CA1157033A - Radiographic scanning agent - Google Patents

Abstract

Abstract A composition and method for the preparation of a technetium-99m-based scanning agent are disclosed. The scanning agent is prepared from 99mTc, in a +3, +4 and/or +5 oxidation state, and a methanehydroxydiphosphonate bone-seeking agent which carries the radionuclide to bone mineral. The methanehydroxydiphosphonate agent provides scan sharpness equivalent or superior to commerical scanning agents, and is superior to commerical infarcts, as compared with commerical scanning agents such as ethane-1-hydroxy-1,1-diphosphonate and methane-diphosphante.

Description

~v RADIOGRAPHIC SCA~ING AGENT

John A. Bevan TECHNICAL FIELD

This invention relates to radiodiagnostic agents and more particularly to a composition and method for preparing a highly effective technetium-99m-based bone scanning agent.
For some time it has been recognized that conven-tional X-ray techniques are not entirely satisfactory for detecting many types of disorders at an early stage. One unfortunate deficiency of X-ray examination is the in-ability of that technique to detect.skeletal metastasesin their incipient stages when meaningful treatment is possible.
Early ~bone scanning" work for detecting metastases was directed to the use of radioactive isotopes, espe-cially the isotope fluorine-18 ~18F) which selecti~ely migrates to the skeleton and especially to "active" sites thereon, such as the joints and tumor sites, where it ~xchanges with the hydroxyl group in calcium hydroxy-apatite. 18F, however, has certain limitations due to ~-its short half-life (110 minutes); viz., a very short "shelf life", as well as high energy emission which makes it unsuited for use with certain detection equlpment, notably the Anger scintillation camera. Additionally, 8F requires very expensive equipment to prepare and is therefore quite unsuited for all but the most well equipped hospitals.
The strontium-85 isotope (85Sr) has also been used in bone scanning. ~his radionuclide seeks the skeleton and exchanges with the calcium in calcium hydroxyapatite, ~ 30 particularly at actively metabolizing sites. Strontium-; 85 is at the opposite end of the usable half-life spectrum .

~157(~33 from 18F, having a half-life of 65 days. While this greatly increased half-life (compared with 18F) provides a desirable "shelf life", it requires that very long exposure times be used to achieve a usable scan, inasmuch as only small amounts can be administered since the total exposure of the patient to radiation must be minimized.
Because of the shortcomings with 18F and 85Sr, more recent work in nuclear medicine has been directed to technetium-99m (99mTc) which has a half-life of six hours. Interest in 99mTc has also increased due to the availability of convenient commercial means for supplying this radionuclide in the hospital, as needed. A radio-nuclide solution in the oxidized pertechnetate (99mTco4 ) form is obtained from commercial sources by elution with an isotonic saline solution from an alumina column.
Organic solvent-extracted "Instant Technetium" is also available.
Pertechnetate from commercial sources is in what is believed to be the +7 oxidation state, which does not combine with bone mineral-seeking agents to provide bone scans, and the like. This problem is easily overcome by reducing the pertechnetate to what is believed to be the +3, +4 and/or +S oxidation state, referred to hereinafter as technetium-99m or 99mTc.
Technetium-99m is different from either 18F or 85Sr in that it does not specifically seek or react with the skeleton. Its use, therefore, depends on compounding or complexing 99mTc with bone mineral-seeking agents.
In general, 99mTc-labeled bone scanning agents are prepared by admixin~ a pertechnetate-99m isotonic saline solution with a pertechnetate reducing agent such as the stannous, ferrous, titanous or chromous salt of sulfuric or hydrochloric acid, and the desired carrier ag~nt for targeting bone mineral. For example, U.S. Patent 4,016,249, issued April 5, 1977, teaches a means for targeting bone mineral with radioactive technetium by using 99mTc in combination with certain soluble phosphates. Liquid, dry . .

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., ~57033 powder mixture and freeze-dried bone scanning kits con-taining phosphate or phosphonate bone seeking agents are :
currently being marketed by various manufacturers.

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BACKGROUND ART

U.S. Patent 3,983,227, Tbfe and Francis, issued Sept. 28, ~76,discloses the use of dry powder mixtures of reducing salts with a great variety of organophosphonate bone-seeking carriers to prepare bone scanning agents from radioactive per-technetate solutions. The methanehydroxydiphosphonates used herein are included among the myriad types of phos-phonates taught by patentees to be useful in dry mixtures suitable for the preparation of bone scanning agents.
The references relating to bone mineral-seeking agents and their use with 99mTc do not suggest the special advantages of methanehydroxydiphosphonate in radiodiagnos-tic products used for targeting bone mineral. For example, the reference which mentions methanehydroxydiphosphonate lS in bone scanning agents (U.S. Pabent 3,983,227) does so only as part of a rather general listing of a variety of organo-phosphonates, and only in the context of the powder mixture-type of product.
It has now been discovered that methanehydroxydi-phosphonate, when used in the manner disclosed herein, unexpectedly provides both sharp bone mineral images and ~ excellent lesion detection. Moreover, the methanehydroxy-; diphosphonates are superior to the other well-known organic phosphonates when used with 99mTc to image myo-cardial infarcts which, in the acute phase, are associated with high levels of calcium.

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~57~:)33 DISCLOSURE OF INVENTION

Radiodiagnostic agents comprising 99mTc and various organophosphonate or inorganic phosphate bone seeking agents are currently used in hospitals. It has now been discovered that the methanehydroxydiphosphonate bone mineral-seeking agent disclosed herein is unique in that ; it unexpectedly provides the dual benefits of sharp radiographic imaging and excellent lesion detection when used with 99mTc. Moreover, the methanehydroxydiphosphon-ate agent can also be used with 99mTc for detecting soft tissue calcification (e.g., myocardial infarct imaging) in the manner of the inorganic phosphate radiodiagnostic agents.
Radionuclide uptake in uncalcified soft tissue is usually a major problem with scannin~ agents prepared from reducing metals/pertechnetate/organophosphonates, since excessive soft tissue uptake, especially in the liver, can obscure large portions of the skeletal scan.
Past efforts to minimize soft tissue uptake have centered mainly on using minimal amounts of the reducing metal, and the ratio of organophosphonate:reducing metal in many commercial products is typically 10-40 to 1.
As disclosed more fully hereinafter, to achieve j~ the special advantages of the present invention it is necessary to use somewhat smaller amounts of the methane-hydroxydiphosphonate than are used with various other organophosphonates in radiodiagnostics. By using said smaller amounts of this diphosphonate, undesirable deposi-tion of the g9mTc in the liver is avoided, and the sharpness/detection/M.I. imaging advantages are secured without the scan being obscured by liver uptake.

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~L~57033 BEST MODE

The present invention is based on the use of methanehydroxydiphosphonic acid (and the water-soluble salts and hydrolyzable esters thereof) as a bone mineral-seeking agent to target bone mineral with radioactivetechnetium. The methanehydroxydiphosphonate is con-veniently supplied in a freeze-dried composition, said composition providing both a reducing metal ion for reducing pertechnetate (Tc04 ) to a lower valence ~oxida-tion state) and the methanehydroxydiphosphonate moietyfor carrying the lower-valent technetium to bone mineral.
In an optional mode, the composition can contain a non-interfering amount of a stabilizer material to inhibit or reduce the oxidation of the pertechnetate reducing agent (e.g., oxidation of Sn+2 to Sn+4) during storage and/or to inhibit or prevent the reoxidation of reduced tech-netium and/or formation of technetium-labeled impurities during use.
In another product form, the methanehydroxydiphos-phonate can be supplied in an aqueous solution in combina-tion with a technetium reducing agent. Since the techne-tium reducing agent is preferably a soluble metal ion which is readily oxidized, it is highly preferred that such aqueous compositions contain a stabilizer material Of the type mentioned above.
In another mode, the methanehydroxydiphosphonate - can be provided as a metal compound, i.e., in chemical combination with the reducing metal for the technetium.
Included among such compounds are the water-soluble stannous methanehydroxydiphosphonates, water-soluble ferrous methanehydroxydiphosphonates, water-soluble chromous methanehydroxydiphosphonates, water-soluble titanous methanehydroxydiphosphonates, and the like.
When such combined reducing metal/bone mineral-seeking compounds are used i~ the preparation of a radiodiag-nostic agent from technetium, it is preferred that some - . . . j . . . , ~ . .

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i7033 excess methanehydroxydiphosphonate over that used to prepare the metal-methanehydroxydiphosphonate compound, itself, be present to ensure good bone mineral imaging.
However, the amount of said excess of methanehydroxy-diphosphonate does not exceed that specified hereinafter, 80 that undesired liver uptake is avoided. Stabilizers of the type disclosed above are also useful in such compositions.
In yet another product form, the compositions of the present invention comprise simple mixtures of techne-tium reducing agent, methanehydroxydiphosphonate and, optionally, a stabilizer.
The present invention, in one aspect, resides in a composition of matter for the preparation of a technetium-based bone mineral or infarct scanning agent, comprising:
(1) a water-soluble reducing agent for radioactive pertechnetate in an amount sufficient to reduce a unit dose of pertechnetate to a lower valence state;
and

(2) a methanehydroxydiphosphonate bone material-seeking agent which is selected from methanehydroxydiphosphonic acid, and the water-~; soluble salts and esters thereof, in an amount sufficient to carry a unit dose of tri-, tetra-, or pentavalent radioactive technetium to bone mineral in the body of a human or lower animal with minimal absorption of technetium in uncalcified tissue and wherein said amount of methanehydroxydiphosphonic acid or water-soluble salt or ester thereof, sufficient to carry said unit dose, is less than about 0.1 mg./kg body weight of said human or lower animal;

~3~57033 - 8a -the weight ratio of methanehydroxydiphosphonate bone mineral seeking agent:reducing agent being in the range of from about 8:1 to about 30:1.

This asnec~ of the invention is also disclosed and is claimed, in Canadian Patent Application No. 332,851 filed July 30, 1979, of which the present application is a divisional.
The invention, in a further aspect, resides in a water-soluble composition of matter selected from the group consisting of 99mTc-methanehydroxydiphosphonate, 99mTc~methanehydroxydiphosphonate-tin, 99mTc-methanehydroxydi-phosphonate-iron, 99mTc-methanehydroxydiphosphonate-chromium and 99mTc-methanehydroxydiphosphonate-titanium.
According to yet another aspect of the invention there is provided a process for preparing a water-soluble salt of methanehydroxydiphOsphonic acid and a heavy metal selected from the group consisting of tin, lron, chromium and titanium, said heavy metal being in a reduced valence state, which comprises reacting methanehydroxydiphosphonic acid or a water-soluble alkali metal, ammonium, alkylammonium or alkanolammonium salt thereof, or an ester thereof which is hydrolyzable under use conditions to the free acid or anion form of said acid, with a water-soluble salt of said heavy metal in a reduced valence state.
The invention additionally provides a process for preparing a water-soluble composition of matter selected from the group consisting of 9gmTc-methanehydroxydiphosphonate, 99mTc-methanehydroxydi.-'.
phosphonate-tin, 99mTc-methanehydroxydiphosphonate-iron, 99mTc-methanehydroxydiphosphonate-chromïum and 99mTc-methanehydroxydiphosphonate-titanium, which comprises reacting ~ I
a water-soluble pertechnetate-99m with methanehydroxydiphos-phonic acid or with a water-soluble salt of methanehydroxy-diphosphonic acid and a heavy metal selected from the group consisting of tin, iron, chromium and titanium, said heavy metal being in a reduced valence state.
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~L57(~33 - 8b -Methanehydroxydiphosphonate ~ ethanehydroxydiphosphonic acid and its related salts and esters can be prepared, for example, by the reaction of phosgene with an alkali metal dialkyl phos-phite. A complete description and methods of preparation are found in U.S. Patent 3,4~2,137, Quimby, granted January 14, 1969, Only those esters which hydrolyze under use conditions to the free acid or anion form can be used herein.
Methanehydroxydiphosphonic acid has the molecular formula HC(OH)(PO3H2)2. While the free acid or any pharmaceutically-acceptable, water-soluble salt or hydro-lyzable ester of methanehydroxydiphosphonic acid can be used in the practice of this invention, the alkali metal (especially sodium) and the ammonium salts are preferred.
These compounds are fully described in the Quimby patent, above.
Representative examples of methanehydroxydiphos-phonates useful herein include the following salts and esters: monosodium, disodium, trisodium, tetrasodium, and mixtures thereof; monopotassium, dipotassium, tri-potassium, tetrapotassium, and mixtures thereof; mono-ammonium, di-ammonium, tri-ammonium, tetra-amm~nium, and ::;

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g mixtures thereof; mono-, bis-, tris-, and tetrakis ~tetraalkyl ammonium) wherein alkyl is, for example, methyl, ethyl or propyl; monomethyl; monoethyl; mono-, bis-, tris- and tetrakis-(alkanolammonium), e.g., mono-(triethanolamm~nium), bis-(triethanolammonium), tris-(triethanolammonium), and tetrakis-(triethanolammonium);
and mixtures of the foregoing me~hanehydroxydiphosphonates which are soluble or are hydrolyzable in water at the usage concentrations of the present invention. The "free acid" form methanehydroxydiphosphonic acid can also be used.
The sodium salts of methanehydroxydiphosphonic acid and the free acid, itself, are most preferred for use herein.

Pertechnetate Reducing.A~ent As used herein the term "pertechnetate reducing agent" includes compounds, complexes, or the like, com-prising a reducing ion capable of reducing heptavalent ` technetium (Tc04 ) to trivalent, tetravalent and/or pentavalent technetium. Free metals such as tin are also known for use as pertechnetate reducing agents, although undissolved metal must be removed from the scanning solution prior to injection into the patient. Thus, it : i5 more convenient to use metal compounds which provide a reducing metal cation in injectable, water-soluble form.
Suitable pertechnetate reducing agents include metallic salts of sulfuric acid and hydrochloric acid, such as stannous chloride, chromous chloride and ferrous sulfate. Other agents capable of reducing pertechnetate-99m include, for example, titanous halides, acid-thiosul-fates, acid-hydrogen-sulfates, iron colloids, and acid-borohydrides. U.S. Patents 3,735,001 granted May 22, 1973; 3,863,004 granted January 28, 1975; 3,466,361 granted September 9, 1969; 3,720,761 granted March 13, 1973; 3,723,612 granted March 27, 1973; 3,725,295 granted April 3, 1973; 3,803,299 granted April 9, 1974; and .
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-~57033

3,749,556,granted July 31, 1973;
disclose various pertechnetate reducing agents comprising reducing ions capable of reducing heptavalent pertechnetate to appropriate lower valence states.
Water-soluble stannous ~Sn~2) compounds, especially stannous chloride, are preferred for use as the pertech-netate reducing agent herein. Stannous bromide, fluoride and sulfate can also be used. Stannous salts of organic acids, such as ~tannous tartrate or maleate, can be used, as can the stannous salt of methanehydroxydiphosphonic acidl -Optional Stabilizer The compositions herein optionally, and preferably, contain a stabilizing amount of a s~abili7er material toprevent or inhibit the oxidation of the pertechnetate reducing agent (e.g., oxidation of Sn+2 to Sn~4) during storage and/or to inhibit or reduce the reoxidation of reduced technetium-99m and/or to reduce the formation of technetium-labeled impurities which may form during use o~ the compositions.
The stabilizers used herein are characterized by their toxicological acceptability under the conditions of use, their ability to stabilize the product for a reason-able period of storage and/or under usage conditions, andby their substantial non-interference with the delivery of the technetium radionuclide to bone mineral.
Stabilizers which meet the foregoing requirements and which are quite suitable for intravenous injection include gentisic acid and its water-soluble salts and esters, ascorbic acid and its water-soluble salts and esters, and erythorbic acid and its water-soluble salts and esters. Gentisic acid, ascorbic acid and erythorbic acid are all known, commercially-available materials.
The sodium salts of these acids are all available, quite water-soluble, and preferred for use herein.

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~7033 As is known in the literature, stabilizer materials such as ascorbic acid can chelate/complex with technetium and cause it to be deposited in uncalcified soft tissue.
Since the practitioner of the present invention will wish to avoid all unnecessary deposition in soft tissue, it will be appreciated that the amount of stabilizer material optionally used in the present compositions should not be so great as to overshadow the bone-directing effect of the methanehydroxydiphosphonate, thereby interfering with the bone scan. Appropriate, non-interfering amounts of stabilizer materials for use in combination with the methanehydroxydiphosphonate are disclosed in more detail, hereinafter.

Methods The compositions of the present invention are intended for intravenous injection into humans or lower animals. Accordingly, appropriate manufacturing and operating conditions are employed to provide suitably sterile, pyrogen-free compositions.
It has been discovered that dosages of methane-hydroxydiphosphonate above about 0.1 mg. per kilogram of ` body weight (mg./kg.) are excessive for a radiodiagnostic product intended for bone mineral scanning, inasmuch as ; liver uptake of the technetium radionuclide becomes excessive and scan quality suffers. Preferably, the total amount of methanehydroxydiphosphonate bone mineral-eeking agent used per scan does not exceed about 0.1 mg./kg., and is more preferably in the range of about 0.001 mg./kg. to about 0.05 mg./kg.; most preferably about 0.4 mg./70 kg.
As disclosed hereinabove, undesirable soft tissue uptake can be further minimized by avoiding excess amounts of the pertechnetate reducing agent. The ~eight ratio of methanehydroxydiphosphonate bone mineral-seeking agent to technetium reducing agent is generally in the .
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~57033 range from about 8:1 to about 30:1, more preferably about 8.1 to about 13:1, most preferably about 12:1.
As a further means for avoiding undesirable soft tissue uptake of technetium, the weight ratio of methane-hydroxydiphosphonate:optional stabilizer material iskept in the range from about 20:1 to about 1:1, more preferably about 2:1 to about 20:1, most preferably abQut 3:1 to about 5:1.
The compositions of the present invention can be prepared by simply dry mixing the technetium ~educing agent and the methanehydroxydiphosphonate agent. The opti~nal stabilizer can also be dry-blended into such mixtures, as can additional, non-interfering agents such as sodium chloride. Conveniently, such compositions are provided in mixing vials fitted with a rubber septum for ease-of-mixing with a pertechnetate-solution and ease-of-use in the hospital. The vials are preferably nitrogen-'~ filled as an added protection against oxidation of the technetium reducing agent on storage.
In an alternate mode, the compositions herein can be provided in freeze-dried form. Such compositiQns are prepared by co-dissolving the methanehydroxydiphosphonate agent and the technetium reducing agent in an aqueous solution, together with any desired optional stabilizers, and freeze-drying the composition using standard equipment.
Preferably, sterile, deoxygenated water is used in pro-cessing and the product is stored under nitrogen. Although somewhat more complicated to manufacture than the dry mixture product, the freeze-dried product offers the advantage that water-insoluble particulate matter which might be present in the raw materials can be removed by filtration prior to the freeze drying step.
In another mode, the compositions herein can be provided as aqueous solutions in sterile, pyrogen-free water. Preferably, the water is deoxygenated and the composition is stored under nitrogen, thereby minimizing undesirable oxidation of the pertechnetate reducing agent : . ,. , ., : : . . .
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on storage. Since the reducing agent is more prone to oxidize in solution than in the dry powder and freeze-dried composition forms, it is preferred that aqueous compositions contain a stabilizer.
Compositions of the present type wherein the weight ratio of methanehydroxydiphosphonate:technetium reducing agent is in the range of about 10:1 to about 15:1, more preferably about 8:1 to about 13:1, are pre-ferred.
Stabilized compositions wherein the weight ratio of methanehydroxydiphosphonate bone mineral-seeking agent:stabilizer is in the range of ~rom about 2:1 to about 20:1, most preferably abGut 2:1 to about 10:1, and wherein the weight ratio of methanehydroxydiphosphonate bone mineral-seeking agent:reducing agent is in the range of from about 8:1 to about 13:1 are-highly preferred.
Preferred compositions herein for preparing excel-lent skeleton and infarct scans using commercial pertechne-tate-99m sources comprise from about 0.1 mg. to about O.S
mg. of a water-soluble stannous salt selected from stannous chloride, stannous sulfate, stannous maleate, and stannous tartrate; and from about 1 mg. to about 5 mg. of a sodium salt of methanehydroxydiphosphonate.
Preferred stabilized compositions comprise from ~5 about 0.1 mg. to about 0.5 mg. of the stannous reducing agent; from about 0.25 mg. to about 1.0 mg. of the genti-sate or ascorbate stabilizer; and from about 1 mg. to about 5 mg. of the methanehydroxydiphosphonate agent.
~;; Compositions of the foregoing type are characterized by a physiologically-acceptable in-use solution pH in the range from about 3.5 to about 8, and, in the main, fall within a preferred pH range of 4 to about 6.
In use, the compositions are dissolved with a pertechnetate-99m isotonic solution from a commercial technetium source to yield a bone mineral scanning agent suitable for intravenous injection. The stability of such scanning agents is ample under ordinary hospital , . , ~ . , -. . ~ , .
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conditions. Administration is preferably done within about eight hours after addition of the pertechnetate solution. Preferably, the concentration of reagents and technetium radionuclide is sufficient that about 1 ml. of the solution i5 used in an adult of about 50-100 kg. body weight. One ml. of solution is preferably injected intravenously over a period of about 30 seconds. The total dosage of radionuclide for a sharp skeletal or myocardial infarct scan ranges from about 5 millicuries to about 3~ mCi, preferably from about 10 mCi to about 20 mCi. Since the methanehydroxydiphosphonate agent pro-vides such sharp scan quality and minimizes soft tissue uptake, the total exposure of the patient to radionuclide can be minimized, as compared with scanning agents which employ different types of bone mineral-seeking agents.
In an alternate mode, the me~hanehydroxydiphos-phonate can be present in the solution to elute the Tc04 from the source, whereafter the reduction can be effected with the reducing agent.
The actual identity of the water-soluble reaction product formed by the 99mTc/methanehydroxydiphosphonate/
reducing agent mixture and introduced into the body is not known with certainty. Water-soluble compounds in-cluding 99mTc-methanehydroxydiphosphonate, or that bi-partite species in combination with the reducing agent (tin, iron, chn~um or titanium) as a soluble tripartite species, are probably present in solution.

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~i7~33 INDUSTRIAL APPLICABILITY

The following examples illustrate the industrialapplicability of this invention, but are not intended to be limiting thereof.

S EXAMPLE I
Ingredient Milligrams Methanehydroxydiphosphonic acid 2.0 Stannous chloride 0.16 Sodium chloride 25.0 The composition of Example I is prepared by dry blending the three ingredients. The composition is stored under nitrogen in a 5-ml. viql, fitted with a rubber septum. On addition of about 5 ml. of a pertech-netate-99m solution from a commercial technetium source, and thorough shaking, the composition dissolves to yield a skeletal scanning agent suitable for intravenous injec-tion into a human or animal patient. Preferably, about 1 ml. of the solution is used in an adult or animal subject of about 50-100 kg. body weight and is injected slowly, over a period of about 30 seconds.
The composition of Example I is modified by re-placing the stannous chloride with an equivalent amount of stannous sulfate, ferrous chloride, titanous chloride and chromous chloride, respectively, and equivalent results are secured.
The composition of Example I is modified by re-placing the methanehydroxydiphosphonic acid with an equivalent amount of the monosodium, disodium, trisodium and tetrasodium salts of methanehydroxydiphosphonic acid, and mixtures thereof, respectively. Equivalent results are secured.
The composition of Example I is adjusted to pH's over the range of about 3.0 to about 8.0 without sub-stantially altering its efficacy as a bone-seeking agent.

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~57033 EXAMPLE II
Methanehydroxydiphosphonate, mixture of di-, and trlsodium salts (2.0 mg.), stannous chloride (0.16 mg.), and sodium gentisate stabilizer ~0.50 mg.) are dissolved in 1 ml. of deoxygenated water at room temperature. The aqueous solution is filtered through a Millipore filter and freeze-dried on a commercial apparatus.
The freeze-dried powder prepared in the foregoing manner is admixed with about 5 ml. of a pertechnetate-99m solution from a commercial source. The freeze-dried powder dissolves readily and a stable skeletal scanning agent suitable for intravenous use is secured.

EXAMPLE III
Methanehydroxydiphosphonate, mixture of di-, tri-15 sodium salts (2.0 mg.), stannous chloride (0.16 mg.), and sodium ascorbate stabilizer (O.50 mg.) are dissolved in 1 ml. o deoxygenated water at room temperature. The aqueous solution is filtered through a Millipore filter and freeze-dried on a commercial apparatus.
The freeze-dried powder prepared in the oregoing manner is admixed with about 5 ml. of a pertechnetate-99m solution from a commercial source. The freeze-dried powder dissolves readily and a stable skeletal scanning agent suitable for intravenous use is secured.

EXAMPLE IV
A stabilized composition suitable for imaging the skeleton as well as calcified soft tissue, especially myocaxdial infarcts, is as follows.

Ingredient Milligrams/vial 30 MHDP* 2.0 SnC12 0.16 Gentisic acid 0.50 NaCi 26.5 *Mixture o~ sodium salts of methanehydroxydiphosphonic acid.

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- ' :' ' ' ' ' .-~57033 The ingredients are dry mixed. Five mls. of eluate from a commercial pertechnetate source are added to one vial of the composition of Example IV to provide sufficient solution for 5 infarct scans. The composition can be used in like manner for bone scanning.

EXAMPLE V
Water-soluble stannous methanehydroxydiphosphonate is prepared by admixing equal volumes of a 0.02 molar aqueous solution of methanehydroxydiphosphonic acid and 0.012 molar aqueous, deoxygenated stannous chloride solu-tion, under nitrogen. The combined solutions are stirred for one hour under nitrogen, filtered to remove insolubles and freeze-dried to yield water-soluble stannous methane-hydroxydiphosphonate.
In like manner, 0.012 molar aqueous solutions of chromous chloride, titanous chloride and ferrous chloride are individually admixed with 0.02 molar aqueous solutions o methanehydroxydiphosphonic acid and the respective water-soluble chromous, titanous and ferrous methane-hydroxydiphosphonateS are secured.
A bone scanning agent which employs the metal methanehydroxy~diphosphonates of the foregoing type is as follows.

Ingredient Milligrams/vial 25 Stannous methanehydroxydiphosphonate 1.0 MHDP*
Sodium ascorbate 0.3 *Mixture of sodium salts of methanehydroxydiphosphonic , acid.
, The ingredients are dry mixed and used in the manner of Example IV as a bone scanniny agent.
In like manner, water-soluble chromous methane-hydroxydiphosphonate, titanous methanehydroxydiphosphonate . .

~L~5~0~33 and ferrous methanehydroxydiphosphonate can replace stannous methanehydroxydiphosphonate in a bone scanning agent.

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Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a water-soluble salt of methanehydroxydiphosphonic acid and a heavy metal selected from the group consisting of tin, iron, chromium and titanium, said heavy metal being in a reduced valence state, which comprises reacting methanehydroxydiphosphonic acid or a water-soluble alkali metal, ammonium, alkylammonium or alkanolammonium salt thereof, or an ester thereof which is hydrolyzable under use conditions to the free acid or anion form of said acid, with a water-soluble salt of said heavy metal in a reduced valence state.

2. A process for preparing water-soluble stannous methanehydroxydiphosphonate which comprises reacting methanehydroxydiphosphonic acid or a water-soluble alkali metal, ammonium, alkylammonium or alkanolammonium salt thereof or an ester thereof which is hydrolyzable under use conditions to the free acid or anion form of said acid, with a water-soluble stannous salt.

3. A process according to claim 1 in which said heavy metal is iron, whereby water-soluble ferrous methanehydroxydiphosphonate is formed.

4. A process according to claim 1 in which said said heavy metal is chromium, whereby water-soluble chromous methanehydroxydiphosphonate is formed.

5. A process according to claim 1 in which said heavy metal is titanium, whereby water-soluble titanous methanehydroxydiphosphonate is formed.

6. A process for preparing a water-soluble composition of matter selected from the group consisting of 99mTc-methanehydroxydiphosphonate, 99mTc-methanehydroxydi-phosphonate-tin, 99mTc-methanehydroxydiphosphonate-iron, 99mTc-methanehydroxydiphosphonate-chromium and 99mTc-methanehydroxydiphosphonate-titanium, which comprises reacting a water-soluble pertechnetate-99m with methanehydroxydiphos-phonic acid or with a water-soluble salt of methanehydroxy-diphosphonic acid and a heavy metal selected from the group consisting of tin, iron, chromium and titanium, said heavy metal being in a reduced valence state.

7. A process according to claim 6 in which said water-soluble pertechnetate-99m is reacted with methanehydroxy-diphosphonic acid, whereby 99mTc-methanehydroxydiphosphonate is formed.

8. A process according to claim 6 in which said water-soluble pertechnetate-99m is reacted with a water-soluble stannous salt of methanehydroxydiphosphonic acid, whereby the water-soluble composition of matter 99mTc-methanehydroxy-diphosphonate-tin is formed.

9. A process according to claim 6 in which said water-soluble pertechnetate-99m is reacted with a water-soluble ferrous salt of methanehydroxydiphosphonic acid, whereby the water-soluble composition of matter 99mTc-methanehydroxydiphosphonate-iron is formed.

10. A process according to claim 6 in which said water-soluble pertechnetate-99m is reacted with a water-soluble chromous salt of methanehydroxydiphosphonic acid, whereby the water-soluble composition of matter 99mTc-methanehydroxy-phosphonate-chromium is formed.

11. A process according to claim 6 in which said water-soluble pertechnetate-99m is reacted with a water-soluble titanous salt of methane-hydroxydiphosphonic acid, whereby the water-soluble composition of matter 99mTc-methanehydroxy-diphosphonate-titanium is formed.

12. A water-soluble heavy metal salt of methane-hydroxydiphosphonic acid, said heavy metal being selected from the group consisting of tin, iron, chromium and titanium, said heavy metal being in a reduced valence state.

13. A water-soluble composition of matter selected from the group consisting of 99mTc-methanehydroxydiphosphonate, 99mTc-methanehydroxydiphosphonate-tin, 99mTc-methanehydroxydi-phosphonate-iron, 99mTc-methanehydroxydiphosphonate-chromium and 99mTc-methanehydroxydiphosphonate-titanium.

14. Water-soluble stannous methanehydroxydiphos-phonate.

15. Water-soluble ferrous methanehydroxydiphos-phonate.

16. Water-soluble chromous methanehydroxydiphos-phonate.

17. Water-soluble titanous methanehydroxydiphos-phonate.

18. The water-soluble composition of matter 99mTc-methanehydroxydiphosphonate.

19. The water-soluble composition of matter 99mTc-methanehydroxydiphosphonate-tin.

20. The water-soluble composition of matter 99mTc-methanehydroxydiphosphonate-iron.

21. The water-soluble composition of matter 99mTc-methanehydroxydiphosphonate-chromium.

22. The water-soluble composition of matter 99mTc-methanehydroxydiphosphonate-titanium.