methyliminodlacetic acid.
Biodistribution studies carried out according to the procedure of Example 8 showed rapid renal clearance.
The stannous chloride reduction procedure of Examples 2, 3 and 8 was employed to prepare the technetium-99m chelate of 5,7-diiodo~8-hydroxyquinoline.
The stannous chloride reduction method of Examples 2, 3 and 8 was used to prepare the technetium-99m chelate of 2,6-pyridinedicarboxylic acid.
. . . .
, . ~ .
;:
' ' bm/J/~
~ ' .
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of preparing a chelate of a radio-isotope selected from the group consisting of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 and indium-113m and a chelating agent selected from the group consisting of iminodiacetic acids and 8-hydroxy-quinolines which comprises contacting, in solution, said radio-isotope with said chelating agent.
2. A method of preparing achelate of a radio-isotope selected from the group consisting of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 and indium-113m and a chelating agent selected from the group consisting of N-methyl-inimodiacetic acid, N-[N'(2,6-dimethylphenyl) carbamoylmethyl] iminodiacetic acid, N-(10-carboxydecyl) inimodiacetic acid, N-(O-bromobenzyl) iminodiacetic acid, N-[3-(1-naphthyloxy)-2-hydroxypropyl] iminodiacetic acid, nitrilotriacetic acid and 2,6-pyridinedicarboxylic acid which comprises contacting, in solution, said radio-isotope with said chelating agent.
3. A method of preparing a chelate of a radio-isotope selected from the group consisting of technetium-99m, cobalt-57 gallium-67, gallium-68, indium-111 and indium-113m and 8-hydroxyquinoline which comprises contacting, in solution, said radio-isotope with said 8-hydroxyquinoline.
4. The method of claim 2 wherein said radio-isotope is technetium-99m.
5. The method of claim 4, whercin said chelate is prepared by reducing a pertechnetate in the presence of said chelating agent.
6. The method of claim 5 wherein said reduction is effected by using stannous chloride as the reducing agent.
7. A chelate of a radio-isotope selected from the group consisting or technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 and indium-113m and a chelating agent selected from the group consisting of iminodiacetic acids and 8-hydroxyquinolines, whenever prepared by the process defined in claim 1 or by an obvious chemical equivalent.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA335,980A CA1096399A (en) | 1975-09-02 | 1979-09-20 | Iminodiacetic acid pharmaceutical |
| CA335,981A CA1083038A (en) | 1975-09-02 | 1979-09-20 | Iminodiacetic acid pharmaceutical |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/609,545 US4017596A (en) | 1975-03-03 | 1975-09-02 | Radiopharmaceutical chelates and method of external imaging |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070695A true CA1070695A (en) | 1980-01-29 |
Family
ID=24441240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,855A Expired CA1070695A (en) | 1975-09-02 | 1975-12-31 | Iminodiacetic acid pharmaceutical |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5233631A (en) |
| BE (1) | BE840556A (en) |
| CA (1) | CA1070695A (en) |
| DE (1) | DE2612698A1 (en) |
| FR (1) | FR2322586A1 (en) |
| NL (1) | NL7604022A (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH607920A5 (en) * | 1976-05-31 | 1978-12-15 | Solco Basel Ag | |
| PL115524B1 (en) * | 1978-04-10 | 1981-04-30 | Uniwersytet Warszawski | Process for manufacturing scintigraphic agent |
| US4272503A (en) * | 1978-05-25 | 1981-06-09 | New England Nuclear Corporation | Reductant composition for technetium-99m and method for making technetium-99m labelled ligands |
| DE2855334A1 (en) * | 1978-12-21 | 1980-07-10 | Hoechst Ag | TECHNETIUM-99M MARKED (2,4,5-TRIMETHYLACETANILIDO) IMINODIACETATE FOR LIVER FUNCTION DIAGNOSTICS AND METHOD FOR THE PRODUCTION THEREOF |
| DE2920174A1 (en) * | 1979-05-18 | 1980-11-20 | Hoechst Ag | TECHNETIUM-99M-MARKED ACETANILIDOIMINODIACETATE FOR LIVER FUNCTION DIAGNOSTICS |
| US4348375A (en) * | 1979-12-31 | 1982-09-07 | Byk-Mallinckrodt Cil B.V. | Radioassay process and compositions useful therein |
| US4387087A (en) * | 1980-04-18 | 1983-06-07 | Research Corporation | Cationic lipophilic complexes of 99m Tc and their use for myocardial and hepatobiliary imaging |
| CA1187897A (en) * | 1980-12-29 | 1985-05-28 | Adrian D. Nunn | N-substituted iminodiacetic acids |
| US4957939A (en) * | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
| EP0089143A1 (en) * | 1982-03-16 | 1983-09-21 | AMERSHAM INTERNATIONAL plc | Diagnosis of kidney function |
| NL194579C (en) * | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostic. |
| GB8413772D0 (en) * | 1984-05-30 | 1984-07-04 | Nyegaard & Co As | Chemical compounds |
-
1975
- 1975-12-31 CA CA242,855A patent/CA1070695A/en not_active Expired
-
1976
- 1976-03-19 JP JP51031906A patent/JPS5233631A/en active Pending
- 1976-03-25 DE DE19762612698 patent/DE2612698A1/en active Pending
- 1976-04-09 BE BE165985A patent/BE840556A/en unknown
- 1976-04-09 FR FR7610530A patent/FR2322586A1/en not_active Withdrawn
- 1976-04-15 NL NL7604022A patent/NL7604022A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2322586A1 (en) | 1977-04-01 |
| BE840556A (en) | 1976-08-02 |
| JPS5233631A (en) | 1977-03-14 |
| DE2612698A1 (en) | 1977-03-17 |
| NL7604022A (en) | 1977-03-04 |
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