NO860980L - RADIOGRAPHY DIAGNOSTIZER AND PROCEDURE FOR ITS MANUFACTURING. - Google Patents

Description

NEW RADIOPHARMACEUTICAL PREPARATIONS AND CHELATING AGENTS

SUITABLE FOR THEIR MANUFACTURE.

Field of the invention

The present invention relates to a dihydropyridine pyridinium salt type of redox, or chemical delivery system for site-specific and/or site-enhanced delivery of a radionuclide to the brain and other organs. More particularly, the invention relates to the realization that a chelating agent which can chelate with a radionuclide and has a primary, secondary or tertiary amino function can be converted to the corresponding analogue in which the function is replaced by the dihydropyridinium salt redox system and then complexed with a radionuclide to give a novel radiopharmaceutical that, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BBB") and allows increased levels of radionuclide concentration in the brain, particularly after oxidation of the dihydropyridine moiety in vivo to the ionic pyridinium salt slows clearance from the brain while the removal from the general circuit is accelerated.

The present radionuclide delivery system is suitable

for use in scintigraphy and similar radiographic techniques.

Background for the invention

Radiographic techniques such as scintigraphy and the like

finds application in biological and medical procedures for diagnosis as well as research. Scintigraphy involves the use of radiopharmaceutical preparations, i.e. compounds containing (or labeled with) a radioisotope (i.e. radionuclide) which, after introduction into a mammal, is localized in specific organs, tissues, or skeletal material that is desired to be imaged. When the radiopharmaceutical preparation is located in this way, traces, plates or scintiphotographs of the existing distribution of the radionuclide can be made using different radiation

detectors known in the field. The observed distribution of the localized radionuclide can then be used to

detect the presence of pathological conditions, abnormal conditions and the like. Radiopharmaceutical preparations are thus often referred to as radiodiagnostics.

In many cases, radiopharmaceutical preparations are prepared using target-specific chelating agents which provide a bridge connecting a radionuclide, e.g. a radioactive metal such as technetium-99m, or similar, and a material that will temporarily localize in the organ, tissue or skeletal material to be imaged. Typical chelating agents for these purposes are: polydentate ligands which form a 1:1 or 2:1 ligand:radioactive metal complex; macrocyclic ligands of suitable ring size and preferably where all coordinating atoms are in a planar configuration, and bicyclic and polycyclic ligands which can encapsulate the radioactive metal.

It is an established fact that the delivery of drugs, including radiopharmaceutical preparations, to the brain is often severely limited by transport and metabolic factors and more specifically by the functional barrier of the endothelial brain-capillary wall which is referred to as the blood-brain barrier or BBB. Site-specific delivery and/or sustained delivery of drugs to the brain is even more difficult.

A dihydropyridine ^ pyridinium redox system is now included

successfully used for delivery to the brain of a number of drugs. Generally speaking, in accordance with this system, a dihydropyridine derivative of a biologically active compound is synthesized, the derivative being able to enter the central nervous system through the blood-brain barrier after systemic administration. Subsequent oxidation of the dihydropyridine part to the corresponding pyridinium salt leads to the release of the medicine to the brain.

Two important methods have so far been used for the delivery of medicines to the brain using this redox system. The first method involved the development of selected drugs containing a pyridinium core as an integral structural component. This method was first used for delivery to the brain of N-methylpyridinium-2-carbaldoxime chloride (2-PAM), the active core of which is a quaternary pyridinium salt, using the dihydropyridine-latentized premedication form thereof. Thus, a hydrophilic compound (2-PAM) was rendered lipoidal (ie, lipophilic) by preparing its dihydropyridine form (Pro-2-PAM) to enable its penetration through lipoidal barriers. This simple premedication method allowed the compound to enter the brain as well as other organs, but this method did not and could not result in any brain specificity. In contrast, this method was limited to relatively small-molecule quaternary pyridinium ring-containing drug types and did not provide the overall ideal result of brain-specific, sustained release of the desired drug, with simultaneous rapid removal from the general circulation associated with improved drug utilization and reduced toxicity. No "entrapment" in the brain of the 2-PAM

that was formed in situ was achieved and there was clearly no brain-specific, sustained supply as a result: 2-PAM was removed as quickly from the brain as it was from the general circulation and other organs. Compare US Patent Nos. 3,929,813 and 3,962,447; Bodor et al., J. Pharm. Pollock. 67, No. 5, pages 685-687 (1978); Bodor et al, Science, Volume 190 (1975), pages 155-156; Shek, Higuchi and Bodor, J. Med. Chem.,

volume 19 (1976), pages 113-117. A more recent development of this method is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09, March 1983, page 2910B. See also Bodor et al, Science, Volume 214, December 18, 1981, pages 1370-1372.

The second method of delivering drugs to the brain uses the redox system which involves the use of a pyridinium carrier which is chemically linked to a biologically active component. Bodor et al., Science, Volume 214, December 18, 1981, pages 1370-1372, outline a scheme for this specific and sustained delivery of drug types to the brain, as depicted in the following Scheme A:

According to the form in Science; a drug [D] is linked to a quaternary carrier [QC]<+>and the resulting [D-QC]<+>is then chemically reduced to the lipoidal dihydro form [D-DHC]. After administration of [D-DHC] in vivo, it is rapidly distributed in the body including the brain. The dihydro form [D-DHC] is then oxidized in situ (constant rate, k^) (by the system NAD NADH system) to the ideally inactive original [D-QC]<+>quaternary salt which, due to its ionic, hydrophilic grade should be rapidly removed from the general body circulation, while blood-brain barriers should prevent removal from the brain (k^ >> k2'^3>;> ^7)* Enzymatic cleavage of the [D-QC]<+>that is "trapped" in the brain causes a sustained supply of the drug type [D] , followed by the normal removal (k ) by means of metabolism. An appropriately selected carrier [QC] + will also be rapidly removed from the brain (k,>> k„). Due to the easy removal of [D-QC] from the general circulation, only minor amounts of medicine are released into the body (k^>> k^); [D] will primarily be released in the brain (k^> k2). The overall result would ideally be a brain-specific sustained release of the target drug type. Specifically, Bodor et al worked with phenylethylamine as a model medicine. This compound was coupled to nicotinic acid and then quaternized to give compounds of formula which were then reduced with the aid of sodium dithionite to the corresponding compounds of formula; Testing of the N-methyl derivative in vivo supported the criterion shown in Scheme A. Bodor et al envisioned that different types of drugs could possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methyl -nicotinic acid esters and amides and their pyridine ring-substituted derivatives were investigated for the delivery of amino- or hydroxyl-containing drugs, including smaller peptides, to the brain. No other possible specific carriers were revealed. Other reports of this work on the redox carrier system appeared in The Friday Evening Post, August 14, 1981, ;Health Center Communications, University of Florida, Gainesville, Florida; Chemical & Engineering News, December 21, 1981, pages 24-25; and Science News, January 2, 1982, Vol. 121, No. 1, Page 7. More recently, the inventor has substantially expanded the redox carrier system with respect to possible carriers and drugs that can be added, see e.g. International ;Patent Application No. PCT/US83/00725 filed by University;of Florida, May 2, 1983 and published under International Publication No. WO83/03968 on November 24, 1983. ;However, there has also been a great need in the field for new, centrally acting drugs that can be site-specifically and persistently delivered to the brain, while avoiding the above-mentioned typical and significant disadvantages and shortcomings associated with penetration of the blood-brain barrier, with dihydropyridine-latent pro-drug forms of the drug types themselves comprising a pyridinium salt -active core, with the necessity for the introduction of critically coordinated and calculated release-rate-controlling substituents on any particular drug-carrier moiety, and/or with the limitation of delivery of only known drug types. This need has led to a new method for delivering drugs to the brain using the redox system. This new method provides new derivatives of centrally acting amines in which a primary, secondary or tertiary amino function has been replaced with a dihydropyridine/pyridinium salt redox system. These new dihydropyridine analogues are characterized by the structural formula; wherein D is the residue of a centrally acting primary, secondary or tertiary amine, and is a radical of formula ; wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydro-pyridine ring; the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; m is zero or one; n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each of R in formula (ii) may be on either of the two fused rings; q is zero, one or two, with the proviso that when q is one or two each of R in formula (iii) may be on either of the two fused rings; and each R is independently selected from the group consisting of halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₂₂ C₂ alkoxycarbonyl, C₂-C₃₆al₂anoyloxy / C₁₂C₂ haloalkyl, C₁₂C₂ alkylthio, C₂-C₂ alkylsulfinyl, C ^-C^alkylsulfonyl, CH=NOR"' wherein R'" is H or C^-C^ alkyl, and ;-CONR'R" wherein R' and R" , which are the same or different,; each is H or C 1 -C 4 alkyl. ;The new dihydropyridine analogues described in the previous section act as a delivery system for the corresponding quaternary compounds in vivo; the quaternary derivatives, which are also chemical intermediates to dihydro compounds, are pharmacologically active and are characterized by site-specific and sustained supply to the brain when supplied via the corresponding dihydropyridine form. Nevertheless, there is still a great need for an efficient general method for site-specific and/or sustained delivery of a desired radionuclide to the brain. It would therefore be desirable to adapt the analogue concept to the radiopharmaceutical area. ;Summary of the invention;It has now been found that a chemical delivery system based on;a dihydropyridine T—Ipyridinium salt-type redox system is uniquely well suited for an effective site-specific and/or sustained and/or enhanced delivery of a radionuclide to the brain or similar organs, via new redox-system-containing radiopharmaceutical preparations, and new redox-system-containing chelating agents and new redox-system-containing precursors therefore, suitable for the production of the aforementioned radiopharmaceutical preparations. Thus, in one aspect, the invention provides new redox system-containing chelating agent precursors of formula; wherein the residue is a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one primary, secondary or tertiary amino functional group, the functional group not being essential for the complexing properties of said chelating agent, the remainder being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino-functional groups from the chelating agent; y is 1 or 2; is a radical with formula ; wherein n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each R of formula (b) may be on either of the two fused rings; q is zero, one or two, with the proviso that when q is one or two, each R in formula (c) may be on either of the two fused rings; and each R is independently selected from the group consisting of halogen, C₁-C₂alkyl, C₁-C₂-, alkoxy, C₂-C₃₆₆₂₆₆sylcarDony1' C₂-C₃8alkan°y1-oxy, C₁-C₂ haloalkyl , C^-Cj alkylthio, C^-C^ alkylsulfinyl, C1-C7alkylsulfonyl, -CH=NOR"' wherein R'" is H or C^-C-, alkyl, and -CONR'R" wherein R' and R", which are the same or different, each is H or C 1 -C 4 alkyl; X- is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion, and s is a number that when multiplied by t equals y. In another aspect, the present invention provides new redox system-containing chelating agents of formula; and non-toxic pharmaceutically acceptable salts thereof, wherein and y has the above meaning, and is a radical of formula ; wherein the dotted line in formula (i) indicates the presence of a double bond at either the 4- or 5-position of the dihydro-pyridine ring; the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring system; m is zero or one, n is zero, one or two; p is zero, one or two, with the proviso that when p is one or two, each of R in formula (ii) may be on either of the two fused rings; q is zero, one or two, with the proviso that when q is one or two, each R in formula (iii) may be on either of the two fused rings; and each R is independently selected from the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₃ 8 alkoxycarbonyl, C₂-C₆alkanoyl oxide, C₁-C₄ haloalkyl, C₁-C₄ alkylthio, C₁-C ^ alkylsulfinyl, ;C1-C7 alkylsulfonyl, -CH=NOR"' wherein R'" is H or;C^-C^ alkyl, and -CONR'R" wherein R' and R" , which are the same or different, are each H or C 1 -C 4 alkyl. ;In a further aspect, the present invention provides, as an effective radionuclide delivery system, new redox system-containing radiopharmaceutical preparations of the formula; and non-toxic pharmaceutically acceptable salts thereof, wherein M is a metal radionuclide and the remaining structural variables are defined as before; in other words, (III) is the chelated or complexed counterpart of (II), formed by complexation of the new redox system-containing chelating agent of formula (II) with a radioactive metal. When a radiopharmaceutical of formula (III) is administered, due to its lipoidal nature it will readily penetrate the BBB. Oxidation of (III) in vivo gives the corresponding pyridinium salt with formula; in which the structure variables are as previously defined. Due to its hydrophilic, ionic nature, the substance of formula (IV) is "locked up" in the brain so that radiographic imaging of the radionuclide present in the complex (IV) is permitted. There is no easily biologically cleavable bond between the redox part of the complex of formula (IV) and its radiolabeled chelate part. Consequently, the quaternary "locked-in" form is not expected to gradually cleave to release the redox and chelate portions of the molecule. On the contrary, maintained levels of the quaternary compound of formula (IV) will be present at the desired site. From a safety point of view for the patient and technician, it is generally considered to be highly desirable to image the target area as soon as possible after administration and to use radioisotopes with relatively short lifetimes. Under these conditions, or even when longer-lived radioisotopes are used, the "locked-in" quaternary form is not expected to be metabolized or to escape from the brain until after the radioactivity has been reduced to a considerable extent. The present invention thus actually provides not only a system for supplying and imaging previously known radiopharmaceutical preparations. By the time the present delivery system would no longer be in its "locked-in" quaternary form, it would generally no longer be sufficiently radioactive for practical imaging. Contrary to the teaching in the Bodor et al publications, e.g. Bodor et al Science, Volume 214, December 18, 1981, pages 1370-1372, emphasizing the desirability of an inactive quaternary form locked in the brain, provides the present invention and actually requires an active quaternary form locked in the brain to permit effective radionuclide- depiction. Technetium-99m is a preferred radionuclide for diagnostic purposes because of its favorable radiation energy, its relatively short half-life, and the absence of corpuscular radiation, and is preferred for use in the present invention. Other radionuclides that can be used diagnostically here in a chelated form are cobalt-57, gallium-67, gallium-68, indium-111, indium-11lm and the like. ;Detailed description of the invention;The following definitions are used:;The term "medicine" as used herein means any substance intended for use in the diagnosis, healing, relief, treatment or prevention of diseases in humans and animals. ;The term "non-toxic pharmaceutically acceptable salts" as used herein generally includes the non-toxic salts of products according to the invention having structures (II) and (III) as set forth above formed with non-toxic, pharmaceutically acceptable inorganic or organic acids of general formula HX. E.g. the salts include those salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like and the salts produced from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, furmaric acid, methanesulfonic acid, toluenesulfonic acid and the like. The term "anion of a pharmaceutically acceptable organic or inorganic acid" as used herein, e.g. in connection with structures (I) and (IV) above, is intended to include anions of such HX acids. ;The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "C 1 -C 4 alkyl" includes straight and branched chain lower alkyl radicals of up to 7 carbon atoms. When R, R', R" and/or R'" are C -C? alkyl, they are preferably methyl or ethyl. The term "C₁-C₁ alkoxy" includes straight-chain and branched lower alkoxy radicals of up to 7 carbon atoms. When R is C₁-C₄ alkoxy, it is preferably methoxy or ethoxy. The designation "C2_('8^^^sy^arbonyl" denotes straight-chain and branched radicals of formula ; ; in which the C^-C^alkyl group has the above meaning. When R is alkoxycarbonyl, it is preferably ethoxycarbonyl or isopropoxycarbonyl. ;The designation "<C>2_C8 al^anoyloxy" denotes straight-chain; and branched radicals of formula; ; in which the C^-C-, alkyl group has the above-mentioned meaning. ; When R is alkanoyloxy, it is preferably acetoxy, pivaloyloxy or isobutyryloxy. ;The designation "C^-C-y haloalkyl" denotes straight-chain and branched lower alkyl radicals of up to 7 carbon atoms and with one or more halogen substituents (F, Cl, Br or I) which may be the same or different. Preferred, when R is haloalkyl , the group contains 1 to 2 carbon atoms and has 1 to 3 halogen substituents, eg, chloromethyl or trifluoromethyl. ;The term "C^-C^ alkylthio" includes straight-chain and branched radicals of the type ; wherein C^-C^alkyl has the above meaning When R is alkylthio is preferably methylthio. The terms "C₁-C₁ alkylsulfinyl" and "C₁-C₁ alkylsulfonyl" denote radicals with formulas; wherein C 1 -C 4 alkyl has the above meaning. When R is alkylsulfonyl or alkylsulfonyl, methylsulfinyl and methylsulfonyl are preferred. When R is -CH=NOR"' it is preferably CH=NOH or;CH=NOCH3- When R is -CONR'R" it is preferably -CONH2 or -CON(CH3)2. In the above formulas (I) to (IV), y is preferably 1; n, m, p or q is preferably 1; and R is preferably in the 3-position in structures (a), (b), (i) or (ii) and in the 4-position in structures (c) or (iii). R is preferably -CH=NOR"' or -CONR'R" in which R', R" and R'" have the broad meaning given above. Most preferred is R -CONH2 or CH=NOCH3. The expression "the residue of a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one primary, secondary or tertiary amino functional group, the functional group not being essential for the complexing properties of the said chelating agent, the remainder being characterized by the absence of at least one of said primary, secondary or tertiary amino-functional groups from the chelating agent" is assumed to be self-evident. As an example, if a chelating agent with a primary amino function that is non-essential with respect to chelating ability can be represented by the structural formula; the corresponding residue could then be depicted as in the formulas (I) to (IV), as the ring nitrogen atoms in the structures (a) to (c) and (i) to (iv) are thus located in the same position in relation to the remainder of chelate structure as was the case with the nitrogen atom in the original amino function. As a specific example, in the case of a chelating agent of the structure the corresponding residue would be and the corresponding redox system-containing chelating agent precursor of formula (I) would have the structure wherein y=l and s, X and t are as defined for formula (I). Similarly, when the chelating agent has the structure is then the corresponding residue and the corresponding redox system-containing chelating agent precursor of formula (I) would have the structure; in which y=l and the other structure variables are as defined for formula (I). ;As a further example, when the chelating agent has the structure ; 12 3 4 wherein R ( R , R and R are each H or C^-C^ alkyl and n is an integer from 0 to 3, then the corresponding residue and the corresponding redox system-containing chelating agent precursor with formula (I) will have the structure in which y=l and s, X and t are as defined for formula (I) 12/ and R , R and n' are as defined immediately above. It will be clear from the above that the exact structure of the amino function in the chelating agents is immaterial as far as the structure of the relevant derivatives with formulas (I) to (IV) is concerned, since in formulas (I) to (IV) the entire amino function in the starting chelating agents is replaced with a dihydropyridine/pyridinium salt redox system. Thus, apparently any chelating agent capable of complexing with a radionuclide and having at least one primary, secondary, or tertiary amino functional group that is nonessential with respect to chelating properties, provide the remainder; in the present chelates rending agent derivatives. Many such illustrative amine groups will be obvious to the person skilled in the art. Most commonly, however, the functional group in the chelating agents to be replaced with the redox system is simply a -Nr^ group. Such an amino group can easily be introduced into the structure of a known chelating agent which does not already include this and then replaced with the present redox system to give the desired derivatives, as described in more detail below. ;It will also be seen that the radical represented by; ; in formulas (II) and (III9) must enable the complex of formula (III) to penetrate the BBB and must also be able to be oxidized in vivo to the corresponding quaternary structure. The ionic part resulting from such in vivo oxidation is prevented from flowing out from the brain, while clearance from the general circulation is accelerated.However, unlike the drug-carrier types discussed in, for example, Science, Vol. 214, December 18, 1981, pages 1370-1372, there is no readily metabolically cleavable bond between medicine and quaternary parts. The active parts supplied in the present case are the quaternary compound of formula (IV) itself. It will also be seen that a compound of formula (III) must be supplied as a free base or in the form of a non-toxic pharmaceutically acceptable salt thereof, i.e. a salt which can be represented by formula ; wherein M, ; y and HX have the previously stated ;meaning; and that regardless of the actual form in which the compound is administered, it will be converted in vivo to a quaver rnary salt of formula (IV), the anion X- being present in vivo. It is not necessary that the anion be introduced as part of the compound that is supplied. Indeed, even if the compound of formula (III) is used in salt form, the anion in the compound of formula (IV) is not necessarily the same as the anion present in the compound of formula (III). Indeed, the exact identity of the anionic part of compound (IV) is immaterial to the in vivo conversion of (III) to (IV). ;With regard to the phrase "wherein said functional group is not essential to the complex-forming properties of said chelating agent" it will be clear that this phrase is not intended to mean that any primary, secondary or tertiary amino- functional group in a chelating agent that can be replaced with the present redox system without destroying the ability of the chelating agent to complex with the radionuclide is considered here to be not essential for the complexing properties. On the other hand, replacement of an amino-functional group which would lead to a structure containing a redox system which could not complex with a radionuclide would not be within the scope of the invention. In accordance with the present invention, the delayed delivery of a radionuclide to the brain in sufficient concentrations for radioimaging can be accomplished with much lower concentrations in the peripheral circulation and other tissues. The present invention will of course allow such imaging of any other organs or glands in which sufficient radioactivity accumulates. Thus, it is e.g. expected that the quaternary form (IV) that is locked up in the brain will also be locked up in the testicles. The new radionuclide delivery system according to the invention begins with the preparation of the new redox system-containing chelating agent precursors of formula (I). The preparation of these precursors will be "tailored" to the particular chelating moiety and redox moiety to be combined, as well as to the presence or absence of other reactive functional groups (amino, mercapto, carboxyl, hydroxy) in either the chelating or redox moiety . Typically, if such other reactive groups are present, they are found in the chelating portion. In any case, when such groups are present and it is desired to protect them, a step introducing suitable protecting groups can be incorporated at an appropriate step of the synthetic route. Protecting groups are well known in the art and include t-butoxycarbonyl for amino groups, N-methyleneacetamido for mercaptans, and N-hydroxysuccinimidyl for carboxyl groups. Acyl or carbonate groups are typically used to protect alcohol hydroxyl groups. When carbonate protecting groups are desired, the step of introducing the protecting groups will include reaction of the alcohol with a halocarbonate of the type R0C0C1 or ROCOBr (formed by reaction between ROH with COCl2 or COBr2), where R is typically lower alkyl. For acyl-protecting groups, the alcoholic hydroxyl group is reacted with an acid halide R'Cl or R'Br, where R' is -COCH3 or -COC(CH3)3. Additional reaction schemes and reaction components will be readily appreciated by one skilled in the art and accordingly the appropriate means for removing such protecting groups after they have performed their function are no longer needed. ;In the formation of the precursors of formula (I), at least one primary, secondary or tertiary amino-functional ;group in a chelating agent will be replaced by ; hydrophilic, ionic pyridinium salt form of dihydropyridine pyridinium salt redox system. It is understood that by means any non-toxic redox moiety of the structure (a), (b) or (c) set forth above comprising, containing or including the pyridinium nucleus, whether or not it is part of any larger base nucleus, and regardless of whether it is substituted or unsubstituted, the only criterion therefore being the ability for chemical reduction to the corresponding dihydropyridine form BBB penetration of in vivo oxidation of 5 to the quaternary pyridinium salt redox part; As mentioned, the ionic pyridinium salt radiopharmaceutical redox moiety of formula (IV) resulting from in vivo oxidation of the dihydropyridine form (III) is prevented from escaping from the brain, while clearance from the general circulation is accelerated. Radioimaging of the radionuclide present in the "locked-in" quaternary compound of formula (IV) allows observation of the distribution of the localized radionuclide for the diagnosis of pathological conditions, abnormalities, etc.; The following synthesis schemes illustrate various methods of preparation of the redox system- containing chelating agent precursors with formula (I), to the corresponding redox-system-containing chelating agents with formula (II) and to the corresponding redox-system-containing radiopharmaceutical preparations with formula (III). Also shown are the corresponding "locked-in" quaternary compounds of formula (IV) formed by in vivo oxidation of the chelates of formula (III), the quaternary compounds of formula (IV) being the primary localized materials whose radionuclide content is imaged by of irradiation detection media. ; ; Thus, Schemes 1 (version 1), 5 (versions 1 and 2) and 9; (version 1) above illustrate typical conversion of a carboxylic acid ester group to the corresponding amide (-CONH 2 ); reduction of the amide function to the corresponding amine (-CH NH„); replacement of the -NH„ group with the desired quaternary function -N ), using a zinc reagent; and reduction of the corresponding quaternary compound of formula (I) to the corresponding dihydro compound of formula (II), or conversion of (I) directly to the radiopharmaceutical compound of formula (III). Variations of this type of reaction sequence are shown in versions 2 and 3 of Scheme 1, version 3 of Scheme 5, and version 2 of Scheme 9, in which a protecting group is introduced before the reaction with the zinc reagent and then removed before the reduction of the quaternary function. In the case of the chelating agents shown in these reaction schemes, reaction with acetone protects both the secondary amino and thiol functions by forming thiazolidine structures so that these functions do not interfere with the reaction with the zinc reagent. The secondary amino and mercapto groups are then regenerated by reacting the protective intermediate with mercuric chloride in an organic solvent such as methanol, suitably at room temperature, and then the resulting complex is cleaved with hydrogen sulfide. See e.g. British Patent No. 585,250 which uses such a procedure for the preparation of esters of penicillamine. ;Schemes 2 (version 1), 4 and 10 above illustrate typical conversion of an alcohol (-CP^OH), which can be obtained from the corresponding carboxylic acid ester, to the corresponding halide (-CH_C1 or -CH„Br); reaction between the halogen ;Z Zy^—V;derivative and the corresponding pyridine derivative H—N J to give the desired quaternary compound of formula (I), and reduction to the corresponding dihydro compound of formula (II) and direct conversion to the corresponding radiopharmaceutical compound of formula (III). Schemes 4 and 10 also illustrate the removal of a protecting group immediately after formation of the quaternary compound, while version 2 of Scheme 2 illustrates the introduction and removal of the thiazolidine protecting group discussed above with respect to versions 2 and 3 of Scheme 1, etc In scheme 3 above, a typical method for introducing a longer alkylene chain between an atom which is involved in forming the chelate structure and a protruding NH2 group to be replaced with the quaternary structure is shown. As depicted in this scheme, a secondary amino group ^NH is reacted with a haloalkamide, e.g. BrCH2CONH2, the hydrogen ;in ^NH is replaced by -CH2CONH2- Reduction of the amide gives the corresponding ^NCH0CH»NH^ compound. This amine can then be reacted with a zinc reagent to replace -NH2 with ; followed by reduction as in the other forms. Preferably, however, any free thiol groups are protected before the reaction with the zinc reagent. Schemes 6, 11 and 12 illustrate further other methods for extending the alkylene chain, the chain here being interrupted by one or more oxygen atoms. Thus, a -CH2OH group is typically converted to the corresponding lithium salt and then reacted with an iodo-alkanol, e.g. ICH? CH OH to convert the -CH20-Li + group into a -CH2OCH2CH2OH group. [It is clear that the chain could be extended by using a longer chain iodo-alkanol, or by repeating the two steps just described (in which case additional intercalated oxygen atoms would be introduced)]. The -CH2OCH2CH2OH group is then converted to the corresponding -CH2OCH2CH2Br or -CH2OCH CH^1, which is then reacted with the selected pyridine derivative to form the desired quaternary salt. In the schemes shown, a protecting group is removed immediately after the quaternization to give the quaternary compound of formula (I) which is then reduced as in the other schemes. In schemes 7, 8 and 13 above, replacement of an -NH„ group with the corresponding quaternary group is; shown, using a zinc reagent. When appropriate, the formation of the quaternary group is followed by removal of protecting groups, as in schemes 7 and 13. The resulting quaternary compound of formula (I) is reduced as shown in the other schemes. Many of the earliest steps in the reaction schemes illustrated in the foregoing parallel reactions to those described in Fritzberg US Patent No. 4,444,690. See e.g. the conversion of 14 to 15 in scheme 2, further conversion of 16 to 32 to 33 in scheme 4, conversion of 15 to 40 to 41 in scheme 5, conversion of 56 to 57 to 58 and conversion of 60 to 61 in scheme 6, and so on. Similar schemes can be shown for the production of the other derivatives in accordance with the invention. The steps of introducing and removing protecting groups are included only when necessary. The order of steps can also be changed. In particular, quaternization can take place earlier in the reaction scheme, of course depending on the particular compounds involved. Other reaction schemes, reaction components, solvents, reaction conditions, etc. will be readily apparent to the person skilled in the art., As far as the quaternary derivatives are concerned, when an anion other than that obtained is desired, the anion in the quaternary salt can also be subjected to anion exchange via an anion exchange resin or, alternatively, using the method of Kaminski et al, Tetrahedron, Vol. 34, pp. 2857-2859 (1978)'. According to the method of Kaminski et al, a methanolic solution of an HX acid will react with a quaternary ammonium halide to produce the methyl halide and the corresponding quaternary ;-X salt. The processes exemplified by Schemes 1, 3, 5, 7, 8, 9 and 13 include the step of reacting a compound containing a -Nr 2 group with a zinc reagent. The zinc reaction can be used to develop the relevant derivatives; in which ; ; is the residue of a primary amine, or their protective counterparts, directly from the corresponding primary amine/parent chelating agent. If, however, it is desirable to prepare the relevant derivatives in which \ J~; is the residue of a secondary or tertiary amine, or their protected counterparts, via the zinc reaction, then one will not use the secondary or tertiary amine starting chelating agent as starting material, but will instead use the corresponding primary amine as starting material. Alternatively, a compound with formula ; wherein Hal is chlorine or bromine and is the residue of the chelating agent as previously defined or its protected counterpart, reacted with a pyridine derivative of formula; wherein R, n, p and q are as defined for formula (I), e.g. nicotinamide, isonicotinamide, picolinamide, 3-quinoline carboxamide, 4-isoquinoline carboxamide or the corresponding oximes in which a -CH=NOCH3 group is present instead of the ;-C0NH2~ group in nicotinamide etc. See e.g. schemes 2, 4, 6, 10, 11 and 12. The starting pyridine derivatives are easily obtainable or can be prepared in a known manner, e.g. 3-quinoline carboxamide can be prepared by treating the corresponding acid with ammonia. When a zinc reagent is used in the reaction sequence, this reagent can be prepared by reacting 1-chloro-2,4-dinitrobenzene with a compound of the formula; wherein R, n, p and q are as defined for formula (I), to give the corresponding zinc reagent of respective formulas; Thus, e.g. the specific zinc reagent depicted in Scheme 7 is prepared by reacting nicotinamide with 1-chloro-2,4-dinitrobenzene. See also Zincke et al, Annalen, 1904, 333, 296; Lettre et al, Annalen 1953, 579, 123; Keijzer et al, Heterocycles, Vol 16, No 10, 1981, 1687. Preferred zinc reagents are those in which n, p or q is one and R is -CONH 2 or -CH=NOCH 3 and is in the 3-position of the pyridinium or quinolinium structure or in the 4-position of the isoquinolinium structure. Typically, the zinc reagent is reacted with the primary amine, which can very easily be used in the form of its acid addition salt, in the presence of a suitable base, e.g. triethylamine, in a suitable organic solvent, e.g. methanol, to give the desired quaternary salt. ;When a starting material with formula; in which ; and Hal is, as previously stated, used to produce the quaternary salt, the aforementioned starting material can be produced from the corresponding alcohol, e.g. using methods as depicted in Schemes 2, 4, 6, 10, 11 or 12. ;Reduction of the quaternary salt of formula (I) to the corresponding dihydro derivative of formula (II) can be carried out at a temperature of from about -10°C to room temperature, for a period of time from approximately 10 min. to 2 hours, preferably at atmospheric pressure. Typically, a large excess of reducing agent is used, e.g. a molar ratio of 1:5 between reducing agent and starting compound of formula (I). The process is carried out in the presence of a suitable reducing agent, preferably an alkali metal dithionite such as sodium dithionite or an alkali metal borohydride such as e.g. sodium borohydride or lithium aluminum borohydride, in a suitable solvent. Sodium dithionite reduction is easily carried out in an aqueous solution; the dihydro product of formula (II) is usually insoluble in water and can thus be easily separated from the reaction mixture. In the case of sodium borohydride reduction, an organic reaction medium is used, e.g. a lower alkanol such as methanol, an aqueous alkanol or other protic solvent. More typically, however, the quaternary compound of formula (I) is reduced in the same reaction mixture as the reduction of the radionuclide (preferably technetium) to an appropriate oxidation state, producing the radiopharmaceutical compound of formula (II) in one step from the quaternary compound of formula (I) . Further details of this one-step reduction are given below. It is clear from the foregoing that a large number of derivatives with formulas (I) to (IV) can be obtained in accordance with the invention. In a particularly preferred embodiment of the invention, however, new chelating agent precursors are provided with the formula; wherein each R. is independently selected from the group consisting of H oa C,-C„ alkvl. or an R. may be combined with the il neighbor grouping; in ; such that ; represents ^C-0, each R9 being independently selected from the group consisting of H and C1-C- alkyl, or an R„ can be combined with the neighboring grouping so that ; represents ;formula; is a radical mea ; wherein each R_ is independently selected from the group consisting of H and C^-Crj alkyl, alk is a straight chain or branched lower alkvlen-oxu<p>De (C-C_) which vtterliaere may contain ;i o ;1, 2 or 3 not -neighboring oxygen atoms in the chain, and ; is as defined for formula (I) above, X and t are as defined for formula (I) and s' is a number which when multiplied by t is equal to one. Preferably, the salts of formula (Ia) have the following partial structure or are positional isomers and/or homologues of the two first partial structures shown. It is also preferred that when each R^ is preferably H and alk is preferably a C^-C^ alkylene group, or a C^-Cg alkylene group interrupted by an oxygen atom in the chain, and that when then alk is preferred a C 1 -C 4 alkylene group, or a C 1 -C 1 alkylene group interrupted by an oxygen atom in the chain. Preferred values for ; in formula (Ia) is as given in connection with formula (I) above. Corresponding to the preferred new chelating agent precursors of formula (Ia) are the preferred new chelating agents of formula ; wherein and R_ are as defined for formula (Ia) and is a radical of formula ; wherein R-j and alk are as defined for formula (Ia) and are as defined for formula (II) above. Preferred compounds of formula (Ila) are the dihydro derivatives corresponding to the preferred compounds of formula (Ia). Also preferred are the new radio-pharmaceutical compounds in which a compound of formula (Ila) is chelated with a radioactive metal, especially with technetium. ;Particularly preferred radio-pharmaceutical compound has the formula ; wherein R, and R^ are as defined for formula (Ia) and is a radical of formula wherein R-. and alk is as defined for formula (Ia) and is as defined for formula (II) above; and the corresponding quaternary compounds, especially of technetium, "locked up" in the brain, having the formula in which R^, R2/s', X and t are as defined for formula (Ia) and is a radical of formula in which R, and alk is as defined for formula (Ia) and ; is as defined for formula (I) above. The preferred complexes of formulas (IIa) and (IVa) are those corresponding to the preferred derivatives of formulas (Ia) and (Ila). In order to further illustrate the present invention and its advantages, the following specific examples are given, as these are to be understood as illustrative and not in any way limiting. ;EXAMPLE 1;To a stirred solution containing 115.6 g (1.6 mol) of isobutylaldehyde 1 in 184 g of carbon tetrachloride, 108 g (0.8 mol) of 97% sulfur monochloride are added dropwise at 40 - 50°C. The addition is carried out over a 2.5 hour period under a nitrogen atmosphere with occasional cooling. The solution is kept at 30-45°C with stirring and for a further 48 hour period under a stream of nitrogen to remove the released hydrogen chloride. The solution is distilled under vacuum to give 72 g of the desired 3,4-dithia-2,2,5,5-tetramethylhexane-1,6-dione, i.e. compound 2 in scheme 1. ;"'"H NMR( CDC13) 6 9 , 1 (s , 2-CHO) , 1, 4 [ s , 12 ,-c (CH_3) 2~ ] . ;EXAMPLE 2;To 10 g (0.07 mol) of ethyl 1-cyanoglyoxylate-2-oxime _3, 125 ml of abs. ethanol, 15 g of hydrogen chloride gas and 1 g of platinum oxide. The mixture is hydrogenated using a pair of hydrogenators. The hydrogen absorption is completed within 3 hours. The product is removed by filtration and taken up in 75 ml of hot 95% ethanol. The ethanol solution is filtered. The filtrate is then cooled and the crystalline product which separates on standing is removed by filtration. Ethyl-2,3-(diammonium)propionate dichloro is obtained in this way, i.e. compound 4 in scheme 1. Yield 5 g (35%), m.p. 164 - 166°C (lit. 164.5-165°C); , 2 ,-NCH_2CH-) , 1, 3 (t, 3 ,-OCH 2 CH 3 ) . ;EXAMPLE 3;Procedure I;To 1.0 g (5 mmol) of the bisaldehyde 2 is added dropwise a solution of 1.0 g (5 mmol) of the ester _4 and 0.9 ml of pyridine in 30 ml of methanol at 0°C under a nitrogen atmosphere. The addition takes place within 10 min. period. The solution is then allowed to stand for 1 hour, after which 10 ml of water is added. The solution becomes cloudy and is heated to 26°C. The solution is stirred for a further 20 min. period after which the white precipitate that forms is deposited from the solution. The precipitate is removed by filtration and then taken up in chloroform. The chloroform solution is dried over sodium sulfate. Removal of the solvent and trituration of the residue with petroleum ether gives white plate-like crystals of the desired product, 5,8-diaza-1,2-dithia-6-ethoxycarbonyl-3,3,10,10-tetra-methylcyclodeca-4, 8- diene, i.e. compound _5 in scheme 1, with 53% yield (1 g), m.p. 98 - 99°C. IR (thin film) 3450, 1740, 1659 cm<-1>;<1>H NMR(CDCl3)6 6.9(m,2,c-N=CH-), 3.0-4.6(m,5, -OCH2CH3, -NCH2CH-N-) , [ 1.5 m,15.2 ^C(CH_3)2, -OCH2CH_3]. ;Procedure II;To 1.0 g (5 mmol) of the bisaldehyde 2 in 10 ml methanol; add dropwise 1.0 g (5 mmol) of the ester _4 and 1 g (12 mmcl) sodium bicarbonate in 20 ml 50:50 volume mixture of methanol and water. The mixture is stirred at 0°C for 10 min. and after this time 10 ml of water is added. The resulting mixture is kept at room temperature with stirring for 2 hours. Water is added until the white precipitate that forms separates from the solution. The precipitate is removed by filtration and taken up in chloroform. Removal of the solvent by rotary evaporation gives 0.4 g (21% yield) of compound 5, with m.p. and<*>H NMR spectrum identical to the product from procedure I.

Procedure III

A solution of 8 g of the ester 4 and 7 ml of pyridine in 200 ml of methanol is added dropwise over a 2 hour period to a solution of 8 g of bisaldehyde 2 in 25 ml of methanol. The reaction mixture is cooled in an ice bath after adding i

1 hour and then allowed to stand at room temperature for 1 hour. The reaction mixture is then placed in a freezer (-20°C) overnight. The solution is concentrated to 1/3 volume, water is added and the aqueous solution is extracted with chloroform. The chloroform extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent leaves a viscous mass which is dissolved in 20 ml of hexane. The hexane solution is cooled in an acetone/dry ice bath until a white powder separates. The product is removed by filtration and taken up in chloroform. The chloroform solution is concentrated. White crystals of compound 5 are formed on standing. Yield 7 g, m.p. 95 - 96°C. NMR and IR are as in procedure L

EXAMPLE 4

Procedure I

A solution of 5 g of the ester 5 in 20 ml of tetrahydrofuran

and 20 ml of aqueous ammonia are stirred at room temperature for 2 hours and after this time the mixture is allowed to stand at room temperature for 24 hours. Removal of the solvent leaves a white powder which is removed by filtration. The product, 6-carbamoyl-5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodeca-4,8-diene, i.e. compound 6 in Scheme 1, is crystallized from a mixture of isopropanol and water. Yield 4 g (88%),

m.p. 181 - 183°C. IR (KBr) 3300, 3100, 1650 cm<-1>, """H NMR

(CDCl3) 6 7.0(m,2,-HC=N-), 6.4 (broadband, 2, -CONH2), 3.8-4.6[m,3,-NCH2-CH(N- )CO-], 1.5, 1.4[s,12, >C(CHj)2].

Procedure II

A solution of 5 g of the ester 5^ in 20 ml of tetrahydrofuran,

20 ml of ethanol and 20 ml of aqueous ammonia (28%) are stirred at room temperature for 16 hours. Removal of the solvent leaves compound 6^ as a white powder which crystallizes from toluene as white plates. Yield 4 g,

m.p. 193 - 194°C. IR and NMR as in procedure I.

EXAMPLE 5

To 3.7 g of the amide 6 in 25 ml of 95% ethanol is added 2 g of sodium borohydride. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 2 hours. The solution is then concentrated under vacuum and water is added to precipitate the product. The white crystalline product is removed by filtration. The recrystallization from a mixture of isopropanol and water gives 6-carbamoyl-5,8-diaza-1, 2-dithia-3, 3, 10, 10-tetramethylcyclodecane, i.e. compound 1_

in scheme 1, as fine small needles melting at 138 - 139°C. Yield 3 g.<1>H NMR(CDCl3) 6 2.3-4.0[m,7,-NCH2CH-N-, 2-NCH2-C(CH3)-S-]. 1, 8 (broadband, 2,-CONH_2), 1,3[m,14, C(CH3)2, -CNH-CH2-J'.

EXAMPLE 6

A solution of 1.8 g of the amide 7 in 50 ml of dry tetrahydrofuran is added dropwise to a slurry of 1 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The addition takes place within 30 min. period. The mixture is then heated under reflux for 20 hours. At the end of this period, the reaction mixture is first cooled and then poured over with saturated Na-K tartrate solution. The aqueous phase is extracted with chloroform. The combined organic phase is dried over sodium sulfate. Removal of the solvent by rotary evaporation gives as a viscous oil 5 aminomethyl 4 , 7-diaza-2 , 9-dimethyldecane-2 , 9-dithiol, i.e. compound 8.in scheme 1.<1>H NMR (CDCl32,8 6 2 ,8[m,9,-NCH2~C(CH2)NH-, 2-NCH2-C(CH3)2S-] .1,5[m,14,>C(CH3)2, ]-SH .

EXAMPLE 7

Methoxyamine hydrochloride (5 g, 0.06 mol) is dissolved in 50 ml of methanol and the solution is neutralized to pH 7 with 1 M methanolic KOH. The resulting mixture is filtered and to the filtered solution is added 3.2 g (0.03 mol) of 3-pyridinecarboxaldehyde. This mixture is heated under reflux for 4 hours. The methanol is evaporated and the solid is crystallized from a mixture of ethanol and water. O-methyl-3-pyridine aldoxime with structural formula is obtained in this way

A mixture of 2.7 g (22 mmol) of 0-methyl-3-pyridine aldoxime and

7 g (33 mmol) of 1-chloro-2,4-dinitrobenzene is kept on a water bath for 1 hour while stirring to a red homogeneous mixture. The resulting mixture is dissolved in 35 ml of methanol, treated with charcoal and filtered. The filtrate is treated successively with two 100 ml portions of ether. The ether mixture is stirred and the product is removed by filtration. In this way, 3-[(methoxyimino)methyl]-1-(2,4-dinitrophenyl)pyridinium chloride, i.e. the zinc reagent identified as compound 9_ in Schemes 1, 3, 5, 8, 9 and 13, is obtained.

EXAMPLE 8

A solution of 1.6 g (5 mmol) of the zinc reagent 9 in 2 ml of methanol is added dropwise to 2.65 g (10 mmol) of the amine 8

in 2 ml of methanol. The reaction mixture is heated under reflux for 2 hours, after which ether is added for precipitation

of the product. Alternatively, the amine 8 can be used as its hydrobromide salt and the reaction can be carried out in the presence of triethylamine (5-10 mmol). 1-[{2',3'-bis-{n-[(2"-mercapto-2"-methyl)propyl]amino)-propyl^-3-[(methoxyimino)-methyl]pyridinium is obtained in this way -chloride, i.e. compound 10 in scheme 1.

EXAMPLE 9

To 3.15 g of the dialdehyde 2, 4.0 g of ethylenediamine is added while stirring and cooling over a period of 10 min. The thick mass that forms is stirred for a further period of one minute and then allowed to stand for 1 hour at room temperature and then cooled for 16 hours in a freezer (-20°C). The solid is removed by filtration and washed with 500 ml of water.

The white product is then taken up in chloroform and the chloroform solution is dried over sodium sulfate. Removal of the chloroform gives 2.5 g of 5,8-diaza-1,2-dithia-3,3,10,10-tetra-methylcyclodeca-4,8-diene, i.e. compound 24 of Scheme 3, as a white crystalline product melting at 168 - 170°C (lit. 162-164°C, 163- 166°C).<1>U NMR(CDCl3) 6 6.9(s,2,-HC=N-), 4 , 2, 3, 0 (doublet of doublet, 2 , 2- CE_ 2~ CB_ 2) , 1.40 [s, 6,-C (CH_3) 2~] . Theoretical analysis for C10C18<N>2<S>2<:>C, 52.13; H, 7.88; N, 12.16; S, 27.83.

Found: C, 52.20; H, 7.90; N, 12.14; S, 27.74.

EXAMPLE 10

A solution of 0.5 g of 24 and 0.3 g of sodium borohydride in

2 3 ml ethanol is stirred at room temperature for 1 hour and then heated at the reflux temperature for 20 min. 10 ml of water is then added and the mixture is stirred for a further 10 min. The solvent is partially removed by rotary evaporation and the residue is extracted three times with 10 ml portions of chloroform. The chloroform extract is dried over sodium sulfate and the solvent is removed by rotary evaporation. The resulting slurry solidifies on cooling. Flash chromatography (eluent hexanes/dichloromethane/isopropanol 5:1:1 as volume ratio) gives 5,8 diaza-1,2-dithia-3,3,10,10.tetramethylcyclododecane, i.e. compound 25 in scheme 3, as a solid which melts at 52 - 53°C.

<1>H BNR(CDC13) 6 3-2,l(m,10 ring protons), l.l,1.2(s,6-

CHj ' CH-j) .

EXAMPLE 11

N-(t-butoxycarbonyl), N-(2-mercaptoethyl)glycyl-homocysteine-thiolactone 67 is prepared as described in Examples 1 and 2 of Byrne et al US Patent No. 4,434,151 and dissolved

(1.0 g; 3 mmol) in 25 ml of tetrahydrofuran (THF). The resulting solution is then cooled to about 0°C and ethylenediamine (1.8 g, 30 mmol) is added to form a new solution. The resulting new solution is maintained for about 1 hour. The volatile components in the solution are then removed using a rotary evaporator. n-butanol (about 10 ml) is added to the "dried" solution components and the liquid components of the resulting mixture are again removed by rotary evaporation. The last step is repeated until the vapors remaining in the evaporation vessel do not cause a moistened pH indicator paper to indicate a basic pH value which also thereby indicates that the ethylene diamine has been largely removed and that N-(t-butoxycarbonyl), N-( 2-mercaptoethyl)-glycyl-N'-(2-aminoethyl)homocysteinamide, i.e. compound 6_8 in scheme

7, obtained in this way is mainly pure.

EXAMPLE 12

A mixture of 8 g (66 mmol) nicotinamide and 20 g (99 mmol) 1-chloro-2,4-dinitrobenzene is kept on a water bath for 1 hour

while stirring. The resulting red homogeneous mixture is dissolved in 100 ml of methanol and decolorized with charcoal.

The filtrate is then treated with 100 ml of ether and the yellow product that separates is removed by filtration and washed with 500 ml of ether. The highly hygroscopic product, 1-(2,4-dinitrophenyl)-3-carbamoylpyridinium chloride is the zinc reagent 6_9, used e.g. in scheme 7 and version 3 in scheme 1. "'"H NMR (D 2 O) 6 8.5,10.0(m,7,ArH,Py-H).

EXAMPLE 13

The procedure in Example 8 is repeated with the exception that an equivalent amount of N-(t-butoxycarbonyl), N-(2-mercaptoethyl)-glycyl-N'-(2-aminoethyl)homocysteine (58) is used instead of the amine 8 and a an equivalent amount of 1-(2,4-dinitroenyl)-3-carbamoylpyridinium chloride (59) is used instead of the zinc reagent 9^ In this way the compound 70 in scheme 7 is obtained.

EXAMPLE 14

The compound 7_0 (0.002 mol) is dissolved with stirring in abs. ethanol (50 ml) and cooled to approximately 0°C in an ice-water bath. HCl gas was bubbled through the stirred solution for 15 min. and the solution is then stirred for a further 15 min. Diethyl ether (200 ml) is then added to the solution to precipitate the salt. The precipitate is filtered and washed with diethyl ether and the solid is then dried under vacuum to give the corresponding deprotected quaternary compound 7_1 in scheme 7.

EXAMPLE 15

N-[2-(S-acetamidomethyl)mercaptopropionyl]glycyl-homocysteine-thiolactone (Compound 77 in Scheme 8), prepared as described in Examples 7 and 9 of Byrne et al, US Patent No. 4,434,151, is suspended (1, 0 g, 3 mmol) in 25 mL THF.

The resulting suspension is cooled to a temperature of about 0°C in an ice-water bath and ethylenediamine (1.8 g, 30 mmol) is added to form a new solution. N-[2-(acetamidomethyl)mercaptopropionyl]-glycyl-N'-(2-aminoethyl)-homocysteinamide, i.e., compound 7-8 in Scheme 8, is then obtained in a manner substantially similar to that described in Example 11 for the analog connection.

EXAMPLE 16

The procedure in Example 8 is basically repeated with the exception that an equivalent amount of N-[2-acetamidomethyl)-mercaptopropionyl glycyl-N]-(2-aminoethyl)homocysteinamide (78) is used instead of the amine 8. In this way the compound is obtained 7_9 in form 8.

EXAMPLE 17

1-{{2',3'-bis-{N-[(2"-mercapto-2"-methyl)propyl]-amino)-propyl^]-3-[(methoxyimino)methyl]pyridinium chloride, ie compound 10 (0.17 mmol) is dissolved in 1.0 ml abs. ethanol and 1.0 mL 1N NaOH. A 1.0 ml generator eluent of 9 9m

TcO^- (5 to 50 milli-Curie) in salt solution is added. Next, 0.5 ml of dithionite solution, prepared by dissolving 336 mg of Na 2 S 2 O 4 per ml of 1.0 NaOH, is added, and the mixture is heated sufficiently to reduce both the technetium and the pyridinium salt and to form the complex between the dihydropyridine-containing ligand and oxotechnate-99m - ion. The complex prepared in this way, i.e. complex 12 in Scheme 1, is buffered by adding 1.0 ml of IN NaCl and 4.0 ml of 0.1 ml of NaH 2 PO 4 , pH 4.5 buffer.

EXAMPLE 18

The general procedure of Example 17 can be repeated to convert compound 20 into complex 2_2, compound 28 into complex 3_0, compound 3_6 into complex 38, compound 4_6 into complex 48, compound 5_0 into complex 52, compound 6_1 into complex 6_3, compound 7_1 into the complex 7_3, the compound 7_9 to the complex 8_1, the compound 8_9 to the complex 9_1, the compound 9_9 to the complex 1()1, the compound 11_0 to the complex 112, the compound 118 to the complex 121, etc.

EXAMPLE 19

To a slurry of 11 g of lithium aluminum hydride in 300 ml of dry tetrahydrofuran, 13 g of the amide §_ in 150 ml of dry tetrahydrofuran are added dropwise over a 2 hour period and under an argon atmosphere. After the addition is complete, the reaction mixture is heated under reflux for 30 hours and saturated Na-K tartrate solution is then poured over. Treatment with 3N hydrochloric acid and then with saturated sodium carbonate solution, followed by filtration and extraction of the filtrate with dichloromethane gives an organic solution which is dried over magnesium sulfate. Removal of the solvent affords the desired amine, compound 8^ of Scheme 1, as a viscous oil.

A sample of the thus obtained free amine is dissolved in diethyl ether and hydrogen chloride gas is added. The white powder which separates is removed by filtration and purified from ethanol/water to give the corresponding hydrochloride salt melting at 225 - 22°C. 1 H NMR (D 2 O) 6 3 . 3-4. 2 (m, 9H, HCl, NH2CH2, -HCl NHCH_2 ), 1.5 [m, 12H, C(CH_3) 2 ] . Theoretically

analysis for C^ ^H^qCI ^N-^S,,.

H 2 O: C, 33.63; H, 8.21; N, 10.69; Cl, 27.07; Pages, 16, 32.

Found: C, 33.93; H, 7.94; N, 10.60; Cl, 27.05; Pages, 16, 25.

EXAMPLE 20

A mixture of 1 g of the amine _8, 75 ml of acetone and a catalytic amount of p-toluenesulfonic acid is heated under reflux for 24 hours. The solvent is removed by rotary evaporation and the residue is taken up in chloroform and treated in sequence with saturated aqueous sodium bicarbonate solution, saturated sodium hydroxide solution (10%) and saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate. Removal of the solvent leaves a viscous mass. Thin layer chromatography (CHCl₂/methanol, 2:1) indicates two major components with R₂ values of 0.13 and 0.73. The component with the lower R^ value shows a positive ninhydrin test confirming that it is the desired primary amine 8a, while the component with the higher Rf value is negative. H NMR of the Rf 0.73 component (CDCl 3 ): δ 2.9, 2.5, 1.3-1.5. ^"H NMR of the Rf 0.13 component (CDCl3):6 3.0, 2.8, 2.3, 1.2 - 1.7. In this way the desired bis-thiazolidone primary amine, compound 8a, is obtained in form 1.

EXAMPLE 21

The reaction between the bisthiazolidine primary amine 8_a and the zinc reagent 9 according to the procedure in Example 8 gives the corresponding quaternary bisthiazolidine, i.e. the compound 10a in Scheme 1, which can then be deprotected, e.g. by reaction with mercuric chloride, followed by treatment with hydrogen sulfide, to give the unprotected quaternary compound, compound 10 in Scheme 1.

EXAMPLE 22

Reaction between the bisthiazolidine primary amine 8_a and the zinc reagent 59 according to the procedure in Example 8 gives the corresponding bisthiazoline quaternary compound, i.e. the compound 10b in Scheme 1. Removal of the protecting groups, e.g. on successive treatments with HgCl^ and H2S, gives the corresponding unprotected quaternary compound, i.e. compound 10c in Scheme 1.

EXAMPLE 2 3

A solution of 7 g (3 mmol) of the ester 5_ (prepared

e.g. as described in example 3) in 50 ml of dry tetrahydrofuran is added dropwise over a period of 1 hour to 1.8 g (47 mmol) of lithium aluminum hydride in 200 ml of dry tetrahydrofuran. The mixture is heated under reflux for 16 hours, after which the reaction is stopped with K-Na tartrate solution.

The organic phase is dried over sodium sulfate. Removal of the solvent leaves a yellow viscous mass. Yield 4 g

(65%) of the desired alcohol, which is compound 18a in Scheme 2. <1>E NMR (CDCl3)6 2.2-2.8, 3.5, 2.3, 1.5.

EXAMPLE 2 4

A solution of 2 g of PBr^ is added at 0°C to 1 g of the alcohol a8a. The mixture is heated under reflux for 30 min., then treated with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is dried over sodium sulphate. Removal of the solvent under vacuum leaves the corresponding bromine compound, ie compound 19 in Scheme 2, as a clear viscous mass.

EXAMPLE 2 5

By following the general procedure in Example 20, however

replacing the amine 8_ with an equivalent amount of the alcohol 18a gives bisthiazolidine alcohol, compound 1.8b in Scheme 2.

EXAMPLE 26

Reaction of the bisthiazolidine alcohol 18b with PBr^ according to the procedure in Example 24 gives the corresponding bromine compound, i.e. the compound 19a in Scheme 2.

EXAMPLE 2 7

A solution of 17 ml of 2N lithium borohydride in tetrahydrofuran is added to 300 ml of dry tetrahydrofuran under an argon atmosphere. 10 g is added to this solution

(0.035 mol) of the ester 40 in 100 ml of dry tetrahydrofuran. The resulting cloudy solution is heated under reflux for 1.5 hours. The reaction is stopped with water and the organic phase is washed with saturated aqueous sodium chloride solution and dried over magnesium sulphate. Removal of the solvent leaves the corresponding primary alcohol as a white powder which is

very soluble in water, namely compound 32 in Scheme 4. Yield 3 g (24%); m.p. 85 - 90°C;<1>H NMR (acetone-dD,) 6 7-8, 4.15, 3.3-4.0.

EXAMPLE 2 8

To 1 g of the alcohol 32 in 40 ml of dry ethanol is added a solution of sodium thiobenzoate prepared from 0.2 g of sodium in 100 ml of ethanol and 1.26 g of thiobenzoic acid in 5 ml of ethanol. The reaction mixture is stirred at room temperature for 10 min., then heated at 45°C for a further 10 min. The mixture becomes very thick and difficult to stir and a yellow product separates. The product, compound 3_3 in scheme 4, is removed by filtration and washed with water. Yield 1.2 g, m.p. 151-152°C;<1>H NMR (DMSO-dafc/acetone-dfa,) 6 7.4-8.3, 3.85, 3.1-3.6.

EXAMPLE 2 9

2 g (4.5 mmol) of the alcohol are added to 50 ml of dichloromethane

3_3 and 0.35 g (4.5 mmol) of dry pyridine. The solution is cooled and 0.8 g (6.8 mmol) of thionyl chloride in 5 ml of dichloromethane is added dropwise over a period of 10 min. period. The solution is stirred overnight at room temperature. A further 50 ml of dichloromethane is then added and the solution is washed successively with 2N hydrochloric acid, saturated sodium bicarbonate solution and water. Drying over magnesium sulfate and removal of the solvent left a yellow solid with Rf (CH 2 Cl 2 /acetone) of 0.47. Yield 1.7 g (81.6%) of the chlorine derivative, compound 34a in scheme 4, which melts at 129 - 131°C.

Chelating agent precursors, chelating agents and radio-pharmaceutical preparations within the scope of the present invention can also be prepared based on the bifunctional chelating agents of Yokoyama et al in US patent document no. 4,287,362. E.g. can thus Yokoyama et al's chelating agents of formula

12 3 4 in which R , R , R and R are each H or C^-C^ alkyl are first converted into the corresponding esters (e.g. by replacing -COOH with -COOC^Hj.), and which can then be reduced to the corresponding alcohols (by replacing -COOC"2H,- with -Cr^OH), which can then be converted to the corresponding -CF^Br or

-CH^Cl derivatives, which in turn can be reacted with it

selected pyridine compound of formula

so that the halogen atom is replaced to give the desired quaternary salt of formula (I). Other process variations will be clear from the many reaction schemes depicted above. Other bifunctional chelating agents which can be easily converted into the redox-system-containing chelating agent precursors, chelating agents and radio-pharmaceutical preparations in accordance with the invention are a compound of formula which is also known as amino DTS and which is described in the literature, e.g. in Jap. J. Nucl. With. 19, 610 (1982). Amino DTS can be readily converted into derivatives in accordance with the present invention by reaction with a zinc reagent of formula wherein is as defined for formula (I) above to give the corresponding precursor of formula (I), which can then be used as generally described herein for the preparation of the corresponding compound of formula (II) and radiopharmaceutical preparations of formulas (III) and (IV). See e.g. form 14 below. Yet another group of known chelating agents which are particularly suitable for conversion into the redox system-containing chelating agent precursors, chelating agents and radio-pharmaceutical preparations in accordance with the present invention can be represented by the formula 12 3 4 in which R , R , R and R are each H or C₁-C₁ alkyl and n is an integer from 0 to 3. See e.g. Yokoyama et al US Patent No. 4,511,550 and Australian Patent No. 533,722. A particularly preferred chelating agent that is included in this group is known as amino-PTS, or AEPM, and has the structure Amino-PTS can be converted into derivatives in accordance with the present invention via a zinc reagent, as described above in connection with amino- DTS. See e.g. form 15 below. The exact structure of the resulting technetium complex 136 has not been determined. It is possible that the C=N and C=S bonds are also reduced during one of the reduction steps. A possible structure of 136 is as follows.

(A similar structure could be depicted for the complex 1_31 in sample 14).

An alternative reaction pathway to derivatives of amino-PTS, amino-DTS and the like is depicted in the following schemes 16 and 17. This pathway can begin by using known, commercially available pyrylium salts, e.g. compound 138, to convert the primary amino group in amino-PTS, amino-DTS or the like to a pyridinium intermediate. The resulting pyridinium intermediate

(eg 140 or 143) can then undergo nucleophilic rearrangement to give the corresponding halogen compound (eg 141 or 144). The halogen derivative can then be reacted with it

selected pyridine compound of formula

to give the corresponding quaternary salt of formula (I), which can be converted into the present derivatives of formulas (II), (III) and (IV) as already described above. Fritzberg US Patent No. 4,444,690 describes an interesting series of 2,3-bis(mercaptoalkanoamido)alkanoic acid chelating agents of the general formula wherein X is H or -COOH, and R and R' are H or lower alkyl, and water soluble salts thereof, used for the preparation of the corresponding radio-pharmaceutical compounds of formula in which X is H or -COOH, and R and R' are H or lower alkyl. These Fritzberg chelating agents are prepared from the corresponding 2,3-diaminoalkanoic acids by esterification with a lower alkanol containing dry HCl, followed by treatment of the resulting alkyl ester with a chloroalkanoyl chloride to form the bis(chloroalkanoamide) ester, followed by treatment of this ester with followed by alkaline hydrolysis of the resulting 2,3-bis-(benzoylmercaptoalkanoamido)alkanoic acid ester to produce the 2,3-bis(mercaptoalkanoamido)alkanoic acid chelating agent. The preparation of an analogue from 3,4-diaminobenzoic acid is also disclosed by Fritzberg. Many of Fritzberg's synthesis steps can be adapted for the preparation of the derivatives of formula (I) in accordance with this invention and which instead of the -COOH group in Fritzberg's chelating agent contain one or similar group, in which

and X is as defined for formula (I) therein

preceding. See e.g. forms 4, 5, 6 and 11 above.

Suitable non-toxic pharmaceutically acceptable diluents or carriers for use with the present complexes of formula (III) will be apparent to those skilled in the art. See e.g. Remington's Pharmaceutical Sciences, 4th edition (1970).

It will be understood that the choice of suitable diluents or carriers will depend on the precise nature of the particular dosage form selected.

The dosage ranges for supplying the complexes in accordance with this invention will vary with the size and nature of the subject, the purpose for which the complex is supplied, the particular dosage form used and the like, as discussed below. The amount of a given dosage form required to provide the required dose of the radiopharmaceutical depends, of course, on the concentration of the complex in any given pharmaceutical preparation/dosage form thereof and its radioactivity.

By way of example only, a 5-50 mg/kg dose of the radiopharmaceutical compound of formula (III), injected into the tail vein or carotid vein of rats, due to the "lock-in" mechanism, will exhibit a very clear difference between the brain and peripheral levels of the radioactivity, with consequent decent radio-imaging of the brain; imaging at approximately 60 - 90 min. after delivery will be most effective, as this will take advantage of this brain/periphery difference.

The present radiopharmaceutical compounds are generally administered intravenously. Delayed release delivery, typically by slow intravenous infusion, will further improve the site-specificity of the relevant redox system. The release rate of the radiopharmaceutical compounds of formula (III) from the sustained release system should be comparable to the rate of in vivo oxidation of the dihydro form (III) to the quaternary form (IV) to achieve the greatest degree of improvement of the specificity.

In a further aspect, the present invention also provides a method for producing a diagnostic means for visualizing an organ such as e.g. the brain. For this purpose, the blood-brain barrier penetrating form, formula (III), is mixed with an aqueous buffer medium having a pH value of about 4 to about 8, preferably about 6.5 to about 7.5, in an effective radioimaging depth .

The production of the radio-pharmaceutical preparation can be carried out in the hospital or similar location where the patient is located in order to reduce the loss of radioactivity caused by the splitting of radioactive metal to a minimum. As the visualization preparation is injectable, it must be sterile and pyrogen-free. Preferably, it is also isotonic. For this purpose, a so-called labeling kit can be provided which allows a simple, fast and safe labeling of the solution to be injected with the radioactive metal, e.g. technetium 99m. Such sets are particularly desirable when a short-lived radioisotope such as e.g. technetium 99m.

The kit includes a collection glass vial to receive

and/or contain an aqueous medium in which the complexation reaction can be carried out. The kit further comprises the chelating agent of formula (II) or the chelating agent precursor of formula (I) and a pharmaceutically acceptable reducing agent for reducing the radioactive element to an appropriate oxidation state for complexation with the chelating agent (and also for reducing pyridinium -moiety to the corresponding dihydro-pyridine form when a chelating agent precursor of formula (I) is present).

In the case of technetium 99m, the radioactive is received

element from a radionuclide generator as an aqueous pertechnetate (TcO^) solution e.g. as an eluate in isotonic salt solution, as is well known in the art. The amount of Tc-99m required to produce an amount of formula (III) radiopharmaceutical compound sufficient for diagnostic purposes is generally from 0.01 milli-curie (mCi) to about 500 mCi per ml 99m-pertechnetate solution. The reducing agent for the pertechnetate can be a thiosulfate or dithionite if the reduction reaction is to be carried out in a basic medium, or a tin (II) salt such as e.g.

SnCl2 if the reduction reaction is to be carried out in an acidic medium.

A kit for the preparation of an injectable radiopharmaceutical preparation, e.g. for complexation of an organ-specific agent labeled with a radioactive metal, includes in separate containers: (1) a biologically tolerable, sterile aqueous medium suitable for complexation with a radioactive metal, (2) a dihydropyridine pyridinium salt redox system- containing complexing agent of formula (I) or (II) which is compatible therewith, and (3) a pharmaceutically acceptable reducing agent for the radioactive metal.

The dihydropyridine pyridinium salt redox moiety can be present in the kit either in its oxidized or reduced state as desired. The reducing agent for the radioactive metal can be selected to also reduce the oxidized form of the redox part, if present, when the radioactive metal is reduced to form the complex before the injection of the radiopharmaceutical preparation into an experimental animal or a patient. In a preferred embodiment in accordance with the invention, a reducing agent is selected which is capable of reducing both the oxidized form of the redox part and the radioactive metal and the chelating agent precursor of formula (I) is present in the kit. In a particularly preferred embodiment, the set comprises in separate containers (preferably aseptically and hermetically sealed vials with

5-25 ml) (1) a biologically tolerable, sterile aqueous medium,

(2) a chelating agent precursor of formula (I), and (3)

a pharmacologically tolerable reducing agent capable of reducing the chelating agent precursor of formula (I)

to a chelating agent of formula (II) and which can also reduce the radioactive metal to an oxidation state in which it is capable of complexing with the chelating agent of formula (II) to form a radio-pharmaceutical compound of formula (III). Most preferred is the reducing agent sodium dithionite. Furthermore, the most preferred radioactive metal is technetium. The dithionite reduction is preferably carried out in a basic medium. This can be accomplished by arranging it so that the aqueous medium (1) above has a basic pH value, or by adding a suitable base (eg NaOH, Na2CH3) when the kit components and the pertechnetate solution are combined. In yet another alternative, the kit may comprise only two separate components: (1) the biologically tolerable sterile aqueous medium of substantially neutral pH containing the chelating agent precursor of formula (1) and (2) the reducing agent,

e.g. sodium dithionite or (2) the reducing agent together with the base, e.g. sodium dithionite and sodium carbonate.

Radioactive metal ions are typically not arranged with the kit due to the relatively short half-lives of commonly used radionuclides. Rather, the radionuclide is provided separately as previously described and mixed with the components of the kit shortly before use, as is known for other delivery systems for radio-pharmaceutical preparations. In the case of technetium 99m, the pertechnetate solution and the aqueous basic medium may first be combined and then heated, e.g. from 40 - 95°C for 10 - 20 min., in the presence of the reducing agent, then cooled to about room temperature or lower before the addition of the precursor of formula (I). In this case, the technetium will be reduced before the reduction of the quaternary moiety to the corresponding dihydro form, and in this case a substantial proportion of the quaternary salt (I) will probably chelate with the reduced technetium to form the quaternary complex (IV) in the reaction mixture as an intermediate to the dihydro-complex (III), rather than the quaternary salt (I) being converted first to the dihydro-chelating agent (II) and then to the dihydro-complex (III). Alternatively, if only minimal or no heating is carried out, the precursor may be present in the initial mixture prepared from the kit, in which case it is likely that the quaternary compound of formula (I) will first be reduced to the dihydro compound of formula (II ), which will then chelate with the reduced technetium to form the complex (III). If the mixture is weakly basic, e.g.

pH 8 - 9, it can be added as is, after the reduction and chelation has taken place to form the radiopharmaceutical compound of formula (III), or the pH can be adjusted to about 7. If the mixture is more basic, e.g. . pH 13, it is generally desirable to set the pH to a slightly alkaline or neutral value.

Regardless of the exact configuration of the kit, it is preferred that it contains an excess of chelating agent precursor (I) or chelating agent (II) relative to the radionuclide to be complexed therewith, e.g. a 1:2 molar excess. The reducing agent is present in a large excess with respect to the chelating agent precursor (I), e.g. 1:5 to 1:10. When the chelating agent (II) rather than the precursor (I) is present, the reducing agent is preferably present in a small excess relative to the radionuclide.

To effect visualization, the diagnostic agent is administered to a patient, intravenously, with or without further dilution by means of a carrier substance such as e.g. physiological salt solution, phosphate-buffered salt solution, plasma or the like. In general, the unit dose to be administered will have a radioactivity of approximately 0.01 milli-curie

(mCi) to about 100 millicuries, preferably about 1 mCi to about 20 mCi. The solution to be injected into an adult patient per unit dose is approximately 0.01 milliliters

(ml) to 1 milliliter.

After intravenous administration, imaging of the organ in vivo can take place after a few minutes. If desired, the imaging can also take place hours after the injection, depending on the half-life of the radioactive material that has been introduced into the patient and the amount of such material introduced. Preferably, the imaging takes place 60 - 90 min. after

intravenous administration.

Any conventional method of imaging for diagnostic purposes may be used in the practice of the present invention.

In summary, the present invention can thus be seen to provide substance mixtures comprising: (1) the residue of a chelating agent with at least one primary, secondary or tertiary amino-functional group, the functional group not being essential for the complex-forming properties of the chelating agent , the remainder being characterized by the absence of at least one of the aforementioned primary secondary or tertiary amino-functional groups, the chelating agent either (a) being capable of chelating with a metal radionuclide or (b) being chelated with a metal -radionuclide;

(2) a dihydropyridine^zz^ pyridinium salt redox system which in its oxidized form comprises a radical of formula

in which n, p, q and R are as previously defined for formula (I) and which in its reduced form comprises a radical of formula

wherein n, p, q, m and R are as previously defined for formula (II), the redox system being directly linked to the said chelating agent residue, the ring nitrogen atom in the said redox system occupying the same position in relative to said chelating agent residue as the position occupied by said primary, secondary or tertiary amino-functional group in said chelating agent.

While the invention is described on the basis of various preferred embodiments, the person skilled in the art will appreciate that various modifications, substitutions, omissions and changes can be made without going outside the scope of the invention. Accordingly, it is intended that the scope of the present invention should only be limited by the scope of the subsequent patent claims.

Claims (51)

1. Substance mixture characterized in that it includes: (1) the residue of a chelating agent with at least one primary, secondary or tertiary amino-functional group, the functional group not being essential for the complex-forming properties of the chelating agent, the residue being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino functional groups, the chelating agent either (a) being capable of chelating with a metallic radionuclide or (b) being chelated with a metallic radionuclide, and (2) a dihydropyridine v pyridinium salt- redox system which in its oxidized form comprises a radical with the formula wherein n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each R can be on either of the two condensed rings, q is zero, one or two , with the proviso that when q is one or two then each R can be on any of the two fused rings, and each R is independently selected from the group consisting of halogen, C-^- C^ alkyl, C^- C^ alkoxy, C2~C8 alkoxycarbonyl, C2"~C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C^ -C^ alkylsulfinyl, C^-C^ alkylsulfonyl, -CH=NOR'" wherein R'" is H or C^-C-, alkyl, and -CONR'r </>' ' wherein R' and R" are the same or different and are each H or C^ -C ^ alkyl, and which in its reduced form comprises a radical of formula wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring, the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline -the ring system, m is zero or one, and n, p, q and R have the above meaning, the redox system being directly linked to the said chelating agent residue, the ring nitrogen atom in the said redox system occupying the same position in relation to said chelating agent residue as the position occupied by said primary, secondary or tertiary amino-functional group in said chelating agent. 2. A salt characterized in that it has the structure formula in which is the residue of a chelating agent capable of chelating with a metallic radionuclide, the chelating agent having at least one primary, secondary or tertiary amino functional group, the functional group not being essential for the complex-forming properties of the chelating agent, the remainder being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino-functional groups, y is 1 or 2, ■is a radical with formula wherein n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each R in formula (b) may be on either of the two fused rings, q is zero, one or two, with the proviso that when q one or two each R in formula (c) may be on either of the two fused rings, and each R is independently selected from the group consisting of halogen, C^ - C^ alkyl, C^ -C-, alkoxy, C2 -Cg alkoxycarbonyl, C2 -Cg alkanoyl oxide, C1~C7 haloalkyl, C^- C^ alkylthio, C] _-c7 alkylsulfinyl, C1-C7 alkylsulfonyl, -CH =NOR"'wherein R'" is H or C^ -C^ alkyl, and -CONR'R" wherein R' and R" are the same or different and are each H or C^ -C"7 alkyl, X~ is the anion of a pharmaceutically acceptable organic or inorganic acid, t is the valence of the acid anion and s is a number which when multiplied by t equals y. 3. A connection, characterized in that it has the structure formula or a non-toxic pharmaceutically acceptable salt thereof, wherein is the residue of a chelating agent capable of chelating with a metallic radionuclide, the chelating agent having at least one primary, secondary or tertiary amino functional group, the functional group not being essential for the complex-forming properties of the chelating agent means, the remainder being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino-functional groups, y is 1 or 2, and is a radical with formula wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring, the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline -ring system, m is zero or one, n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two each R in formula (ii) can be on whichever preferably of the two fused rings, q is zero, one or two, with the proviso that when q is one or two, each R in formula (iii) may be on either of the two fused rings, and each R is independent selected from the group consisting of halogen, C 1 -C 7 alkyl, C^ -C^ Alkoxy, C2~ Cq Alkoxycarbonyl, C2~ C8 alkanoY oxy' C^- C- j haloalkyl, C^- C^ alkylthio, C^- C^ alkylsulf inyl, C1-C7 alkylsulfonyl, -CH=NOR "' in which R'" is H or C^-C^ alkyl, and - CONR'R" wherein R' and R" are the same or different and are each H or C₁-C₁ alkyl. 4. A radio-pharmaceutical compound characterized in that it has the structural formula or a non-toxic pharmaceutically acceptable salt thereof, wherein the residue is a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one primary, secondary or tertiary amino functional group, being functional group is not essential for the complex-forming properties of the chelating agent, the remainder being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino-functional groups, y is 1 or 2, is a radical with formula wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring, the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline -ring system, m is zero or one, n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two each R in formula (ii) can be on whichever preferably of the two fused rings, q is zero, one or two, with the proviso that when q is one or two, each R of formula (iii) may be on either of the two fused rings, each R being independent selected from the group consisting of halogen, C₁ -C₁ alkyl, C^-Cy alkoxy, C2~ C8 al^oxy*carb°nyl' C2~ C8 al^an°yloxy - C1 -C7 haloalkyl, C^- C^ alkylthio, C^- C^ alkylsulfinyl, C1 -C7 alkylsulfonyl, -CH=NOR '" wherein R'" is H or C^-C^ alkyl, and -CONR'R" wherein R' and R" are the same or different and are each H or C^-C^ alkyl, and m is a metal radionuclide, the radiopharmaceutical compound of formula (III) being a chelate of said metal radionuclide with a compound of the structural formula in which and y has the above meaning. 5. A radio-pharmaceutical compound having the structural formula wherein >- is the residue of a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one primary, secondary or tertiary amino-functional group, the functional group not being essential for the complex-forming properties of the chelating agent, the rest being characterized by the absence of at least one of the aforementioned primary, secondary or tertiary amino-functional groups, y is 1 or 2 , is a radical with formula wherein n is zero, one or two, p is zero, one or two, with the proviso that when p is 1 or two, each R in formula (b) can be seq on either of the two fused rings, q is zero, one or two, with the proviso that when q is one or two, each R in formula (c) may be on either of the two fused rings, each R being independently selected from the group consisting of halogen, C^ -C^ Alkyl, C^-C-, Alkoxy, C^-Cg Alkoxycarbonyl, C2-C8 Alkanoyloxy, C^- Crj Haloalkyl, C^- C^ Alkylthio, C^- C^ Alkylsulfinyl, C1-C7 Alkylsulfonyl , -CH=NOR"' wherein R'" is H or C1-C7 alkyl, and -CONR'R" wherein R' and R" are the same or different and are each H or C^-C7 alkyl, X- is the anion of a pharmaceutically acceptable organic or inorganic acid, t is the valence of the acid anion, s is a number which when multiplied by t is equal to y, and M is a metal radionuclide, the radiopharmaceutical compound of formula (IV) being a chelate of said metal radionuclide with a salt with structural formula in which X , t and s have the above meaning. 6. A chemical compound as specified in claim 2, 3, 4 or 5, characterized by atyerl. 7. Chemical compound as stated in claim 6, characterized in that n, p, q or m is one. 8. Chemical compound as stated in claim 7, characterized in that R is in the 3-position of the pyridinium or dihydropyridine ring, in the 3-position of the quinolinium or dihydroquinoline ring system, or in the 4-position of isoquinolinium or whichever preferably of the dihydroisoquinoline ring systems. 9. Chemical compound as stated in claim 7, characterized in that R is -CH=NOR'" in which R'" is H or C1~C7 alkyl. 10. Chemical compound as stated in claim 7, characterized in that R is -CONR'R" in which R' and R" are the same or different and are each H or C1 -C7 alkyl. 11. Chemical compound as stated in claim 8, characterized in that R is -CH=NOR"' in which R'" is H or C₁-C₁ alkyl. 12. Chemical compound as stated in claim 8, characterized in that R is -CONR'R" in which R' and R" are the same or different and are each H or C1 -C7 alkyl. 13. A salt as stated in claim 2, characterized in that it has the structural formula wherein each R is independently selected from the group consisting of H and C-,-C7 alkyl, or an R, may be combined with neighboring standing so that represents each R 2 is independently selected from the group consisting of H and C 1 -C 4 alkyl, or one R 2 may be combined with adjacent ic-R 2 so that / represents ^C=0, is a radical with formula wherein each R^ is independently selected from the group consisting of H and C^-C^ alkyl, alk is a straight chain or branched lower alkylene group which may further contain 1, 2 or 3 non-adjacent oxygen atoms in the chain, and is as stated in claim 2, X and t are as stated in claim 2, and s' is a number which when multiplied by t is equal to one. 14. Salt as specified in claim 13, characterized in that it has the structural formula in which s) X and t are as stated in claim 13. 15. Salt as specified in claim 2, characterized in that it has the structural formula in which X- and t are as stated in claim 2, s' is a number which when multiplied by t is equal to 1, n is an integer 1 2 from 0 to 3, and R and R are each H or C 1 -C 4 alkyl. 16. Salt as specified in claim 15, characterized in that it has the structural formula in which s', X and t are as stated in claim 15. 17. A salt as stated in claim 2, characterized in that it has the structural formula 18. Compound as stated in claim 3, characterized in that it has the structural formula wherein each is independently selected from the group consisting of H and C,-C_ alkyl, or an R, may be combined with neighboring standing so that represents ^C=0, each R 2 is independently' selected from the group consisting of H and C-.-C-, alkyl, or an R 0 may be combined with neighbours so that by formula wherein each R^ is independently selected from the group consisting of H and C-^-C^ alkyl, alk is a straight-chain or branched lower alkylene group which may additionally contain 1, 2, or 3 non-adjacent oxygen atoms in the chain, specified in claims 3. is like 19. Compound as stated in claim 18, characterized in that it has the structural formula in which is as stated in claim 18. 20. Compound as stated in claim 3, characterized in that it has the structural formula in which is as set forth in claim 3, n' is an integer from 0 to 3 and R and R are each H or C -C -C alkyl. 21. Compound as stated in claim 20, characterized in that it has the structural formula in which r is as stated in claim 20. 22. Compound as stated in claim 3, characterized in that it has the structural formula 23. A radio-pharmaceutical compound as set forth in claim 4 or 5, characterized by more technetium-99m. 24. Radio-pharmaceutical compound as stated in claim 4, characterized in that the radio-pharmaceutical compound is a chelate of the aforementioned metal radionuclide with a compound of structural formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 7 alkyl, or an R 1 may be combined with neighboring standing so that represents each R^ is independently selected from the group consisting of H and C^-C7 alkyl, or an R2 may be combined with adjacent so that represents is a radical with formula wherein each R^ is independently selected from the group consisting of H and C^-C7 alkyl, alk is a straight chain or branched lower alkylene group which may further contain 1, 2 or 3 non-adjacent oxygen atoms in the chain, and is as stated in claim 4. 25. Radio-pharmaceutical compound as stated in claim 24, characterized in that the compound of formula (Ila) has the structural formula in which is as stated in claim 24. 26. Radio-pharmaceutical compound as stated in claim 4, characterized in that the radio-pharmaceutical compound is a chelate of the mentioned metal radionuclide with a compound with the structural formula in which is as set forth in claim 4, n' is an integer from 0 to 3 and R and R are each H or C₁ -C₁ alkyl. 27. Radio-pharmaceutical compound as stated in claim 26, characterized in that the compound of formula (IIb) has the structural formula in which is as stated in claim 26. 28. Radio-pharmaceutical compound as stated in claim 24, 25, 26 or 27, characterized in that the metal radionuclide is oxotechnate-99m ion. 29. Radio-pharmaceutical compound as stated in claim 4, characterized in that the radio-pharmaceutical compound is a complex of oxotechnate-99m ion with a compound of structural formula 30. Radio-pharmaceutical compound as set forth in claim 5, characterized in that the radio-pharmaceutical compound is a chelate of the aforementioned metal radionuclide with a salt of structural formula wherein each R^ is independently selected from the group consisting of H and C^-C7 alkyl, or one R^ may be combined with adjacent so that represents ^C=?0 , each R 2 is independently selected from the group consisting of H and C-^-C-y alkyl, or an R 2 may be combined with adjacent so that represents wherein R 3 is independently selected from the group consisting of H and C 1 -C 7 alkyl, alk is a straight or branched lower alkylene group which may further contain 1, 2 or 3 non-adjacent oxygen atoms in the chain and is as stated in claim 5, X and t are as stated in claim 5, and s' is a number which when multiplied by t is equal to one. 31. Radio-pharmaceutical compound as stated in claim 30, characterized in that the salt of formula (Ia) has the structural formula in which s', X and t are as stated in claim 30. 32. Radio-pharmaceutical compound as stated in claim 5, characterized in that the radio-pharmaceutical compound is a chelate of the mentioned metal radionuclide with a salt with the structural formula in which X and t are as stated in claim 5, s' is a number which when multiplied by t is equal to one, n' is an integer 1 2 from 0 to 3 and R and R are each H or C 1 -C 4 alkyl. 33. Radio-pharmaceutical compound as stated in claim 32, characterized in that the salt of formula (Ib) has the structural formula in which s', X and t are as stated in claim 32. 34. Radio-pharmaceutical compound as stated in claim 30, 31, 32 or 33, characterized in that the metal radionuclide is oxotechnate-99m ion. 35. Radio-pharmaceutical compound as stated in claim 5, characterized in that the radio-pharmaceutical compound is a complex of the oxotechnate-99m ion with a salt of structural formula 36. Method for radio-imaging the brain, characterized in that a patient is administered a radio-pharmaceutical compound as stated in claim 4 in a sufficient amount to provide an effective radio-imaging amount of the radionuclide to the brain and then the brain is imaged using irradiation-imaging agents. 37. A kit for the preparation of an injectable radio-pharmaceutical preparation, characterized by the fact that in separate containers it includes: (1) a compound of formula (II) as set forth in claim 3, (2) a pharmaceutically acceptable reducing agent capable of reducing a radioactive metal to an oxidation state in which the metal is capable of complexing with the compound of formula (II); (3) a biologically tolerable sterile aqueous medium. 38. Kit for the production of an injectable radio-pharmaceutical preparation, characterized by the fact that in separate containers it includes: (1) a salt of formula (I) as set forth in claim 2, (2) a pharmaceutically acceptable reducing agent capable of reducing the salt of the corresponding compound of formula in which and y is as stated in claim 2 and is a radical of formula wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring, the dashed line in formula (ii) indicates the presence of a double bond in either the 2- or the 3-position of the dihydroquinoline ring system, m is zero or one, n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each R in formula (ii ) be on either of the two fused rings, q is zero, one or two, with the proviso that when q is one or two, each R in formula (iii) can be on either of the two fused rings, and each R is independently selected from the group consisting of halogen, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 2 -C 8 alkyloxycarbonyl, C 1 -C 8 alkanoyloxy, C 1 -C 7 haloalkyl, C 1 -C 7 alkylthio, C 1 -C 7 alkylsulfinyl, C1-C7 alkylsulfonyl, -CH=NOR"'wherein R'" is H or C-C^alkyl, and -CONR'R"wherein R' and R" are the same or different and each is H or C^-C ^ alkyl, the reducing agent also being capable of reducing a radioactive metal to an oxidation state in which the metal is capable of complex formation with the compound of formula (II), and (3) a biologically tolerable, sterile aqueous medium. 39. Set as stated in claim 38, characterized in that the radioactive metal which the reducing agent is capable of reducing is technetium. 40. Set as stated in claim 38, characterized in that the reducing agent is sodium dithionite. 41. Set as stated in claim 38, characterized in that the aqueous medium has a basic pH. 42. Kit for the production of an injectable radio-pharmaceutical preparation, characterized by the fact that in separate containers it includes: (1) a salt of formula (I) as set forth in claim 2, in a biologically tolerable, sterile aqueous medium, and (2) a pharmaceutically acceptable reducing agent capable of reducing the salt of the corresponding compound of formula in which and y is as stated in claim 2 and is a radical wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4- or 5-position of the dihydro-pyridine ring, the dotted line in formula (ii) indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring system, m is zero or one, n is zero, one or two, p is zero, one or two, with the proviso that when p is one or two, each R in formula (ii) may be on either of the two fused rings, q is zero, one, or two, with the proviso that when q is one or two, each R in formula (iii) may be on either of the two fused rings, and each R is independently selected from the group consisting of halogen, C^-C7 alkyl, C^-C7 alkoxy, C2-C8 alkoxycarbonyl, C^-C8 alkanoyloxy, C^-C7 haloalkyl, C1-C7 alkylthio, <C>1 ~C7 alkylsulfinyl, C1~ C7 alkylsulfonyl, -CH=NOR"' in which R'" is H or C1~C7 alkyl, and -CONR'R" in which R' and R" are the same or different and are each H or C^-C7 alkyl, the reducing agent also being in capable of reducing a radioactive metal to an oxidation state in which the metal is capable of complex formation with the compound of formula (II). 43. Set as stated in claim 42, characterized in that the radioactive metal as reducing agent capable of reducing is technetium. 44. Set as stated in claim 42, characterized in that the reducing agent is sodium dithionite. 45. Set as stated in claim 42, characterized in that the aqueous medium has approximately neutral pH. 46. Set as stated in claim 42, characterized in that (2) contains a base in addition to the said reducing agent. 47. Process for producing a salt of formula (I) as stated in claim 2, characterized in that the method comprises: (a) a primary amine of formula in which is as stated in claim 2, is traded with a zinc- reagent with formula in which is as set forth in claim 2, or (b) a compound of formula wherein Hal is chlorine or bromine and is as stated in claim 2, is reacted with a compound of formula wherein R, n, p and q are as set forth in claim 2, (c) and, if desired, when the residue contains protecting groups, followed by removal of the protecting groups from the resulting salt of formula (I), (d) and, if desired, followed by replacement of the anion Cl<-> or Br- in the resulting salt of formula (I) with another X~ anion, X~ being as set forth in claim 2. 48. Process for the preparation of a compound of formula (II) as stated in claim 3, characterized in that a salt of formula (I) is reduced as stated in claim 2. 49. Method for the production of a radio-pharmaceutical compound of formula (III) as stated in claim 4, characterized in that the method comprises complex formation of a metal radionuclide with a compound of formula (II) as stated in claim 3. 50. Process for the production of a radio-pharmaceutical compound of formula (III) as stated in claim 4, characterized in that the method comprises the reduction of a radio-pharmaceutical compound of formula (IV) as stated in claim 5. 51. Method for the production of a radio-pharmaceutical compound of formula (IV) as stated in claim 5, characterized in that the method comprises (a) complexation of a metal radionuclide with a salt of formula (I) as set forth in claim 2, or (b) oxidation of a radiopharmaceutical compound of formula (III) as set forth in claim 4.