CA1083038A - Iminodiacetic acid pharmaceutical - Google Patents
Iminodiacetic acid pharmaceuticalInfo
- Publication number
- CA1083038A CA1083038A CA335,981A CA335981A CA1083038A CA 1083038 A CA1083038 A CA 1083038A CA 335981 A CA335981 A CA 335981A CA 1083038 A CA1083038 A CA 1083038A
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- Prior art keywords
- chelate
- iminodiacetic acid
- acid
- technetium
- chelating agent
- Prior art date
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Abstract
ABSTRACT OF DISCLOSURE
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 preparative methods therefor.
This divisional application is particularly directed to a composition comprising a mixture of (1) the chelate of technetium-99m and an iminodiacetic acid chelating agent and (2) the stannous chelate of said chelating agent.
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 preparative methods therefor.
This divisional application is particularly directed to a composition comprising a mixture of (1) the chelate of technetium-99m and an iminodiacetic acid chelating agent and (2) the stannous chelate of said chelating agent.
Description
:3L fD83~3~1 B~C~;G~OUND OF 'rllE INVENT~ON
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 ~or this utility. The field of applica-tion 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.
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 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-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 ; oxgan utili~ing conventional radio scanning techniques.
The problems associated with prior art attemp*s in this direction center mainly on combining the requirements ~
that the biological agent be specific to the organ to be imaged
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 ~or this utility. The field of applica-tion 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.
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 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-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 ; oxgan utili~ing conventional radio scanning techniques.
The problems associated with prior art attemp*s in this direction center mainly on combining the requirements ~
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 vlvo to permit effective imaging and ~4) that the labeled biological agent retains its organ specificity~
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It is an object of the present invention to provlde a raaiolabeled biological agent havlng a high degree of ln ivo stability and which is highly organ selective. It is a ~urther object o~ the inventiorl to provlde a method of external lmagin~
employing sai~ agent. It is still a further object of the invention to pr~vide a method for the preparation of said agent.
SI~ RY OF THE INVENTION
The above objects are achieved by providing a radio-labeled diagnostic agent which combines the hiyh target organ specificity of various drugs and biochemicals with the excellent nuclear imaging properties of the radiometals technetium-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 desired radio-isotope with the chelating agent.
DE~AILED 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 s~lutions generally as alkali metal pertechnetate solutions at ~
S-100 mCi. A urther discussion of preparative methods appears -in U. S. Patents 3,468,808 and 3,382,152.
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It is an object of the present invention to provlde a raaiolabeled biological agent havlng a high degree of ln ivo stability and which is highly organ selective. It is a ~urther object o~ the inventiorl to provlde a method of external lmagin~
employing sai~ agent. It is still a further object of the invention to pr~vide a method for the preparation of said agent.
SI~ RY OF THE INVENTION
The above objects are achieved by providing a radio-labeled diagnostic agent which combines the hiyh target organ specificity of various drugs and biochemicals with the excellent nuclear imaging properties of the radiometals technetium-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 desired radio-isotope with the chelating agent.
DE~AILED 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 s~lutions generally as alkali metal pertechnetate solutions at ~
S-100 mCi. A urther discussion of preparative methods appears -in U. S. Patents 3,468,808 and 3,382,152.
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The technctium-g9m chelate is most pre,f,erabl~ prepared by r~ducing 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.
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 ' 10 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 radiome-tal 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 i' ' -administered to the patient. Generally, this may be accomplished ' ;
by administering 0.2-l ml of a solution containing from about 2 to about 100 mg of combined chelate product. Radioassay of the '' xadio-isotope in the desired org'an may be accomplished utillzing conventlonal equipment, such as a scintillation camera, etc. '~
~ 30 Oxgan specificity is determined by the particular ''' : ~' ' ; ,. ':
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chelating a~ent employed. All of the chelates accordiny to th~ present invention, however, are cleared through either the kidneys or liv~r. Therefore, the chelates of thc above radio-metals with most substituted iminodiacetic acids and 8-hydroxy-quinolines may be utilized for the imagin~ of these organs.
Preferably, the che]ating agents are of the formula CH - COOH ~ ~ 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 characteris-tics are known.
Other specific chelating agents suitable for use in ~-the practice of the invention are N-methyl-iminodiacetic acid, N-(10-carboxydecyl) imlnodiacetic 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. An example of ~ ~-such an acid is 2,6-pyridinedicarboxylic acid.
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The g~llium and ind:ium chelates are pxepared by the addition of either GaC13 or indium chloride in .05 M ~ICL 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 a1pha-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/I-I20 mixture for 48 hours.
The mixture was evaporated to dryness to yield a yellow residue.
25 ~1 of H20 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) carbamoylmethyl] 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-LN'-(2,6-dimethylphenyl ! carbamoylmethyl]
iminodiacetic àcid prepared according to Example 1 in an amount of 150 mg.tO.51 mmoles) was dissolved in 3 ml of 0.1 N NaOH.
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The pll of the solution w~s adjusted to 3.5 wi-th 1 N IICl.
Extra 0.lN NaO~ ~a~ added thereto to compensa-te for the acidic SnC12 solution which follows. 0.3 cc of 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 pertechn~tate 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-1~ mation. There was substantially no free technetium-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 pert~chnetate 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 little colloid formation. There was substantially no free technetium-99m (TRf = .75).
EXAMPLE 4 ,, 2 ~ Ci ttechnetium-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 ' :: ':
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function o~ time. See Fig. 1.
EX~MPLE 5 The procedure o~ ~xample 4 was followed utilizing the product of Example 3. The ln vivo distribution of this product in mice as a function of time were plotted. See Fig.
2.
E~MPLE 6
The technctium-g9m chelate is most pre,f,erabl~ prepared by r~ducing 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.
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 ' 10 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 radiome-tal 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 i' ' -administered to the patient. Generally, this may be accomplished ' ;
by administering 0.2-l ml of a solution containing from about 2 to about 100 mg of combined chelate product. Radioassay of the '' xadio-isotope in the desired org'an may be accomplished utillzing conventlonal equipment, such as a scintillation camera, etc. '~
~ 30 Oxgan specificity is determined by the particular ''' : ~' ' ; ,. ':
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chelating a~ent employed. All of the chelates accordiny to th~ present invention, however, are cleared through either the kidneys or liv~r. Therefore, the chelates of thc above radio-metals with most substituted iminodiacetic acids and 8-hydroxy-quinolines may be utilized for the imagin~ of these organs.
Preferably, the che]ating agents are of the formula CH - COOH ~ ~ 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 characteris-tics are known.
Other specific chelating agents suitable for use in ~-the practice of the invention are N-methyl-iminodiacetic acid, N-(10-carboxydecyl) imlnodiacetic 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. An example of ~ ~-such an acid is 2,6-pyridinedicarboxylic acid.
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The g~llium and ind:ium chelates are pxepared by the addition of either GaC13 or indium chloride in .05 M ~ICL 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 a1pha-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/I-I20 mixture for 48 hours.
The mixture was evaporated to dryness to yield a yellow residue.
25 ~1 of H20 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) carbamoylmethyl] 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-LN'-(2,6-dimethylphenyl ! carbamoylmethyl]
iminodiacetic àcid prepared according to Example 1 in an amount of 150 mg.tO.51 mmoles) was dissolved in 3 ml of 0.1 N NaOH.
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The pll of the solution w~s adjusted to 3.5 wi-th 1 N IICl.
Extra 0.lN NaO~ ~a~ added thereto to compensa-te for the acidic SnC12 solution which follows. 0.3 cc of 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 pertechn~tate 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-1~ mation. There was substantially no free technetium-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 pert~chnetate 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 little colloid formation. There was substantially no free technetium-99m (TRf = .75).
EXAMPLE 4 ,, 2 ~ Ci ttechnetium-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 ' :: ':
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,, ., . ~ ,-, . . . .. : : .. : - : .
function o~ time. See Fig. 1.
EX~MPLE 5 The procedure o~ ~xample 4 was followed utilizing the product of Example 3. The ln vivo distribution of this product in mice as a function of time were plotted. See Fig.
2.
E~MPLE 6
4 mCi (technetium-99m) of the product of Example 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 inlages 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. Su~ficient cholecystokinin was in-jected into the dog intravenously to effect contraction of the : .
gall bladder. Sequential studies revealed radiopharmaceutical -.
activity progressing through the small intes~ines. 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 ", , intes~ine. The images were obtained using a gamma scintillation camera (Pho Gamma III) and a parallel hole high sensitivity .~ , .
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collimator.
The procedure of 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 sengal. Both before and after plasma loading with bromosulphthalein (BSP) to simulate hyperbilirubinemia, sSP levels of 4-7 mg percent did not substantially alter the plasma clearance or imaging characteristics of the technetium-99m labeled product. These images were of much better quality when compared to those ob-tained subsequently in the same dog using T-131 Rose Bengal.
See Fig. 5.
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 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 and 20~ in the intestines.
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' The gallium-67 chelate o~ ~-hydroxy~uinoline was prepared by adding Ga67C13 in 0.05M IIC1 to an aqueous-7 m-molar ~-hydroxyquinoline solution having a pH of 3.5.
Following a 25 minute incubation period the pH is raised to 6.
Chloroform extraction of the reaction product produced 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. Blodistribution 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.
; ' ', ' EXAMPLE 11 ~ -The cobalt-57 chelate of N-[N'-(2,6-dimethylphenyl) i~ carbamoylmethyl] iminodiacetic acid was prepared by heating 2-5 ~I Ci of Co57C12 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 ~.-. .
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carried out using the ~rocedure of Example 8. ~t 3~ 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=l.
, Biodis-tribution studies of the chelate according 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=1.) 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 minutes) with a h~gh uptake in the : :
liver (40%) and intestines (30%) at 30 minutes. : ..
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EXAMPLE 14 . . ~:
The procedure of Example ll was followed to prepare the cobalt-57 chelate o~ meth~liminodiacetic acid.
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EX~MPLE i.5 ~ he procedure of ~xamplc 9 was ~ollowed to prepaxe the gallium-67 chelate of methyli.m.inodlacctic acid.
Biodistribution studies carried out according to the procedure of Example 8 showed rapid renal clearance.
EX~MPLE 16 The st.annous chloride recluction procedure of Examples 2, 3 and 8 was employed to prepare the techrletium-99m chelate of 5,7-diiodo-8-hydroxyquinoline. -EXAMPLE l7 The stannous chloride reduction method of Examples 2, 3 and 8 was used `to prepare the technetium-99m chelate of 2,6-pyridi.nedicarboxylic acid.
. This appli~cation is a division of Canadian Patent --Appl.ication Serial No. 242,855 filed December 31, 1975.
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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. Su~ficient cholecystokinin was in-jected into the dog intravenously to effect contraction of the : .
gall bladder. Sequential studies revealed radiopharmaceutical -.
activity progressing through the small intes~ines. 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 ", , intes~ine. The images were obtained using a gamma scintillation camera (Pho Gamma III) and a parallel hole high sensitivity .~ , .
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collimator.
The procedure of 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 sengal. Both before and after plasma loading with bromosulphthalein (BSP) to simulate hyperbilirubinemia, sSP levels of 4-7 mg percent did not substantially alter the plasma clearance or imaging characteristics of the technetium-99m labeled product. These images were of much better quality when compared to those ob-tained subsequently in the same dog using T-131 Rose Bengal.
See Fig. 5.
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 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 and 20~ in the intestines.
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' The gallium-67 chelate o~ ~-hydroxy~uinoline was prepared by adding Ga67C13 in 0.05M IIC1 to an aqueous-7 m-molar ~-hydroxyquinoline solution having a pH of 3.5.
Following a 25 minute incubation period the pH is raised to 6.
Chloroform extraction of the reaction product produced 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. Blodistribution 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.
; ' ', ' EXAMPLE 11 ~ -The cobalt-57 chelate of N-[N'-(2,6-dimethylphenyl) i~ carbamoylmethyl] iminodiacetic acid was prepared by heating 2-5 ~I Ci of Co57C12 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 ~.-. .
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carried out using the ~rocedure of Example 8. ~t 3~ 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=l.
, Biodis-tribution studies of the chelate according 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=1.) 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 minutes) with a h~gh uptake in the : :
liver (40%) and intestines (30%) at 30 minutes. : ..
~ .,' '.
EXAMPLE 14 . . ~:
The procedure of Example ll was followed to prepare the cobalt-57 chelate o~ meth~liminodiacetic acid.
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EX~MPLE i.5 ~ he procedure of ~xamplc 9 was ~ollowed to prepaxe the gallium-67 chelate of methyli.m.inodlacctic acid.
Biodistribution studies carried out according to the procedure of Example 8 showed rapid renal clearance.
EX~MPLE 16 The st.annous chloride recluction procedure of Examples 2, 3 and 8 was employed to prepare the techrletium-99m chelate of 5,7-diiodo-8-hydroxyquinoline. -EXAMPLE l7 The stannous chloride reduction method of Examples 2, 3 and 8 was used `to prepare the technetium-99m chelate of 2,6-pyridi.nedicarboxylic acid.
. This appli~cation is a division of Canadian Patent --Appl.ication Serial No. 242,855 filed December 31, 1975.
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Claims (2)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition comprising a mixture of (1) the chelate of technetium-99m and an iminodiacetic acid chelating agent selected from the group consisting of N-methyl-iminodiacetic acid, N-{N'(2,6-dimethylphenyl) carbamoylmethyl} iminodiacetic acid, N-(10-carboxydecyl) iminodiacetic acid, N-(O-bromobenzyl) iminodiacetic acid, N-{3-(1-naphthyloxy)-2-hydroxypropyl} iminodiacetic acid, nitrilo-triacetic acid and 2,6-pyridinedicarboxylic acid and (2) the stannous chelate of said chelating agent.
2. A composition comprising a mixture of (1) the chelate of technetium-99m and an iminodiacetic acid chelating agent selected from the group consisting of N-methyl-iminodiacetic acid, N-{N'(2,6-dimethylphenyl) carbamoylmethyl} iminodiacetic acid, N-(10-carboxydecyl) iminodiacetic acid, N-(O-bromobenzyl) iminodiacetic acid, N-{3-(1-naphthyloxy)-2-hydroxypropyl} iminodiacetic acid, nitrilo-triacetic acid and 2,6-pyridinedicarboxylic acid, (2) the stannous chelate of said chelating agent, and (3) said chelating agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA335,981A CA1083038A (en) | 1975-09-02 | 1979-09-20 | Iminodiacetic acid pharmaceutical |
Applications Claiming Priority (4)
| 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 |
| US609,545 | 1975-09-02 | ||
| CA242,855A CA1070695A (en) | 1975-09-02 | 1975-12-31 | Iminodiacetic acid pharmaceutical |
| CA335,981A CA1083038A (en) | 1975-09-02 | 1979-09-20 | Iminodiacetic acid pharmaceutical |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1083038A true CA1083038A (en) | 1980-08-05 |
Family
ID=27164261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA335,981A Expired CA1083038A (en) | 1975-09-02 | 1979-09-20 | Iminodiacetic acid pharmaceutical |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1083038A (en) |
-
1979
- 1979-09-20 CA CA335,981A patent/CA1083038A/en not_active Expired
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