US 3663688 A
Description (OCR text may contain errors)
3,663,688 DIAGNOSTIC MATERIAL AND PROCESS USING CHELATED RADIOACTIVE Y'ITERBIUM Ivan M. Grotenhuis, Blaine, Minn, assignor to Minuesota Mining and Manufacturing Company, St. Paul, Minn. No Drawing. Filed June 26, 1968, Ser. No. 740,050
Int. Cl. A61k 27/04; C07f /00 US. Cl. 424-1 16 Claims ABSTRACT OF THE DISCLOSURE Compositions of matter comprising radio-ytterbium and a chelating agent therefor, the said compositions being soluble in Water and body fluids and having a stability constant above about 10 are used by parenteral administration to study the kidneys and the brain in warmblooded animals. The chelating agent prevents the dissipation of the chemically active radio-nuclide into body tissues other than the kidneys, since chelates, although soluble, are preferentially excreted by the kidney. A useful diagnostic tool is provided.
BACKGROUND OF THE INVENTION (1) Field of the invention This invention relates to diagnostic procedures and more particularly to procedures for determining the condition of body organs by detection of radioactive substances dispersed in such organs.
(2) Description of the prior art Heretofore, kidney function and condition have been studied by means of radioactive materials, by a process in which a compound known to concentrate in and excreted through the kidney, e.g. Chlormerodrin (1-[3- (chloromercuri)-2-methoxy-propyl1urea) labeled with Hg; or iodohippuran, labeled with 1 is administered parenterally. The injected material is permitted to accumulate in the kidney and then autoradiography or scanning with suitable monitoring elucidates the condition of the kidney.
The same materials have been used to study blood flow patterns in the brain. However, these materials, when used for this purpose, would be injected into a vessel that feeds the brain, e.g. the carotid artery. Radiosotope scanning procedures are also used to indicate brain condition, especially the presence of tumors, as the radioactive material passes through the brain.
In these known methods, it was necessary to use radionuclides of extremely short half-life, as the compounds were to a significant extent metabolized, thus releasing the radionuclide which then could be expected to concentrate itself in other body areas. Thus whenever radioactive iodine isotopes are used it is necessary to block the thyroid with normal iodine to prevent radiation damage to the thyroid gland.
Chelating agents have been used to make complexes with radio-chromium, e.g. Cr which were used to determine glomerular filtration rates, as reported in The Lancet, Apr. 15, 1967, pages 818-819. Such complexes have not been used for kidney or brain visualization, however.
Chelating agents have also been used heretofore in cases where radionuclides have accidentally been introduced into the human body. In this situation, these agents tend to assist in removing the radioactive material, acting as a kind of scavenger. They have also been used to contain or temporarily bind radionuclides for diagnostic puposes, e.g. idium used with diethylene triamine pentaacetic acid for kidney and brain scanning. Combinations of this 3,663,688 Patented May 16, 1972 type, which have been used heretofore, have been undesirable in having a very short half-life, too short for making storable compositions. Similar compositions in which indium is used have longer half-life but their emission of radiation includes undesirable gamma radiation, which is a serious disadvantage.
SUMMARY OF THE INVENTION The present invention has the objective of providing a means for more safely studying kidney function and condition by the use of radioisotopic or radioactive material. In accomplishing the aims of the invention, ytterbium is sequestered in chelating agent which is excreted substantially unchanged by the kidney. Such compositions are water-soluble, and for the purpose of determining kidney function, are administered parenterally in suitable doses.
After administration, the kidney is monitored using a suitable radioactivity-detecting device, e.g. a scintillation counter or by autoradiography, to determine when the radioactive material first arrives in the kidney. Thereafter, after the material has accumulated for a period of time, the kidney area is again monitored to determine the distribution of the radioactive material within the kidney.
In a similar way, this invention provides a safer and more efficient means for studying brain condition, especially for tumor identification. The chelated ytterbium temporarily accumulates in the extracellular spaces of the brain after the composition is injected into a blood vessel which feeds the brain. The composition remains in the brain for a time sufficiently long to permit scanning of the radioisotope by conventional means. The composition is released into the venous outflow and transported to the kidney, then excreted.
Because the radio-ytterbium is sequestered within the chelating agent, it is not broken down in the body and the radioactive material is not released. Consequently, there is substantially no danger of forming a deposit of the radionuclide in an unwanted area of the body, such as the bones or other organs, Where the continued exposure of the tissue to radioactivity might be deleterious.
After the composition containing the radio-ytterbium has accumulated for a short time in the kidney, it is excreted substantially unchanged in the urine. In this way, after a very short period of dwell time in the body, long enough to permit the estimation of kidney function and visualization of the kidney structure, the radionuclide material passes out of the body, thus ending the exposure of the tissues to the radiation.
Compositions comprising the chelated radio-ytterbium dispersed in pharmaceutical extending media are quite stable under the usual conditions of storage. They can be sterilized, e.g. by autoclaving, sterile filtration or the like, packaged and then stored for relatively long periods of time until they are used. The compositions can be used for diagnostic or therapeutic purposes.
The chelating agents which are suitable for use in the process of the invention and in forming the compositions of the invention are materials such as ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid and other amino polycarboxylic acids and the like. Any chelating agent capable of sequestering cations, having a constant for the formation of the complex Yb-chelating agent of 10 to 10 as determined in the manner set forth in the publication Tables of Stability Constants, published by the Chemical Society of London, 1964, is useful for the purpose. A simple test for determining suitability of such agents consists in preparing a calcium complex with the selected chelating agent, injecting this intravenously into the mammalian organism, using as a test organism, for example, the dog, and recovering the material from the urine of the test animal. Chelating agents useful for the purpose of the invention can be recovered in amounts up wards of about 95 percent in this test, still containing the radionuclide.
The amount of chelating agent used for the purposes of the invention is about 2 to 50 moles of chelating agent per mole of ytterbium. Preferably a 2 to 20-fold molar excess of chelating agent is used.
The radionuclide used for the purpose of the invention is ytterbium, ytterbium oxide, or a ytterbium salt, e.g. the halide or sulfate and the like.
The amount of radio-ytterbium required for diagnostic or therapeutic use is very small and usually is not sufficient to react completely with the amount of chelating agent used. Therefore, non-radioactive ytterbium may be used to furnish ions to react with the excess chelating agent, or some other metal which is non-toxic, i.e., physiologically acceptable for the purpose, can be used to furnish metal ions to react completely with the chelating agent. Iron, calcium or the like can be used for this purpose.
Ytterbium" in the form of a chelate of high stability as described herein is an especially advantageous and useful composition for the purposes set forth. Because of its half-life of 32 days, ytterbium chelate can be prepared and stored before use for as much as sixty days or even longer before its activity has been declined to levels which are no longer practically useful. Thus, it is possible to provide diagnostic or therapeutic preparations directly to the physician without the necessity that these be prepared from radioisotopes immediately before use.
The emission from radio-ytterbium is particularly useful in that substantially no alpha or beta radiation is emitted, wherefore there is no possible tissue damage from this cause. The energy levels of the gamma radiation from ytterbium falls within the ranges which are especially adapted for the presently used scanning techniques.
Because the complexes of the invention are rapidly excreted after injection, they are, for biological purposes, equivalent to radioisotopes of very short half-life. However, their long radioactive half-life, which enables advance preparation and storage of the compositions, makes these compositions unexpectedly useful.
:In another embodiment of the invention, the radioytterbium chelate complex is prepared in the form of a solution of dispersion in a pharmaceutical extending medium, containing from about microcuries to 500 millicuries of radionuclide per'ml. The ordinary dose which is injected ranges from 1 to 10 ml. Suitable pharmaceutical extending media for the purpose include isotonic sodium chloride solution, Ringers solutions, gum acacia solution and the like. As such preparations are required to be sterile, they are e.g. autoclaved, filtered through porcelain sterilizing filters, or subjected to ultraviolet light, and are preserved and used under sterile conditions.
The following examples, in which all parts are by Weight unless otherwise specified, will more particularly illustrate the process and compositions of the invention.
EXAMPLE 1 To a solution of ytterbium chloride (Yb 1 mc.) in hydrochloric acid (0.05 N) are added 200 micrograms of ferric iron in the form of a solution of ferric chloride in dilute (0.05 N) hydrochloric acid, with thorough stirring. 1.6 milligrams of diethylenetriaminepentaacetic acid (DTPA) is added as 1 ml. of a dilute solution in pyrogenfree water. The chelate of radio-ytteribum and iron (which completes the reaction with the DTPA) is rapidly formed- The solution is evaporated to dryness under reduced pressure on the steam bath to give a white powder of radioactive complex. This can be stored and redissolved as required, with the usual precautions when handling radioactive materials.
-For the immediate preparation of a solution suitable for injection for diagnostic purposes, the reaction mixture is not evaporated to dryness. Instead, the solution is made isotonic with sodium chloride. It is titrated to pH 4.5 to 5.5 with 0.5 N sodium hydroxide. A deep yellow coloration due to the formation of the iron-ytterbium-DTPA complex is a useful internal indicator that the end-point of the titration has been reached. The solution is sterilized by filtration through a sterilizing filter.
EXAMPLE 2 To a solution of ytterbium chloride (Yb 1 mc.) in hydrochloric acid (0.05 N) are added 200 micrograms of ferric iron as 0.2 ml. of a solution of ferric chloride in 0.05 N hydrochloric acid. The solution is thoroughly stirred. Ethylenediaminetetraacetic acid (EDTA) is added as a solution containing 1.6 milligrams in 1 ml. of pyrogenfree water. The solution is made isotonic with sodium chloride. It is titrated to pH 7.0 to 7.5 with 0.5 N sodium hydroxide. Sterilization is done by autoclaving.
EXAMPLE 3 The sterile solution of Example 1 (Yb 1 me.) was injected intravenously into a dog in the form of one single injection. Renal scans were made using a Picker scanner. Good images of the kidneys were obtained. Similar results were obtained when one half of the dose was administered rapidly and the remainder was infused slowly while a renal scan was being done.
EXAMPLE 4 A sterile solution of radionuclide chelate complex made by the procedure of Example 1 was administered to a dog by intravenous injection. Scintillation radiation detectors were placed above the kidneys and the bladder, and the arrival times and the subsequent intensity of the radiation in the organs were continuously monitored. The readout from this operation was a measure of renal function. Subsequent assay of urine indicated that over percent of the nuclide was excreted.
EXAMPLE 5 A sterile solution of radionuclide chelate complex of Example 1 was administered to a human patient suffering from severe bilateral renal disease, exhibiting marked nitrogen retention (serum urea nitrogen -150 mg. percent). Previous attempts to visualize any functioning renal mass had been unsuccessful; for example Hg chlormerodrin had failed to visualize the kidneys.
After injection the patient was scanned after the manner of Example 5. The scan showed that both kidneys were of normal size. This information was used in diagnosing the patients illness.
What is claimed is:
1. A composition of matter containing radionuclide material, comprising a chelating agent capable of sequestering cations, having a constant for formation of the complex Yb-chelating agent of 10 to 10 having sequestered therein ytterbium said composition being soluble in water and body fluids to form a true solution and having stability constant above about 10 and containing about 2 to 50 moles of chelating agent per mole of ytterbium.
2. A composition according to claim 1, in which the chelate complex contains radio-ytterbium in amount less than that necessary to react completely with the chelating agent and a physiologically acceptable metal in amount sufficient to complete the reaction with the chelating agent.
3. A composition according to claim 1, in which the chelating agent is diethylenetriaminepentaacetic acid.
4. A composition according to claim 1, in which the chelating agent is ethylenediaminetetraacetic acid.
5. A composition according to claim 1, in which the chelating agent is present in amount of about 2 to 50 moles for each mole of radio-ytterbium.
6. A composition according to claim 2, in which the physiologically acceptable metal is iron.
7. A composition according to claim 2, in which the chelating agent is diethylenetriaminepentaacetic acid and the physiologcally acceptable metal is iron.
8. A composition according to claim 2, in which the chelating agent is ethylenediaminetetraacetic acid and the physiologically acceptable metal is iron.
9. A solution adapted for use in ascertaining kidney function and condition, consisting essentially of a solution, in a pharmaceutical extending medium suitable for parenteral use, of a composition comprising a chelating agent capable of sequestering cations, having a constant for formation of the complex Yb-chelating agent of to 10 having sequestered therein ytterbium said composition being soluble in water and body fluids to form a true solution and having stability constant above about 10 and containing from about 10 microcuries to 500 millicuries of radioactivity per ml., the said chelating agent being present in amount of about 2 to 50 moles for each mole of ytterbium.
10. A solution according to claim 9, in which the chelating agent is diethylenetriaminepentaacetic acid in amount of about 2 to 50 moles per mole of radio-ytterbium.
11. A solution according to claim 9, in which the chelating agent is ethylenediaminetetraacetic acid in amount of about 2 to 50 moles per mole of radio-ytterbium.
12. A solution according to claim 10, in which iron is present as a reaction product with excess chelating agent.
13. A solution according to claim 11, in which iron is present as a reaction product with excess chelating agent.
14. A method for ascertaining kidney or brain function and condition which comprises parenterally injecting into a mammalian organism a composition comprising a chelating agent having ytterbium sequestered therein, said composition being soluble in Water and body fluids to form a true solution and having stability constant above about 10 and said chelating agent capable of sequestering cations, having a constant for formation of the complex Yb-chelating agent of 10 to 10 and being present in amount of about 2 to 50 moles per mole of ytterbium dispersed in a pharmaceutical extending medium.
15. A method according to claim 14, in which the chelating agent is diethylenetriaminepentaacetic acid.
16. A method according to claim 14, in which the chelating agent is ethylenediaminetetraacetic acid.
References Cited Nuclear Science Abstracts, vol. 15, No. 21, Nov. 15, 1961, pp. 3558-3559, Abstract No. 27600.
Moeller et al., J. Inorg. Nucl. Chem., 1962, vol. 24, pp. 499-510, Pergamen Press Ltd., London, England.
Nuclear Science Abstracts, vol. 21, No. 5, March 15, 1967, p. 704, #6584, Abstract from Winter, C. J. Urol, 95, 5847 (April 1966).
BENJAMIN R. PADGETT, Primary Examiner US. Cl. X.R.