CA1096399A - Iminodiacetic acid pharmaceutical - Google Patents

Iminodiacetic acid pharmaceutical

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Publication number
CA1096399A
CA1096399A CA335,980A CA335980A CA1096399A CA 1096399 A CA1096399 A CA 1096399A CA 335980 A CA335980 A CA 335980A CA 1096399 A CA1096399 A CA 1096399A
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CA
Canada
Prior art keywords
chelate
iminodiacetic acid
technetium
solution
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA335,980A
Other languages
French (fr)
Inventor
Michael D. Loberg
Patrick S. Callery
Malcolm Cooper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Corp
Original Assignee
Research Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US05/609,545 external-priority patent/US4017596A/en
Priority claimed from CA242,855A external-priority patent/CA1070695A/en
Application filed by Research Corp filed Critical Research Corp
Priority to CA335,980A priority Critical patent/CA1096399A/en
Application granted granted Critical
Publication of CA1096399A publication Critical patent/CA1096399A/en
Expired legal-status Critical Current

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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 the chelating agent N-{N'-(2,6-dimethylphenyl)carbamoylmethyl}
iminodiacetic acid.

Description

3'~
BACKGROIJND O~' TllJi` INVEN'TION
Radiopharmaceutical imaging agents have been utilized heretofore for the cxternal 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 - ga~-na 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 , organ utilizing conventional radio scanning techniques.
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 ager,t retains its organ specificity.
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It is an object of the present invention to provide a xadiolabeled biological agent having a high degree of in vlvo stability and which is highly organ-selective. It is a further -object of t}le 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.

SUMM~RY OF THE INVENTION

The above objects are achieved by providing a radio-labeled diagnostic agent which combines the high 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.

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 supplie~ 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.

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1~t6399 The technetium-99Jn 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. ~ny suitable reducing agent may be employed - inclu~ing 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 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 ~he 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/ ~

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chelating a~ent employed. ~11 of the chelates accordin~ to the present invention, however, are cleared throu~h either the kidneys or liver. Therefore, the chelates of the abovc radio-metals with most substituted iminodiacetic acids and 8-hydroxy-quinolines may be utilized for the imaging of these organs.
Preferab]y, the chelating agents are of the formula , ' ~ .
Cll ~ COOH
R - N or ~R

; CH2 - COOH ~ -H
wherein R may be alkyl of up to about 2~ carbon atoms preferably about 1~ carbon atoms, alkenyl, ary] alkyl or cyclo-aliphatic groups substituted Witll halogen, hydroxy, carboxy, nitro, amino, keto or heterocycl;c groups. The groups may be interrupted by ether or thio-ether linka~es.
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-iminodi~cetic acid, N-(10-carboxydecyl) iminodiacetic acid, N-[N'-(2,6-dimethyl-phenylj carbamoylmeth~l] 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 gallium and indium chelates are prepared by the add;.tion of either GaC13 or indium chloride in .05 M EICL to thc 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.
EX~MPLE 1 2 grams (~01 moles) of alpha-chloro-2~6-Acetylxylidide and 2 grams (0.01 moles) of iminodiacetic acid (disodium salt) ; 10 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) 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-[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.

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The pll of the solu~ion was adjusted to 3.5 with 1 N ~ICl.
Ext~ia 0.lN NaO1I was added thereto 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 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 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 pertechnetate was added. The product was chromatographed in saline and recorded on a radiochromato-gram scanner. The resulting graph showed a ~eak at the solvent front, Rf=l due to the chelated compound. There was litt~e ; 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 ln vivo distribution of the product of Example 2 in the mice were plotted as a bm/~

' 1~963~g function of time. See Fig. 1.

The procedure of Example ~ was followed utilizing the pxoduct of ~xample 3. The in vivo distribution of this ,.............................................. .
product in mice as a function of time were plotted. See Fig.
2.

4 mCi (technetium-99m) of the product of ~xample 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 camera (Pho Gamma III) and a parallel hole high sensitivity . ' , ' .

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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 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 characteristlcs 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 I-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-hydroxy~uinoline 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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EXA~PLE 9 ; . The gallium-67 chelate of 8-hydroxy~uinoline was prepared by adding Ga67Cl3 in O.OSM HCl to an a~ueous 7 m-molar 8-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 ~he intestines and 20% in the blood after 60 minutes.

The technetium-99m chelate of nitrilotriacetic acia 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.

EXAMPLE ll ':`' ' .
The cobalt-57 chelate of N-[N'-(2,6-dimethylphenyl) carbamoylmethyl] iminodiacetic acid was prepared by heating 2-5 ~ Ci of Co5 C12 in the presence of l ml (20 mg/ml) of a solution of the compound (pH 4-5) for l hour at 100C. The chelate was chromatographed an~ biodistribution studies . .
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carried out using the procedure of Example 8. At 30 minutes, 28% of the injectcd dose appears in the liver and 12% in the intestines.

The technetium-99M chelate of 10-carboxydecylimino-diacetic acid was preparcd according to the stannous chlorïde reduction method of Examples 2, 3 and 8. The product was chromatoyraphed in saline. >98% the material had an Rf=l.
Biodistribution 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 Iiver 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 ; 20 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 minutes) with a h~igh uptake in the liver (40%) and intestines (30%) at 30 minutes.

~` EX~MPLE 14 .`
~ The procedure of Example 11 was followed to prepare j the cobalt-57 chelate of methyliminodiacetic acid.
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~ ~he procedurc of Examplc 9 was ol'10wed to prepare ; the gallium-67 chclatc o~ mcthyliminodiacct;c acid.
Biodistribution studics carried out according to the procedure ' of Example 8 showed rapid renal clearance.

EX~MPLE 16 The stannous chloride re~uct,ion procedllre of Examples 2, 3 and 8 was employcd to prepare the technetium--99m chelate of 5,7-diiodo-8-hydroxyquilloline.

EXAM~LE ~7 The stannous chloride reduction method of Examples 2, 3 and 8 was used to prepare the technetium-99m chelate of 2,6-pyridinedicar~oxylic acid.
' This appli~cation is a division of Canadian Patent Application Serial No. 242,8-5 filed December 31, 1975.

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Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing N-(N'-(2,6-dimethyl-phenyl carbamoylmethyl) iminodiacetic acid which comprises contacting, in solution, .alpha.-chloro-2,6-acetylxylidide and imino-diacetic acid.
2. N-{N'-(2,6-dimethylphenyl carbamoylmethy]}
iminodiacetic acid, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
CA335,980A 1975-09-02 1979-09-20 Iminodiacetic acid pharmaceutical Expired CA1096399A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA335,980A CA1096399A (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
CA335,980A CA1096399A (en) 1975-09-02 1979-09-20 Iminodiacetic acid pharmaceutical

Publications (1)

Publication Number Publication Date
CA1096399A true CA1096399A (en) 1981-02-24

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Application Number Title Priority Date Filing Date
CA335,980A Expired CA1096399A (en) 1975-09-02 1979-09-20 Iminodiacetic acid pharmaceutical

Country Status (1)

Country Link
CA (1) CA1096399A (en)

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