NO860981L - RADIOGRAPHICAL MEDICINE. - Google Patents

Abstract

A redox or chemical supply system of dihydropyridine. The pyridinium salt type for site-specific and / or site-enhanced delivery of a radionuclide to the brain. A chelating agent capable of chelating with a radionuclide and having a reactive hydroxyl, carboxyl, amino, amide or imide group is coupled to a carrier moiety comprising a di hydropyrinyl pyridineimaltBalt group and then complexed with radionuclide to provide a novel radionuclide composition which in its lipoidal dihydropyridine form penetrates the blood-brain barrier ("BBB") and permitted levels of radionuclide concentrations in the brain, especially since the oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt This circuit is well suited for use in scintigraphy and similar radiographic methods.

Description

CONNECTIONS FOR IN SITU ENHANCED SUPPLY OF

RADIONUCLIDES AND THEIR USES

Field of the invention

The present invention relates to a dihydropyridine pyridinium salt type of a redox or chemical delivery system for a radionuclide to the brain and other organs.

More particularly, the invention relates to the realization that a chelating agent capable of chelating with a radionuclide and having a reactive hydroxyl, carboxyl, amino, amide or imide group can be coupled to a carrier moiety comprising a dihydropyridine - —1 pyridinium salt core and then complexed with a radionuclide to give a new radiopharmaceutical compound which, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BBB") and allows elevated levels of radionuclide concentration in the brain, esp. as oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt delays clearance from the brain while accelerating clearance from the general circulation.

The present radionuclide delivery system is suitable for use in scintigraphy and similar radiographic methods.

Background for the invention

Radiographic methods such as scintigraphy, and

similar, finds application in biological and medical procedures for diagnosis as well as research. Scintigraphy • involves the use of radio-pharmaceutical compounds, i.e. compounds that contain (or are labeled with) a radioisotope (i.e. radionuclide) which, after introduction into a mammal, is localized in specific organs, tissues or skeletal material that is sought to be imaged. When the radio-pharmaceutical compound is located in this way, tracks, plates or scintiphotographs of the existing distribution of the radionuclide can be made using various radiation detectors known in the field. The observed

distribution of the localized radionuclide can then be used to detect the presence of pathological conditions, abnormalities etc. Radio-pharmaceutical compounds are therefore often referred to as radiodiagnostic agents.

In many cases, radio-pharmaceuticals are produced

compounds 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 forming a 1:1 or 2:1 ligand:radioactive metal complex; macrocyclic ligands of appropriate ring size and preferably in which all coordinating atoms are in a planar configuration; and bicyclic or polycyclic ligands that can encapsulate the radioactive metal.

It is a well-established fact that delivery of drugs, including radio-pharmaceutical compounds, 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 considered blood-brain. - the barrier. Site-specific delivery and/or sustained delivery of drugs to the brain is even more difficult.

It has previously been proposed to inject a type of drug, specifically N-methylpyridinium-2-carbaldoxime chloride (2-PAM) into the brain, the active core of which in itself constitutes a quaternary pyridinium salt in the form of the dihydropyridine latent promedicine form thereof. Such a method is severely limited to quaternary pyridinium ring-containing drugs with relatively small molecules and does not provide the overall ideal result of brain-specific, sustained release of the desired drug, with simultaneous rapid removal from the general circulation, improved drug efficacy and reduced toxicity. Consequently, no "trapping" in the brain of the 2-PAM formed in situ results and it is clear that no brain-specific, sustained supply occurs as a result: 2-PAM is removed from the brain as rapidly as from the general circulation and other bodies. For this, compare US Patent Nos. 3,929,813 and 3,962,447; Bodor et al., J. Pharm. Sei, 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. One more

recent development of this principle is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09,

March 1983, page 2910B. It is also intended to add, e.g. an anti-tumor agent, to the brain by using a dihydropyridine/pyridinium redox carrier part for this, but this particular hypothesis necessarily entails that the dihydropyridine/pyridinium carrier must be derivatized with a substituent which is itself critically determined to control the release the rate of the active medicine types from the quaternary derivative thereof, as well as being critically functionally coordinated with the particular chemical and therapeutic activity/nature of the anti-tumor medicine type itself; Bodor et al., J. Pharm. See., supra. See also Bodor, "Novel Approaches for the Design of Membrane Transport Properties of Drugs", in Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Roche, E.B.

(editor), APhA Academy of Pharmaceutical Sciences, Washington, D.C., pp. 98-135 (1976).

More recently, Bodor et al., Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372, have reported site-specific sustained release of drugs to the brain. The Science publication outlines a scheme for specific and sustained delivery of drug types to the brain, as depicted in the following Scheme 1:

According to the scheme in Science, a drug [D] is attached 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^) (using the NAD NADH system) to the ideally inactive parent [D-QC]<+>quaternary salt which, due to its ionic , hydrophilic character should be rapidly removed from the general circulation of the body, while the blood-brain barrier should prevent its removal from the brain (^3>> ^2"^3>:> ^7) . Enzymatic cleavage of the [D- QC]<+>which is "trapped" in the brain causes a sustained supply of the drug type [D], followed by its normal metabolic removal (k^). An appropriately chosen carrier [QC]<+>will also be rapidly removed from the brain (k^>> k2). Due to the easy removal of [D-QC]<+>from the general circulation, only small 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. Bodor et al have reported in Science their work with phenylethylamine as a model drug, which was coupled to nicotinic acid and then quaternized to give compounds of formula which were then reduced with sodium dithionite to the corresponding compounds of formula

Testing of the N-methyl derivative in vivo supported the criteria outlined in Scheme 1. Bodor et al envisioned that different types of drugs could be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotine -acid esters and amides and their pyridine-ring-substituted derivatives were investigated for the delivery of amino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were revealed.

Other reports of Bodor et al's work have appeared in

The Friday Evening Post, August 14, 1981, Health Center Communications, University of Florida, Gainsville, Florida; Chemical & Engineering News, December 21, 1981, pages 24-25, and Science News, January 2, 1982, Volume 121, Number 1, Page 7. These publications do not suggest any carrier systems other than the specific N-methyl- and N-benzyl-nicotinic acid type carriers discussed in the Science publication. Other classes of drugs as well as a few specific drugs have been mentioned as possible candidates for derivatization, e.g. steroid hormones, cancer drugs and memory-enhancing agents are indicated as targets for possible future work, as are enkephalins and specifically dopamine and testosterone. The publications do not suggest how to attach such medicins to the carrier, possibly except when the medicins are simple structures containing a single N^ or possibly simple structures containing a single OH, of primary or secondary type, as in the case of phenylethylamine or testosterone. There are e.g. no suggestion as to how the ordinary person skilled in the art would form a medicine-carrier combination when the medicine has a more complicated chemical structure than phenylethylamine, e.g. dopamine or an enkepamine. For further details regarding the work with phenylethylamine, dopamine and testosterone, see also Bodor et al, J. Med. Chem. Volume 26, March 1983, pages 313-317; Bodor et al, J. Med. Chem., Volume 25, April 1983, Pages 528-534; Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pages 337-386 (April 1983) and Bodor et al., Science, Vol. 221, July 1983, pages 65-67.

In light of the foregoing, it is clear that it has occurred

an acutely serious, long-term need for a truly effective, general, but nonetheless flexible method of site-specific or sustained delivery, or both, of drug types to the brain. This need is addressed in International Patent Application No. PCT/US83/00725 (filed by the University of Florida on May 12, 1983 and published under International Publication WO83/03968 on November 24, 1983), which provides such a general method for situs-specific, sustained delivery of drugs to the brain using a dihydropyridine vs pyridinium salt type of redox carrier system. According to the PCT application, a drug (typically with a reactive -OH, -COOH or -NH2~ group) can be coupled to a dihydropyridine^=i pyridinium carrier; the lipoidal dihydro form of the drug-carrier system readily escapes through the blood-brain barrier, the dihydropyridine moiety is then oxidized in vivo to the ideally inactive quaternary form that is "locked up" in the brain while being readily removed from the general circulation; enzymatic cleavage of the "locked-in" quaternary form causes a sustained supply of the medicine itself to the brain to achieve the desired biological effect. Diagnostic means such as radiopharmaceuticals are generally discussed in the PCT application as possible candidates for the carrier system, but the synthetic basis of the said application, which uses the medicine itself as starting material, is not desirable when radioactive materials, especially when it comes to radionuclides with relatively short lifespan. In the case of radionuclides would further

the former purpose of an ideal inactive form that was locked in the brain did not achieve the desired result. There has thus still been a serious need for an effective general method for site-specific and/or sustained delivery of a desired radionuclide to the brain.

Summary of the invention

It has now been found that a chemical delivery system based on

a dihydropyridine ^ * pyridinium salt-type redox carrier is uniquely suited for an effective site-specific and/or sustained and/or enhanced delivery of a radionuclide to the brain or similar organs, via novel carrier-containing radiopharmaceutical compounds, and novel carrier-containing chelating agents and new carrier-containing precursors to these, useful in the production of the aforementioned radiopharmaceuticals. Thus, according to one aspect, the present invention provides novel carrier-containing chelating agent precursors of formula

wherein I j is the residue of a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one reactive functional group selected from the group consisting of aminocarboxyl, hydroxyl, amide and imide, the functional group is not essential for the complexing properties of the chelating agent, the rest being characterized by the absence of a hydrogen atom from at least one of the mentioned reactive functional groups in the chelating agent;

y is 1 or 2; [,QC<+>J is the hydrophilic, ionic pyridinium salt form of a dihydropyridine pyridinium salt redox bearer;

X~ is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion, and m is a number that when multiplied by n equals y.

According to another aspect, the present invention provides novel carrier-containing chelating agents of formula

and non-toxic pharmaceutically acceptable salts thereof, wherein and y has the above meaning and LDHCJ is the reduced biooxidizable blood brain barrier penetrating form of dihydropyridine v v pyridinium salt redox carrier. According to another aspect, the present invention provides as an effective radionuclide delivery system new carrier-containing radiopharmaceutical compounds 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 carrier-containing chelating agent of formula (II) with a radioactive metal. When a radiopharmaceutical compound of formula (III) is administered, it easily penetrates the BBB. Oxidation of (III) in vivo gives the corresponding pyridinium salt of formula

in which the structure variables are as defined above. Due to its hydrophilic, ionic nature, the substance of formula (IV) becomes "locked up" in the brain and thus allows radiographic imaging of the radionuclide present in complex (IV). While the quaternary "locked in" form will gradually cleave to release the carrier and chelate portion of the molecule, this cleavage will generally occur after the most desirable period for radiographic imaging has already passed. From a standpoint of patient and technician safety, it is generally considered most desirable to image the target area as quickly as possible after administration and to use radioisotopes with a relatively short lifetime. Under such conditions, the "locked in"

quaternary form most likely does not break down to the non-carrier-containing chelate until after the radioactivity has decreased to a considerable extent. The present invention thus does not actually provide a system for the delivery and imaging of previously known radio-pharmaceutical compounds. At the time that the present delivery system breaks down into a chelate of a known chelating agent and a radioactive metal, the chelate will generally no longer be sufficiently radioactive for practical imaging. Furthermore, when such degradation first takes place, the known chelate may not be contained in the brain in sufficient quantities to permit imaging thereof. Thus, contrary to the teachings of the Bodor et al publications and the aforementioned PCT application, which emphasize the desirability of an inactive quaternary form locked in the brain, the present invention provides and indeed requires an active quaternary form locked in the brain to allow effective radionuclide imaging .

The present chelate/carrier system for radionuclides is characterized by improved efficiency and reduced toxicity. Accordingly, the systemic toxicity is actually substantially reduced by accelerating the removal of the quaternary carrier system from the general circulation.

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 are a chelated form of cobalt-57, gallium-67, gallium-68, indium-111, indium-lllm etc.

Detailed description of the invention

The following definitions apply:

The term "medicine" as used herein means any substance intended for use in the diagnosis, cure, alleviation, treatment or prevention of disease in humans and animals.

The term "lipoidal" as used herein denotes a carrier moiety that is lipid-soluble or lipophilic.

The term "non-toxic pharmaceutically acceptable salts" as used herein generally includes the non-toxic salts of products of the invention having structures (II)

and (III) in the foregoing 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 acids, 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 , pam acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid,

salicylic acid, sulfanilic acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, etc. 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.

It will be seen from the foregoing that a compound of formula (III) can be added as the free base or in the form of a non-toxic pharmaceutically acceptable salt thereof, i.e. a salt which can be represented by formula

where M,

[DHC], y and HX are as previously stated. Regardless

the relevant form in which the compound is administered, it will be converted in vivo to a quaternary salt of formula (IV) where the anion X- is present in vivo. It is not necessary that the anion be introduced as part of the compound that is supplied. Indeed, even when the compound of formula (III) is used i

in its salt form, the anion of the compound of formula (IV) in vivo is not necessarily the same as that present in the compound of formula (III). In fact, the exact identity of the anionic part of the compound of formula (IV) is immaterial for the in vivo conversion of (III) to (IV).

In the phrase "at least one reactive functional group selected from the group consisting of amine, carboxyl, hydroxyl, amide and imide" as used herein, the designating reactive functional groups have the following meanings: The meaning "amino" means any primary or secondary amino function, i.e. -NH 2 or -NHR where R is typically C 1 -C 1 alkyl or is part of the chelating agent residue itself. The secondary amine function is also represented herein as -NH-, especially since the exact identity of the R moiety of -NHR is immaterial, so long as it does not prevent the formation of the chelating agent residue and its binding to the carrier moiety or otherwise interferes with the purpose of the invention.

The meaning "carboxyl" means a -COOH function.

The meaning "hydroxyl" means an -OH function.

The term "amide" means a functional carbamoyl group (-CONH 2 ) or a functional substituted carbamoyl group (-CONHR wherein R is C 1 -C alkyl). The -CONHR group may also be represented herein as -CONH- as the exact identity of the R portion of -CONHR is immaterial, as long as it does not prevent the formation of the chelating agent residue and its binding to the carrier moiety or otherwise interfere with the purposes of the invention .

The term "imide" means a functional group with the structure

i.e. the structure that characterizes imides (i.e. compounds such as succinimide, phthalimide and so on).

The expression "since the said functional group is not essential for the complexing properties of the said chelating agent" is considered to be self-evident.

Any functional group in the chelating agent which can be linked to the carrier part without destroying the ability of the chelating agent to complex with the radionuclide is considered herein not to be essential for the complexing properties. On the other hand, the derivation of a functional group which would lead to a Baer-containing structure incapable of complexation with a radionuclide is not within the scope of the invention.

In accordance with the present invention, the persistent supply of radionuclide to the brain in sufficient concentrations for radioimaging can be carried out 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. It is thus expected that the quaternary form (IV) which is confined in the brain will also be confined in the testicles. See the aforementioned PCT application.

The new radionuclide delivery system according to the invention begins with the preparation of the new carrier-containing chelating agent precursors of formula (I). The preparation of these precursors will be adapted to the particular chelating part and carrier part to be combined and especially the nature of the chemical bond between them,

e.g. whether the bond is an ester or amide bond, as well as the presence or absence of other reactive functional groups (amino, mercapto, carboxyl, hydroxyl) in either the chelating part or the carrier part. 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 pathway. 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 involve reacting the alcohol with a halocarbonate of the type

R0C0C1 or ROCOBr (formed by reaction between ROH and

COCl2 or COBr2/where R is typically lower alkyl). For acyl-protecting groups, the alcoholic hydroxyl group is reacted with an acyl halide RC1 or RBr, where R is -COCH^ or -COCtCH^). to remove such protective groups after they have performed their function and are no longer needed.

In forming the precursors of formula (I), at least one group -COOH, -OH, primary or secondary amino, amide or imide group in a chelating agent will be bound to [QC<+>] , the hydrophilic , ionic pyridinium salt form of a dihydropyridine^=±. pyridinium-salt-r-edox carrier.

It will be seen that by [QC<+>] is meant any non-toxic carrier moiety comprising, containing or including the pyridinium core, whether or not this is part of a larger basic core, and whether substituted or unsubstituted, the only criterion therefore is its ability for chemical reduction to the corresponding dihydropyridine form [DHC] , BBB penetration of [DHC] and in vivo oxidation of [DHC] back to the quaternary pyridinium salt carrier moiety

[QC<+>].

As mentioned, the ionic pyridinium salt radiopharmaceutical compound/carrier entity of formula (IV) resulting from in vivo oxidation of the dihydropyridine form (III) is prevented from efflux from the brain, while removal 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. Subsequently, the coupling between the particular radioactive moieties ol3 ^a quaternary carrier [QC <+>] likely to be metabolically cleaved and this results in easy removal of the carrier moiety [QC<+>]. The link between the chelate moiety and the quaternary support may be a single direct chemical bond, e.g. an amide bond or ester bond, or any other similar bond, or the linkage may also comprise a linking group or function illustrated in the examples or the ethylenediamine group illustrated in Schemes 3 and 4. Nevertheless, the bond is intended to include and is defined herein as including all such options.

Any cleavage of the quaternary compound of formula (IV) with easy removal of the carrier moiety [QC<+>] is characteristic of an enzymatic or chemical cleavage, e.g. by means of an amidase, although any type of cleavage in the brain that would be achieved, whether enzymatic, metabolic or otherwise, is of course within the scope of the invention.

The many different dihydropyridine ^ £ pyridinium salt redox carrier types illustrated for use in the following are only examples of the many classes of carriers encompassed by the invention. While the following list of carrier classes is not intended to be exhaustive (and additional carrier classes are also illustrated hereinafter as well as in the aforementioned PCT application, PCT/US83/00725) the following major classes of quaternary compounds and the corresponding dihydro-forms primary examples of the types covered herein: (1) for binding to a chelating agent with at least one functional group -Nf^, -NH- or -H, during replacement of a hydrogen atom from at least one of the said functional groups with one of the following groups [QC<+>]: in which the alkylene group may be straight-chain or branched and may contain 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the RQ radicals may be the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 aralkyl; R 1 is C 1 -C 4 alkylene, X is -CONR'R" wherein R' and R" , which are the same or different, are each H or C 1 -C 4 alkyl, or X is -CH=NOR"' wherein R'" is H or C 1 -C 4 alkyl; the carbonyl-containing groups in formulas (a) and (c) and the X substituent in formula (b) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (d) and (f) and the X-substituent in formula (e) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the carbonyl-containing groups in formulas (g) and (j) and the X-substituent in formula (h) may be attached to the 1-, 3- or 4-position of the isoquinolinium ring. (2) For binding to a chelating agent with at least one -COOH functional group under replacement of a hydrogen atom from at least one of the aforementioned -COOH groups with one of the following [QC<+>] groups: (a ) When there are one or two -COOH groups to be derivatized: wherein the alkylene group is straight chain or branched and may contain 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the RQ radicals may be the same or different; Z' is C-pCg straight chain or branched alkylene, preferably C1-C2 straight chain or branched alkylene; Q is -O- or -NH-; R 1 is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C^-C^alkyl, or X is -CH=NOR'" wherein R'" is H or C^-C^ alkyl; The X-substituent in formula (ii) and the carbonyl-containing groups in formulas (i) and (iii) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; The X-substituent in formulas (v) and the carbonyl-containing groups in formulas (iv) and (vi) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the X substituent in formula (viii) and the carbonyl-containing groups in formulas (vii) and (ix) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. (b) Alternatively, when there is only one -COOH group to be derivatized:

'~ x iv

where j is the skeleton of a sugar molecule; n is a positive integer corresponding to the total number of -OH functions in the sugar molecule from which the said skeleton is derived; nV is a positive integer which is one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of the structures (xii), (xiii) and (xiv) can independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group, the residue being characterized by the absence of a hydrogen atom from which said -COOH functional group in the chelating agent; and each in each of structures (x) and (xi) may independently be hydroxy,

wherein the alkylene group is straight chain or branched and may contain 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups can be the same or different and the RQ radicals can be the same or different; D' is defined as having the structure (xii), (xiii) and (xiv); R 1 is C 1 -C 4 alkyl,

C^-C^haloalkyl or C2~ C10 ara^ Y^ ' 0<3 ^e depicted carbonyl-containing groups may be attached to the 2-, 3- or 4-position of the pyridinium or quinolinium ring, or at the 1-, 3 - or the 4-positions of the isoquinolinium ring; with the condition that at least one R'^ in each of the structures (x) and (xi) is

wherein the alkylene, R , p and R 1 and the position of the carbonyl-containing groups are as defined above; and with the further proviso that when more than one of the R'^ radicals in a given compound are the above-mentioned carbonyl-containing groups, all such carbonyl-containing groups in the compound are equal. (3) For binding to a chelating agent with at least one -NH- functional group that is part of an amide or imide structure or at least one primary or secondary amine functional group with a low pKa value replacing a hydrogen atom from at least one of the mentioned functional groups with one of the following [QC<+>] groups:

wherein the alkylene group may be straight chain or branched and contain 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups may be the same or different and the RQ radicals may be the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 3 aralkyl; R is hydrogen, C^-C^ alkyl, C^-Cg cycloalkyl, C-C7 haloalkyl, furyl, phenyl or phenyl substituted with one or more groups of halogen, lower alkyl, lower alkoxy, carbamoyl, lower alkoxy, carbonyl, lower alkanoyloxy , lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 1 is to the alkylene; X is -CONR'R" wherein R' and

R" are the same or different and are each H or C^-Cj alkyl, or X is -CH=NOR"' wherein R'" is H or C^-C^ alkyl; the carbonyl-containing groups in formulas (k) and ( m) and the X-substituent in formula (1) can be linked to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (n) and (p) and the X-substituent in formula (o) may each be attached to the 2-, 3-, or 4-position of the quinolinium ring; and the carbonyl-containing groups of formulas (q) and (s) and the X-substituent of formula (r) may each be attached to the 1-, 3 - or the 4-position of the isoquinolinium ring.

Here and throughout the preparation, the term "C-C-C-y haloalkyl" means C-C-C-alkyl substituted with one or more halogen atoms. Also here and throughout the preparation, the alkyl radicals, including the alkyl parts and the alkyl parts of other radicals, can be straight-chained or branched unless otherwise stated.

The expression "Rq is a radical identical to the corresponding

part of a natural amino acid" is assumed to be self-evident. Thus, for example, RQ can be hydrogen, as in glycine; methyl as

in alanine; - CE{CH^) 2 as in valine; -CH 2 -CH(CH 2 ) 2 as in leucine;

-CH2OH as in serine; -CHOH-CH3 as in threonine; -(CH2)2-SCH.j as in methionine; -CH2-CONH2 as in asparagine; -CH2CH2-CONH2 as in glutamine;

cysteine; -Cr^COOH as in aspartic acid; and -Cr^Cr^COOH as in glutamic acid. The term "natural amino acid" as used herein does not include dopa or L-DOPA. Preferred amino acids encompassed by the designation RQ include glycine, alanine, valine, leucine, phenylalanine, isoleucine, methionine, aspargine and glutamine.

The dihydro forms [DHC] corresponding to the above quaternary compounds are as follows:

(1') For groups (1) above:

wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R o is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formulas (a'), (b') and (c') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (d'), (e') and (f') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; R 1 is C 1 -C 7 alkyl, C 1 -C 1 haloalkyl or C 7 -C 10 aralkyl; R 3 is C to C 3 alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C 1 -C 7 alkyl, or X is -CH=NOR"' wherein R'" is H or C 1 -C 7 alkyl; the carbonyl-containing groups in formulas (a') and (c') and the X-substituent in formula (b') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (d') and (f') and the X-substituent in formula (e') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas (g') and (j') and the X-substituent in formula (h') may each be attached to the 1-, 3- and 4-position of the dihydroisoquinoline ring; (2') For group (2) (a) above: wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formulas (i'), (ii') and (iii') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (iv'), (v') and (vi') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; Z' is the C 1 -C 8 straight chain or branched alkylene, preferably the C 1 -C 8 straight chain or branched alkylene; is -O- or -NH-; R 1 is C 1 -C alkyl, C 1 -C 1 haloalkyl or C 1 -C 4 aralkyl; R 1 is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C^-C^ alkyl or X is -CH=NOR"' wherein R'" is H or C^-- C^ alkyl; The X-substituent in formula (ii') and the carbonyl-containing group in formulas (i') and (iii') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; The X-substituent in formula (v') and the carbonyl-containing group in formulas (iv') and (vi') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the X-substituent in formula (vii') and the carbonyl-containing groups in formulas (vii') and (ix') can each be linked to the 1-, 3- or 4-position of the dihydroisoquinoline ring;

(3') From group (2) (b) above:

wherein the alkylene group is straight chain or branched and 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formula (xii') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formula (xiii') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; f » is the skeleton i

a sugar molecule; n<1V>is a positive integer corresponding to the total number of -OH functions in the sugar molecule from which the skeleton is derived; nv is a positive integer one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of the structures (xii'), (xiii'), (xiv') and (xiv" ) can independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group, wherein the residue is characterized by the absence of a hydrogen atom from the said -COOH functional group in the chelating agent; and each R. in each of the structures (x') and (xi') may independently be hydroxy,

wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R o is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line is as defined for structures (xii') and (xiii'); D' is as defined by structures (xii'), (xiii'), (xiv') and (xiv" ); R^ is C1~C7alkyl, C^-Cy haloalkyl or C^-C^ q aralkyl; and the depicted carbonyl groups may be attached to the 2-, 3-, or 4-position of the pyridinium ring or the quinolinium ring or, unless otherwise indicated, at the 1-, 3-, or 4-position of the isoquinolinium ring; with the condition that at least one R^ in each of the structures (x') and (xi') is in which the alkylene, R, p, R^, the dashed lines and the position of the carbonyl-containing groups are as defined above; and with the further condition that when more than one of the R^ radicals in a given compound are the above-mentioned carbonyl-containing groups, then all these carbonyl-containing groups in the said compound are identical; (4') For group (3) above:

wherein the alkylene group is straight chain or branched and contains from 1 to 3 carbon atoms; RQ is a radical identical to the corresponding part of a natural amino acid;

p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups are the same or different and the RQ radicals are the same or different; R is hydrogen, C^-C^alkyl, C^-Cg cycloalkyl, C^-C^ haloalkyl, furyl, phenyl or phenyl substituted with one or more groups halogen, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy , lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio,

lower alkylsulfinyl or lower alkylsulfonyl; the dashed line in formulas 8k'), (1') and (m') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (n'), (o') and (p') indicates the presence of a double bond in either

the 2- or 3-position of the dihydroquinoline ring; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 aralkyl; R 1 is C 1 -C alkylene; X is -CONR'R" wherein R' and R" , which are the same or different, are each H or C₁-C₁ alkyl, or X is

-CH-NOR'" wherein R'" is H or C₁-C₁ alkyl; the carbonyl-containing groups in formulas (k') and (m') and the X-substituent in formula (1') may each be linked to the 2-, 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (n') and (p') and the X-substituent in formula (o') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas

(q') and (s') and the X substituent in formula (r') may each be attached to the 1-, 3- or 4-position of the dihydroisoquinoline ring.

The hitherto preferred dihydropyridine - pyridinium salt redox carrier types in accordance with the invention are those in which p is 0 or 1, most preferably 0; the alkylene, when present (ie, p= 1 or 2), is -Cf^-; R , when present (ie p = 1 or 2), is H, -CH3<-CH(CH3)2,

-CH2-CONH2 or -CH2CH2~CONH2; R , when present,

is -CH 2 ; R 1 , when present, is -CH 2 CH 2 ~; X, when present is -CONH2; the depicted carbonyl-containing groups in formulas (a) and (c) and the X substituent in formula (b) are attached at the 3-position; the depicted carbonyl-containing groups in formulas (d) and (f) and the X substituent in formula (e) are attached at the 3-position; the depicted carbonyl-containing groups in formulas (g) and (j) and the X substituent in formula (h) are attached at the 4-position; Z', when present, is C- or C 3 straight or branched alkylene;

Q when present is -NH-; The X-substituent in formulas

(ii) and (v) and the depicted carbonyl-containing groups in formulas (i), (iii), (iv) and (vi) are attached at the 3-position; The X substituent in formulas (viii) and the depicted carbonyl-containing groups in formulas (vii) and (ix) are attached at the 4-position; and the depicted carbonyl-containing groups comprised by formulas (x), (xi), (xii), (xiii) and (xiv) are in the 3-position of the pyridinium or quinolinium ring and in the 4-position of the isoquinolinium the ring; all R'^ in structures (x) and (xi) are -OH with the exception of one R'^ in each structure which must be the carrier moiety; all A in structures

f N

(xii), (xiii) and (xiv) are -OH; \ » is the skeleton of a glucose molecule; R in formulas (k), (1) and (m) is hydrogen, methyl or CCl 2 ; and the depicted carbonyl-containing groups in formulas (k) to (s) are in the 3-position of the pyridinium ring or quinolinium ring and in the 4-position of the isoquinolinium ring, and the corresponding dihydro types.

Particularly preferred dihydropyridine ^ ^pyridinium salt redox carrier types are the quaternary compounds of group (1), structures (a), (b), (d), (e), (g) and (h); the compounds of group (2), structures (i), (ii), (iv), (v), (vii), (viii), (x) and (xii); and the compounds of Group 3, structures (k), (1), (n), (o), (q) and (r); and the corresponding dihydro forms, most particularly when they contain the preferred structural variables identified in the preceding paragraph.

The following synthesis schemes illustrate different methods for the preparation of the carrier-containing chelating agent precursors of formula (I), to the corresponding carrier-containing chelating agents of formula (II) and to the corresponding carrier-containing radiopharmaceutical compounds of 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 primarily localized materials whose radionuclide content is imaged by radiation detection means.

Scheme 1 above thus illustrates a typical synthesis route for compounds in which the bond between the carrier part and the chelate part is through a -COOH function in the chelating agent. In the first step, the alcohol reaction component can generally be represented as HO-Z-I, where Z' is c^_cg straight chain or branched alkylene; in the second step, the depicted reaction component, the nicotine amide, could easily be replaced by picolinamide, isonicotinamide, 3-quinoline carboxamide, 4-isoquinoline carboxamide or the like.

(3-quinoline carboxamide and 4-isoquinoline carboxamide can be prepared in a known manner, e.g. by treating the corresponding acids with ammonia). Other process variations will be apparent to the person skilled in the art, especially from the teaching in the previously mentioned international application PCT/US83/00725.

Such an alternative to form 1 is depicted in form 2.

In the first step of Scheme 2, the alcohol reaction component (prepared by reacting 2-iodoethanol with nicotinamide) could contain a shorter or longer alkylene bridge (C^-Cg) and shown and the pyridinium moiety could be replaced by an equivalent pyridinium support , produced in an analogous way. Thus, e.g. in the first step an alcohol with formula

wherein n = 1-8, preferably 1-3, is reacted with 1_ or another -COOH-containing chelating agent or precursor thereof. Alternatively, an α-alcohol of the formula (prepared by reacting nicotinic acid with 1,2-propylene glycol in the presence of dicyclohexylcarbodiimide) or a positional isomer or homolog thereof or a corresponding derivative of quinoline carboxylic acid or an isoquinoline carboxylic acid can be quaternized , e.g. by reaction with methyl iodide, and is used in place of the alcohol reaction component shown in Scheme 2. As a further variation, bromoglucose can be reacted with nicotinamide, picolinamide or isonicotinamide or the appropriate quinoline carboxamide or isoquinoline carboxamide to give a starting alcohol of formula

which can be used in place of the alcohol reaction component used in the first step of Scheme 2. Even more variations would include reaction between nicotinic acid or other suitable pyridine ring-containing acids with a suitable di- or polyhydroxy compound such as ethylene glycol, propylene glycol, inositol or a simple sugar, linking the resulting intermediate via its free hydroxyl group(s) to the carboxylic acid function of the chelating agent or precursor therefore, and then quaternizing this intermediate.

Schemes 3 and 4 above illustrate the type of procedure used to prepare compounds in which the bond between the carrier moiety and the chelate moiety occurs over a

-NH2or -OH function in the chelating agent or

the precursor thereof. The activated ester of nicotinic acid, 16, can of course be replaced by another activated ester of this or another similar pyridine ring-containing acid. Equivalent activated esters, e.g. an ester in which

will be apparent to the expert. The production of these esters takes place according to known procedures, e.g. by reacting the acid chloride or anhydride of the acid in the presence of DCC or with N-hydroxysuccinimide or another alcohol, then the product is quaternized, e.g. with methyl iodide or dimethyl sulfate.

Scheme 5 illustrates a further possible method when the bond between the carrier part and the chelate part is above one

-0H function in the chelating agent or its precursor. The first step in this sequence is described in Fritzberg US Patent No. 4,444,690. The resulting ethyl ester 3_0 is then reduced to the corresponding alcohol using a suitable reducing agent, e.g. LiAlH^. The reduction thus introduces a -Ct^OH function instead of the acid function in 1_. Other -COOH-containing chelating agents or their precursors can be similarly converted to the corresponding -CH^OH-containing compounds, which can then be derivatized to the carrier-containing parts as generally described above. Such a derivatization is shown in scheme 5. The transformations 31 —> 32 —v 33 —» 34 are parallel to reactions shown in scheme 2 above as well as in the Fritzberg patent. The carrier-containing part can be easily introduced into the structure after obtaining 3_4 wood

using a number of methods, e.g. by using the activated quaternized ester 17 used in Schemes 3 and 4 or other activated ester; or by reaction with bromoacetyl chloride, followed by reaction with nicotinamide, isonicotinamide, 3-quinolinecarboxamide, picolinamide, 4-isoquinolinecarboxamide or the like, to form 3_6 or a similar derivative. Subsequent reduction to the dihydropyridine form as described herein and in International Application No. PCT/US83/00725 can be carried out separately, or it can be carried out more simply simultaneously with the reduction of technesium to an appropriate oxidation state.

Scheme 6 illustrates a method which is particularly useful when the bond between the carrier part and the chelate part is above one

-NH function that is part of an amide or imide or a primary or secondary amine with a low pKa value. Conversion of an ester group to the corresponding amide is carried out with an excess of ammonium. Then the chelating agent precursor 4_2 with a -CONP^ functional group is subjected to N-hydroxyalkylation, e.g. by reaction with an aldehyde [e.g. formaldehyde, benzaldehyde, acetaldehyde or chloral(C13CCH0)]; thus, e.g. in the case of chloral, the CONf^ group becomes a function

and thus forms a suitable bridging group. The resulting compound is then subjected to any method described herein or in said PCT application for attachment of the support to an -OH function. Such a method, e.g. by reacting the alcohol with nicotinic acid in the presence of dicyclohexyl carbodiimide, is shown in scheme 6.

Scheme 7 illustrates a process in which the -NH group to which the carrier is to be attached is part of an imide structure. The earliest steps in this scheme are described in the above-mentioned Fritzberg patent. 5_1 is then reacted with an excess of ammonia to form the corresponding succinamide which, when heated, loses ammonia to give the succinimide 52.

This intermediate is then reacted with an aldehyde, as generally described in the previous section, and the resulting -OH-containing group is then derivatized, also as described in the previous section.

Form 8 illustrates a further alternative to forms

1 and 2; 3,4-diaminobenzoic acid is discussed as a starting material for chelating agents in the Fritzberg patent. Scheme 8 follows the reaction sequence in scheme 2 and could be varied in any of the many ways described in connection with scheme 2 above. Furthermore, could 5_? alternatively, the reactions shown in forms 5 and 6 and/or discussed in connection with these forms are submitted; ie the -COOH group could be converted to a -CB^OH group or a -CONP^ group and then derivatized as shown in and discussed in connection with these schemes.

Schemes 9, 12 and 14 above illustrate typical conversion of a carboxylic acid ester group to the corresponding amide (-CONP^); reduction of the amide function to the corresponding amine (-CF^Nf^); reaction of the -NH^ group with an activated ester of nicotinic acid; quaternization with methyl iodide; and reducing the resulting quaternary compound of formula (I) to the corresponding dihydro compound of formula (II), or converting (I) directly to the radiopharmaceutical compound of formula (III). These processes can be varied as discussed in connection with forms 3, 4 and 5 above.

Schemes 10 and 15 above illustrate typical conversion of an alcohol (-CP^OH) obtainable from the corresponding carboxylic acid ester, to the corresponding nicotinoyl ester; reaction of the ester derivative with methyl iodide to give the desired quaternary compound of formula (I), and reduction to the corresponding dihydro compound of formula (II) or conversion directly to the corresponding radiopharmaceutical compound of formula (III). For process variations see the discussions for forms 3, 4 and 5

in the foregoing.

In Scheme 11 above, a typical method of introducing a longer alkylene chain between an atom involved in forming the chelate structure and a free-standing NP^ group to be attached to the support moiety is shown. As pictured

in this scheme, a secondary amino group ^NH is reacted with a halogen alkamide, e.g. BrCf^CONr^/the hydrogen in ^NH is replaced by -Cr^CONI-^. Reduction of the amide gives the corresponding ^ NCP^CI^Nr^-f orb compound. This amine can then be reacted with an activated ester of nicotinic acid, followed by quaternization and reduction as in the other schemes. For variations see especially forms 3, 4 and 5 above. Schemes 13 and 16 illustrate further methods for extending the alkylene chain, the chain here being interrupted by one or more oxygen atoms. Thus, a -Cr^OH group is typically converted to the corresponding lithium salt and then reacted with an iodalkanol, e.g. ICf^CH-^OH, to convert

-CH20-Li<+> group to a -CH2OCH2CH2OH group. [Of course, the chain can be lengthened by using an iodo alcohol with a longer chain, or by repeating the two steps just described

(in which case additional intercalated oxygen atoms would be introduced)]. The group -CH2OCH2CH2OH is then converted to the corresponding nicotinic acid ester which is then quaternized to form the corresponding quaternary salt. Again, the reaction forms can be varied as discussed in connection with forms 3, 4 and 5 above.

Scheme 17 above shows the reaction between a -NH2~ group with an activated ester of nicotinic acid, followed by quaternization. The resulting quaternary compound of formula (I) is then reduced as shown in the other schemes.

Many of the earliest steps in the reaction schemes parallel reactions described in Fritzberg US Patent No. 4,444,690. See e.g. the conversion of _7 to 30

in scheme 10, conversion of 3_0 to 40 to 41 in scheme 12, conversion of 111 to 1.12 to 113 to 1JL4 in scheme 13

etc.

Scheme 18 above, like scheme 11 which has already been discussed, shows another typical method for introducing a longer alkylene chain between the nitrogen atoms.

Here, the secondary amino group ^NH is converted to the corresponding ^NCH2CH2CH2NH2~ group. The resulting amine can then be reacted with an activated ester of nicotinic acid, followed by quaternization and reduction as in the other schemes. As a preferred alternative in this and many of the other reaction schemes depicted herein, the quaternary chelating agent precursor in accordance with the invention can be prepared directly from the reaction between the corresponding amine and a quaternized activated ester of nicotinic acid. Other variations will appear, e.g. from forms 3, 4 and 5 above.

Form 19 represents an alternative route to the derivatives

which is obtained according to scheme 1. It is clear that this scheme can be varied in a number of ways, particularly in the fourth step, where nicotinamide could be replaced by another amide

(e.g. one of those discussed in connection with form 1)

and where IC^C^OH could be replaced by another compound of the type I-Z'-OH in which Z' is C-^-Cg straight chain or branched alkylene.

Scheme 20 illustrates an alternative route to the derivatives in scheme 8. This scheme represents a particularly attractive synthetic route to the protected quaternary derivative 6_2. Furthermore, the intermediate 17_6 can be varied as discussed in connection with scheme 19. This process can also be adapted to the preparation of derivatives of other -COOH-containing chelating agents,

e.g. those in forms 1 and 2.

In scheme 21, the intermediate 179, prepared as in scheme 20, is used for the production of even further compounds in accordance with the invention derived from 3,4-diaminobenzoic acid.

Form 22 illustrates a further variation of the procedure

in scheme 8. Scheme 22 can easily be adapted to the preparation of other derivatives in accordance with the invention. See for this e.g. the discussions in connection with forms 8 and 20 above.

In form 23, two very advantageous alternatives are depicted

routes to the quaternary salt 7_6 in Scheme 9. These alternative routes use the quaternary activated esters of nicotinic acid to prepare the quaternary derivative 7_5 directly from the corresponding primary amine 7_4. Use of either the quaternary succinimidyl or phthalimidyl intermediate

(17 or 19_1) is illustrated. Other quaternary activated esters for use in this fraction will be apparent from the various processes described herein. After formation of the quaternary compound of formula (I) such as e.g. 7_6, the process in scheme 9 can then be used for the production of the other derivatives in accordance with the invention.

Scheme 24 depicts yet another highly advantageous alternative route to the quaternary salt 76 of Scheme 9. In this particularly preferred scheme, a protecting group is introduced prior to the introduction of the carrier function. The protecting group is then removed prior to the reduction of the quaternary function to the corresponding dihydro form. In the case of the chelating agent shown in this scheme, the reaction with acetone protects both the secondary amino functions and the thiol functions by forming thiazolidine structures so that these functions do not interfere during the addition of the carrier moiety . Then the secondary amino groups and mercapto groups are regenerated by reacting the protected intermediate with mercuric chloride in an organic solvent such as methanol, advantageously at room temperature, and then cleaving the resulting complex with hydrogen sulfide. See e.g. British Patent No. 585-250 which uses such a procedure for the preparation of esters of penicillamine. After preparation of the quaternary salt 76 in this way, the process in scheme 9 can be used for the preparation of the other derivatives in accordance with the invention. Variations in the procedure used, e.g. as discussed in connection with scheme 23, can be used to obtain further derivatives in accordance with the invention.

Scheme 25 represents an alternative route to the compounds obtained via Scheme 14. This route uses the preferred route of introducing the carrier moiety in its quaternary form and can be easily adapted to the preparation of derivatives of other -COOH-containing chelating agents and/or the introduction of other carrier moieties discussed herein.

In form 26, a process for connecting a

function or analog carrier part of a

freestanding primary amino function in a chelating agent. This process utilizes the thiazolidine structure to protect the secondary amino and thiol functions of the particular chelating agent depicted, as fully discussed in connection with Scheme 24 above.

An alternative route to the derivatives depicted in Scheme 26 is

shown in Scheme 27 in which the primary amino group in the protected primary amine is first converted to the corresponding -NHCO-R^-Br group which is then reacted with nicotinamide similarly to give the protected quaternary intermediate.

Scheme 27 depicts a process for the preparation of carrier-containing derivatives of yet another type of chelating agent. The desired chelating agent in this case contains oxime functions which are introduced after the quaternary form of the carrier has been attached. Derivatization of yet another type of chelating agent is depicted in

Form 29.

Similar schemes can be shown for the preparation of the other derivatives in accordance with the invention. The steps of introducing and removing protecting groups are included only when necessary. Also the order of steps can be changed. In particular, quaternization can take place earlier in the reaction scheme, of course depending on the other special compounds involved. Other reaction schemes, reaction components, solvents, reaction conditions etc. will be clear to the person skilled in the art. As far as the quaternary derivatives are concerned, when an anion which is different from the anion obtained is desired, the anion in the quaternary salt can also be subjected to anion exchange via an anion exchange resin or better by applying the method of Kaminski et al, Tetrahedron, Volume 34, Pages 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.

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 during a period of from about 10 min. to 2 hours, advantageously at atmospheric pressure. Typically, a large excess of reactant 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 sodium borohydride or lithium aluminum borohydride in a suitable solvent. Sodium dithionite reduction is advantageously carried out in an aqueous solution. The dihydro product of formula (II) is usually soluble in water and can thus be easily separated from the reaction mixture. In the case of the sodium borohydride reduction, an organic reaction medium is used, e.g. a lower alkanol such as methanol, an aqueous alkanol or another protic solvent. More typically, however, the quaternary compound of formula (I) is reduced in the same reaction mixture as the reduction of technetium to an appropriate oxidation state and gives the radiopharmaceutical compound of formula (III) in one step from the quaternary compound of formula (I). Further details of this one-step reduction are given below.

It will be clear from the foregoing that a large number of different 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 and C-C alkyl. or an R,, can be combined with i / neighboring ^ C- Rb c so that represents C=0; each R^ is independently selected from the group consisting of H and C^-C^ alkyl, or an R^ may be combined with adjacent C-R, so that represents is a radical of formula wherein each R 7 is independently selected from the group consisting of H and C C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group (C^-Cg) which may further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being adjacent to each other and also not adjacent to -A'-; X and n are as indicated for formula (I); m' is a number which when multiplied by n is equal to one; s is zero or one; -A'- is -NH-, -C00-, -O-. wherein R is C 1 -C 4 alkyl, or wherein R 8 is C 1 -C 4 alkyl; when -A'- is -NH-, -O- or - [QC<+>] is a radical of any of the formulas (a) to (i) above; when -A'- is -CONH- or

has the imide structure depicted above, then [QC<+>]

a radical with any of the formulas (k) to (s)

in the foregoing; and when -A'- is -COO- then [QC<+>] is a radical of any of the formulas (i) to (xiv) above. The salts of formula (Ia) preferably have the partial structure

or are positional isomers and/or homologues of the first two partial structures shown. It is also preferred that when each R7 is preferably H and (alk) is preferably a C1~C6alkYlene_aruPPe'or a C^-C^ alkylene group interrupted by an oxygen atom in the chain; and that when

(alk) is then preferably a C₁-C₁ alkylene group, or a C₁-Cg alkylene group interrupted by an oxygen atom in the chain. When HN^ ^ ^ NH is any of the preceding,

Q'

are then hitherto preferred values for -(alk)g -A'-, -COO-, -CH2O-, -CONH-, -CH2NH- and -CH2OCH2CH2O-. Preferred values for [QC<+>] in formula (Ia) are 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 R- and R^ are as defined by formula (Ia) and

HN NH

DH

is a radical with formula

wherein R^, (alk), s and -A'- are as defined by formula (Ia); when -A'- is -NH-, -O- or -N- wherein RQ is C.-C_

In ol/

8

alkyl, then [DHC] is a radical of any of the formulas (a') to (j " ) above; when -A'- is

v x-

-CONH— or wherein R 8 is C 1 -C 4 alkyl or

has the imide structure depicted above, then [DHC] is a radical of any of the formulas (k') to

(s" ) above; and when -A'- is -C00-, then [DHC] is a radical of any of the formulas (i') to (xiv" ) above. Preferred compounds of formula (Ila) are the dihydro derivatives corresponding to the preferred compounds of formulas (Ia).

Likewise preferred are the new radiopharmaceutical compounds in which a compound of formula (Ila) is chelated with a radioactive metal, especially with technetium. Particularly preferred radiopharmaceutical compounds have the formula

and R, is as defined by formula (Ia) and is a radical of formula

wherein R^, alk, s and -A'- are as defined by formula (Ia)

and [DHC] is as defined by formula (Ila) above; and the corresponding quaternary compounds "locked up" in the brain, especially compounds with technetium, which have the formula

wherein Rr, R,,, m', X and n are as defined by formula (Ia) and N ^^ JS is a radical of formula

Q

wherein R-,, alk, s, -A'- and QC<+> are as defined by formula (Ia) above. The preferred complexes of formulas (IIa) and (IVa) are those corresponding to the preferred derivatives of formulas (Ia) and (Ila).

Chelating agent precursors, chelating agents and radio-pharmaceutical compounds within the scope of the present invention can also be prepared by reacting

and then reacting the amino group in the obtained compound 29 with the carboxyl group in compounds such as e.g. the 2-oxo-propionaldehyde bis-(thiosemicarbazone) derivatives with a free carboxyl group. Examples of such compounds are 3-carboxy-2-oxopropionaldehyde-bis(N-methylthiosemicarbazone), which is a bifunctional chelating agent described in Yokoyama et al, US Patent No. 4,287-362. The COOH-containing chelating agents according to Yokoyama et al can also be derivatized as generally described above for the derivatization of COOH groups, e.g. as depicted in schemes 1 and 2. Furthermore, the chelating agents according to Yokoyama et al of formula 12 3 4 wherein R , R , R and R are each H or C₁-C₁ alkyl can first be converted to the corresponding esters (f .eg by replacing -COOH with - 00002^^) which can then be reduced to the corresponding alcohols (under replacement of -COOC2H5 with -CH2OH) or converted into the corresponding amides; the alcohols or amides can then be converted into the corresponding carrier-containing derivatives; see e.g. the discussion for forms 9 to 16 above. Other process variations will be clear from the many reaction schemes depicted above.

A further bifunctional chelating agent which can be easily converted into the redox system-containing chelating agent precursors, chelating agents and radio-pharmaceutical compounds in accordance with the invention is 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 easily converted to the derivatives according to

the present invention by reacting it with an activated ester of nicotinic acid or the like and quaternizing the resulting ester 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 radio-pharmaceutical compounds of formulas (III)

and (IV). See e.g. form 30 below.

Yet another group of known chelating agents

which is particularly suitable for conversion to the redox system-containing chelating agent precursors, chelating agents and radio-pharmaceutical compounds in accordance with the invention can be represented by formulas

12 3 4

wherein R , R , R and R are each H or C 1 -C 4 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 included in this group is known as amino-PTS, or AEPM, and has the structure

Amino-PTS can be converted into the derivatives in accordance with the present invention via the activated ester, as described above in connection with amino-DTS. See e.g. forms 33 below. The exact structure of the resulting technetium complex 22_4 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 for 2_24 is as follows.

(A similar structure could be depicted for the complex 16^5

in form 30).

A preferred alternative route to derivatives of amino-PTS, amino-DTS and the like is illustrated by Schemes 31 and 32

in the following. This pathway reacts a quaternized activated ester with the ligand containing a primary amino group to form the quaternary chelating agent precursor of formula

(I) in one step. Variations in this highly desirable single step, as well as in alternatives with two steps shown in schemes 30 and 33, will be apparent from the discussion of a number of reaction schemes depicted in the foregoing. It should also be noted that the introduction of the carrier moiety in its quaternary form, typically a quaternized activated ester such as 191 or 17, is generally advantageous over the two-step method, and any of Schemes 6 to 7 and 9 to 17 above can be easily modified accordingly.

In a similar way, the present carrier system can be incorporated into the structure of a new technetium-99m radiopharmaceutical compound whose chelate moiety is the residue of an amino- or hydroxy-substituted iminodiacetic acid, e.g. N-[3-(1-naphthyloxy)2-hydroxypropyl]-iminodiacetic acid. Such substituted iminodiacetic acid chelating agents are known and are described in Loberg et al US patent document no.

4,017,596. Such chelating agents can be protected to the required extent and then the trigonellinate or other carrier structure is introduced by reaction with -NH2 or

-OH group in the chelating agent.

Similarly, suitable chelating agents and their precursors which include a dihydropyriding—* pyridinium salt carrier system can be prepared by reacting compound 17 or the like with a chelating agent which is a substituted alkyl monophosphonic acid such as aminobutylphosphonic acid, 1,5-diaminopentylphosphonic acid and the like. Chelating agents of this general type are also known and are illustrated by the agents described in Kohler et al US Patent No. 3,976,762.

Additional chelating agents containing one or two carboxyl functions are described in Fritzberg US Patent No. 4,444,690. Support-containing technetium chelates corresponding to the Fritzberg chelates can be prepared as generally described above and as illustrated in schemes 1

and 2 in the foregoing.

Fritzberg US Patent No. 4,444,690 describes an interesting series of 2,3-bis(mercaptoalkanoamide)alkane 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 radiopharmaceutical compounds of formula wherein X is H or -COOH, and R and R ' is H or lower alkyl. Fritzberg's 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. Preparation of an analogue from 3,4-diaminobenzoic acid is also discussed by Fritzberg. Many of Fritzberg's synthesis steps can be adapted to the preparation of the derivatives of formula (I) in accordance with the invention in which instead of the -COOH group in Fritzberg's chelating agent there is a group (alk)g-A'-[OC<+>3 in which the structure variables are as defined in connection with formula (Ia) above. See e.g. forms 12, 13 and 16 above.

Radio-pharmaceutical compounds containing a dihydropyridine^=é pyridinium salt-carrier system can also be prepared using a new chelating agent precursor obtained by reacting the previously mentioned compound 29 with a nitrilotriacetic anhydride in pyridine as solvent according to to the known general procedure illustrated in Nunn et al US Patent No. 4,418,208.

The dicarboxyl-pyridinium salt obtained from the preceding reaction is obtained in purified form as follows: The volatile components of the reaction mixture are evaporated to an oily semi-solid on a rotary evaporator. A solution of 10% aqueous sodium hydroxide (weight/volume) is used to dissolve the oily semi-solid substance. The resulting solution is extracted with methylene chloride to remove the remaining pyridine from the aqueous phase. The pH of the aqueous phase is then lowered to a value of about 6 to 8. The resulting aqueous solution is then reduced in volume to about the volume of the original pyridine solution and about five times this volume of a saturated solution of picric acid is added to form a picrate derivative precipitate.

The picrate precipitate is washed with cold distilled water and then dissolved in a 10% aqueous solution of hydrochloric acid (volume/volume). The resulting solution is extracted with methyl chloride until there is no more yellow color in the aqueous phase or the methylene chloride phase. The resulting colorless aqueous phase is concentrated to approximately the volume of the original pyridine solution and then freeze-dried to provide the chelating agent in dry form. The dried chelating agent is then dissolved in ethanol and precipitated using the diethyl ether flow technique described in the following Example 4.

An additional useful chelating agent precursor can be prepared by reacting equimolar amounts of ethylenediamine tetraacetic acid and acetic anhydride in dry pyridine following the teachings of Nunn et al US Patent No. 4,418,208 and then reacting an additional equimolar amount of compound 29 to form the monoamide adduct. The tridentate chelating agent salt is obtained as described

immediately preceding.

The tridentate chelating agent precursor salt thus obtained is then reacted with 99m pertechnetate ion as described in subsequent Example 5, which reduces both the technetium and the pyridinium salt, to form a 1:1 ligand:radioactive metal ion complex drug delivery system in accordance with the invention. The thus formed complex is ionically neutral in that the five valences of the reduced technetium 99m metal are occupied by an oxygen atom and three carboxylate oxygens and the pyridinium ring is in its reduced, dihydropyridine form.

As mentioned, the production of the chelating agent precursors, chelating agents and radio-pharmaceutical compounds in accordance with the invention must be adapted to the particular starting material used, especially with regard to the presence of reactive functional groups in addition to the group to be attached to the carrier part . The step in which the carrier is introduced and the manner in which the carrier is introduced is determined accordingly. Often the carrier must be introduced in quaternary form at an early stage of the synthesis as illustrated above. When this is not necessary, it may be more desirable to convert a suitable starting material such as e.g. nicotinic acid anhydride with an Nf^- or OH-containing ligand or ligand precursor and quaternized in a later step, after coupling of the ligand (the chelating agent) and the 3-pyridinecarbonyl group.

The processes illustrated in the foregoing are intended to be illustrative only. E.g. many variations can be made in the chelating parts of the molecule, and these variations will of course affect the synthesis scheme, especially with regard to the necessity of introducing protective groups and their subsequent removal.

To further illustrate the present invention

and the advantages thereof are given in the following specific examples, it being understood that these are merely illustrative and not

in any way limiting.

Example 1: N-(t-butoxycarbonyl),N-(2-mercaptoethyl)glycyl-N'-(2-aminoethyl)homocysteinamide

(Compound 14 in Scheme 3)

N-(t-butoxycarbonyl),N-(2-mercaptoethyl)glycyl-homocysteine-thiolactone (13) is prepared as described in examples 1 and 2

in Byrne et al US Patent No. 4,434,151 and dissolves

(1.0 g; 3 mmol) in 25 milliliters of tetrahydrofuran (THF). The resulting solution is then cooled to about 0°C and ethyldendiamine (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 milliliters) is added to the "dried" solution components and the liquid components of the resulting mixture are removed again 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 thereby also indicates that the ethylenediamine has been largely removed and that N-(t-butoxycarbonyl),N The -(2-mercaptoethyl)-glycyl-N'-(2-amino-ethyl)homocysteinamide obtained in this way is essentially pure.

Example 2a: Succinimidyl nicotinate

(Compound 16 in Scheme 3)

Nicotinic acid (12.3 g; 0.1 mol) and N-hydroxysuccinimide

(11.5 g; 0.1 mol) is dissolved in 300 milliliters of hot dioxane. The mixture is cooled in an ice-water bath and dicyclohexylcarbodiimide (20.6 g; 0.1 mol) in 30 milliliters of dioxane is added. The reaction mixture is stirred with cooling for about 3 hours and then cooled for at least 2 hours. The precipitated dicyclohexylurea is removed by filtration, the solution is condensed under vacuum and the yellowish solids that precipitate are recrystallized from ethyl acetate. White crystals (14 g) of succinimidyl nicotinate are obtained (yield

63.6%). The structure sv product is confirmed by means of

NMR.

Example 2b: Succinimidyl trigonellinate

(Compound 17 in Scheme 3)

Succinimidyl nicotinate 16 (3.3 g; 15 mmol) is dissolved in 50 milliliters of dioxane and 3.7 milliliters (8.2 g; 60 mmol) of methyl iodide is added. The reaction mixture is refluxed for approximately 48 hours. The yellow crystals that precipitate during the reaction are removed by filtration, washed with ethyl ether and dried under vacuum at 40°C. Succinimidyl trigonellinate (5.2 g) is obtained (yield 96.3%). The structure of the av-product has been confirmed by NMR.

An improved method for the preparation of compound 17 is as follows:

A solution of 9.0 g (41 mmol) of the ester 16 and 11.6 g

(82 mmol) of methyl iodide in 40 ml of anhydrous acetone is heated in a pressure vessel under an argon atmosphere for 16 hours. The yellow precipitate that forms is removed by filtration. Yield 14 g of compound 17 which darkens at 170°C and melts at 197°C.

Example 3: N-(t-butoxycarbonyl), N-(2-mercaptoethyl)-glycyl-N'-[1-methyl-3-(2-N-ethyl)carbamoyl-pyridinium-iodide]homocysteinamide

(Compound 18 in Scheme 3)

N-(t-butoxycarbonyl),N-(2-mercaptoethyl)glycyl-N'-(2-aminoethyl)homocysteinamide --Compound 14-- (1.12 g, 0.003 mol) and succinimidyl trigonellinate --compound 17- -(0.70 g; 0.0025 mol) is dissolved in 25 milliliters of dry pyridine while stirring. An appropriately sized Dean-Stark "micro" trap with condenser is added to the reaction coupling and the solution is heated to maintain a temperature of 80°C until substantially all of the succinimidyl ester has been replaced. The pyridine is removed on a rotary evaporator using n-butanol as a "stripping agent" as previously described for the ethylenediamine removal. After the pyridine has been removed, the dried residue is treated by trituration with THF and the solid is removed by filtration and washed several times with THF so that drying does not occur by means of air suction. The solid thus obtained is then dried under vacuum to give the compound 18 N(t-butoxycarbonyl), N-(2-mercapto-ethyl) glycyl-N'-[1-methyl-3-(2-N-ethyl)carbamoyl- pyridinium-iodide]homocysteinamide.

Example 4: N-(2-mercaptoethyl)glycyl-N'-[1-methyl-3-(2-N-ethyl)carbamoylpyridinium iodide]-homocysteinamide

(Compound 19 in Scheme 3)

N-(t-butoxycarbonyl), N-(2-mercaptoethyl)glycyl-N'-[1-methyl-3-(3-N-ethyl)carbamoylpyridinium iodide]homocysteinamide --compound 18 -- (1/24 g ; 0.002 mol) dissolve with stirring in abs. ethanol (50 milliliters) and cooled to approximately 0°C in an ice-water bath. HCl gas is bubbled through the stirred solution for 15 min. and the solution is then stirred for a further 15 min. Diethyl ether (200 milliliters) is then added to the solution to precipitate the salt. The precipitate is filtered and washed with diethyl ether with care so that the precipitate is not dried by air suction. The solid is then dried under vacuum to give N-(2-mercaptoethyl)glycyl-N'-[1-methyl-3-(2-N-ethyl)carbamoylpyridinium iodide]homocysteinamide.

Example 5: Complex between N-(2-mercaptoethyl)glycyl-N'-[1-methyl-3-(N-2-ethyl)carbamoyl-1,4-dihydropyridyl]homocysteinamide and the oxotechnate-99m ion

(Compound 20 in Scheme 3)

N-(2-mercaptoethyl)-glycyl-N'-[l-netyl-3-(2-N-ethyl)carbamoyl pyridinium iodide]homocysteinamide—Compound 19 —

(89 milligrams; 0.17 millimoles) dissolve in 1.0 milliliters

abs. ethanol and 1.0 milliliters of 1N NaOH. A 1.0 milliliter

9 9m —

generator eluant of TcO^ (5 to 50 milliCurie) in salt solution is added. 0.5 milliliters of dithionite solution, prepared by dissolving 336, is then added

mg Na2S20^per milliliters of 1.0 NaOH, and the mixture is heated sufficiently to reduce both the technetium and the pyridine salt and form the complex between N-(2-mercaptoethyl)glycyl-N'-[l-methyl-3-(N-ethyl)carbamoyl-1,4 -dihydropyridyl]homocysteinamide and the oxotechnate-99m ion. The complex produced on

this way is buffered by adding 1.0 milliliters of IN

HCl and 4.0 milliliters of 0.1 molar Na^PC^, pH 4.5 buffer.

Example 6: Complex between N-(2-mercaptoethyl)glycyl-N'-[1-methyl-3-(N-2-ethyl)carbamoyl)-1,4-dihydroquinolyl]homocysteinamide and the oxo-technate-99m ion.

A radio-pharmaceutical compound linked to a carrier

based on a reduced, dihydroquinoline carrier such as e.g. the complex mentioned in the title can be prepared by following the steps outlined in Examples 1-5, but by replacing the nicotinic acid in Example 2a with an equivalent amount of 3-quinoline carboxylic acid.

Example 7: N-[2-(acetair.idomethyl)mercaptopropionyl]-

glycyl-N'-(2-aminoethyl)homocysteinamide

(Compound 25 in Scheme 4)

N-[2-(S-acetamidoethyl)mercaptopropionyl)-glycyl^homocysteine-thiolacetone (Compound 2_4 in Scheme 4), 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 milliliters of 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 is then obtained in a manner substantially similar to that described in Example 1 for the analogous compound.

Example 8: N~[2-fecetamidomethyl)mercaptopropionyl -

glycyl-N'-1-methyl-3-(2-N-ethyl)carbamoyl-pyridinium-iodide]homocysteinamide

(Compound 26 in Scheme 4)

The compound 26 in the synthesis core 4 is obtained in a manner analogous to that used in example 3 for the preparation of the compound 19, but the compounds 17 and 25 are used as starting materials.

Example 9: Complex between N-(2-mercaptopropionyl)-glycyl-N'-[1-methyl-3-(2-N-ethyl)carbamoyl-1,4-dihydropyridine]homocysteinamide and the oxotechnate-99m ion --

(Compound 27 in Scheme 4)

Compound 2_6 in example 8 (0.17 mmol) is dissolved in 1.0 milliliters of abs. ethanol and 1.0 milliliters of 1N NaOH. The complex in this example is then prepared in a manner analogous to that described for the complex in example 5. Here, the basic solution releases the 2-mercaptopropionyl group from its protective N-methyl-acetamido group, while the dithionite reduces both the pvridinium salt and others the technetium salt.

Example 10: 3,4-dithia-2,2,5,5-tetramethylhexane-

1,6-dione (Compound 68 in Scheme 9)

To a stirred solution containing 115.6 g (1.6 mol) of isobutyraldehyde 6_7 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 maintained at 30-45°C with stirring 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 6_8 in scheme 9.<1>H NMR(CDC13) 69 , 1 (s , 2 . CHO) , 1, 4[s,12,-C(CH3)2-] .

Example 11: Ethyl 2,3-(diammonium)propionate dichloride

(Compound 70 in Scheme 9)

To 10 g (0.07 mol) ethyl cyanoglyoxylate-2-oxime 6_9 is added 125 ml abs. ethanol, 15 g of hydrogen chloride gas and 1 g of platinum oxide. The mixture is hydrogenated using a Parr hydrogenation apparatus. 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 dichloride, i.e. compound 70 in scheme 9, is obtained in this way. Yield 5 g (35%), m.p. 164 - 166°C (lit. 164.5-165°C); ^ NMR(D2O) 6 4.5(m,3,-NCHCO-, -OCH2CH3), 3.5(m,2,-NCH2CH-), 1.3(t,3,-OCH2<CH>3) .

Example 12: 5,8-diaza-1,2-dithia-6-ethoxycarbonyl-3,3,10,10-tetramethylcyclodeca-4,8-diene

(Compound 71 in Scheme 9)

Procedure I

To 1.0 g (5 mmol) of the bisaldehyde 68 is added dropwise

a solution of 1.0 g (5 mmol) of the ester 70 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 has formed 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-tetramethylcyclodeca-4,8- dien,

i.e. the compound 7_1 in Scheme 9, with 5 3% yield (1 g),

. m.p. 98 - 99°C. IR (thin film) 3450, 1740, 1650 cm"<1>;

"""H NMR(CDC13) 6 6.9(m,2,C-N=CH-). 3 , 0-4 , 6 (m, 5 ,-OCH2CH3 ,

-NCH2CH-N-) , 1.5[ m, 15.2 ^C(CH3)2, -OCf^CH^].

Procedure II

To 1.0 g (5 mmol) of the bisaldehyde 6_8 in 10 ml of methanol, 1.0 g (5 mmol) of the ester 70 and 1 g (12 mmol) of sodium bicarbonate in 20 ml of a 50:50 volume-based mixture are added dropwise of methanol and water. The mixture is stirred at 0°C for 10 min., after which 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 out of 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 the compound 7_1 with m.p. and''"H NMR spectrum identical to the product from procedure I.

Procedure III

A solution of 8 g of the ester 70 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 68 in 25 ml of methanol. The reaction mixture is cooled in an ice bath after adding i

1 hour and then allowed to remain at room temperature for 1 hour. The reaction mixture is then placed in a deep freezer (-20°)

over the night. The solution is concentrated to one-third 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/carbonic acid 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 the compound 7_1 are formed on standing. Yield 7 g, m.p. 95 - 96°C. NMR and IR are as in procedure I.

Example 13: 6-carbamoyl-5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodeca-4,8-diene

(Compound 72 in Scheme 9)

Procedure I

A solution of 5 g of the ester 71 in 20 ml of tetrahydrofuran and 20 ml of aqueous ammonia is stirred at room temperature for 2 hours, after which it 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 72 in Scheme 9, 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>;<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(CH3)2].

Procedure II:

A solution of 5 g of the ester 71 in 20 ml of tetrahydrofuran, 20 ml of ethanol and 20 ml of aqueous ammonia (28%) is stirred at room temperature for 16 hours. Removal of the solvent leaves compound 7_2 as a white powder which crystallizes from toluene as white plates. Yield 4 g, m.p. 19 3 - 194°C. IR and NMR as in procedure I.

Example 14: 5-carbamoyl-5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane

(Compound 7_3 in Scheme 9)

To 3.7 g of the amide 7_2 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. 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 7_3 in Scheme 9 as fine white needles melting at 138 - 139°C. Yield 3 g.<1>H NMR(CDCl3) * 2.3-4.0 tm, 7,NCH2CH-N-, 2-NCH2-C (CH-j)-S- ] , 1, 8 (broadband, 2,

-CONH2), 1,3[m,14, C(CH3)2, -CNH-CH2~]»

Example 15: 5-aminomethyl-4,7-diaza-2,9-dimethyldecane-2,9-dithiol

(Compound 7_4 in scheme 9)

A solution of 1.8 g of the amide 7_3 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 at the reflux temperature for 20 hours. At the end of this time, the reaction mixture is first cooled and then saturated Na-K-tartrate solution is poured over. The aqueous phase is extracted with chloroform. The combined organic phase is then 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 74 in scheme 9;<1>H NMR (CDC13) 6 2,8[m,9,-NCH2CH-C(CH2)NH-, 2-NCH2~C(CH3)2S-],

1,5[m,14,>C(CH3)2,]-SH .

Example 16: 5,8-diaza-1,2-dithia-3,3,10,10-tetra-methylcyclodeca-4,8-diene

(Compound 8_7 in scheme 11)

To 3.15 g of the dialdehyde 6_8, 4.0 g of ethylenediamine is added while stirring and cooling over a period of 10 min. The resulting thick mass is stirred for a further period of 1 min. and then allowed to stand for 1 hour at room temperature and then cooled for 16 hours in a deep 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-tetramethylcyclodeca-4,8-diene, i.e. compound 8_7 in Scheme 11, as a white crystalline product melting at 168 - 170°C (lit. 162-164°C, 163-166°C).<1>HNMR(CDC13) 6 6.9(s,2,,

-HC=N-), 4.2,3.0(doublet of doublet, 2,2-CH2-CH2), 1.40 [ s , 6 ,-C (CH_3) 2~ ] . Analysis theoretical for C2.0C18N2S2: 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 17: 5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane

(Compound 8_8 in Scheme 11)

A solution of 0.5 g of 8_7 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. Then 10 ml of water is added and the mixture is heated 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 liquid solidifies on cooling. Flash chromatography (eluent hexanes/dichloromethane/- isopropanol 5:1:1 by volume) gives 5,8-diaza-1,2-dithia-3,3,10,10-tetramethylcyclodecane, i.e. compound 8_8 in scheme 11, as a solid which melts at 52 - 53°C. 1 H~NMR (CDCl 3 ) 6 3-2.1(m,10 ring protons) , 1.1,1.2(s,6 CH_3 , CH3) .

Example 18: N-[(4,7-diaza-2,9-dimercapto-2,9-dimethyl-dec-5-yl)methyl]nicotinamide

(Compound 15 in Scheme 9)

A solution of 9 mmol of the activated ester 16 in 30 ml of dimethoxyethane is added dropwise over a period of 1 hour to 8.4 mmol of the amine 7-4 in 70 ml of dimethoxyethane. Thin layer chromatography after 1 hour using a solvent system of petroleum ether/acetone/dichloromethane/isopropyl alcohol (10:5:5:1 by volume) indicates that a major component has been obtained. The solvent is removed by evaporation and the residue is treated with water. The resulting mixture is extracted with chloroform and dried over sodium sulfate. Removal of the solvent gives the desired product, compound 7_5 in scheme 9.

Example 19: 3-(N-[(4',7'-diaza-2',9'-dimercapto-2',9'-dimethyldec-5'-yl)methyl Jcarbamoyl}-1-methyl-pyridinium iodide

(Compound 7_6 in Scheme 9)

The compound 7_5 is reacted with methyl iodide according to

the general procedure described in example 2b above. Prepared in this way, the desired quaternary salt is obtained, i.e. in compound 76 in scheme 9.

Example 20: Complex formation

The general procedure in Example 5 can be repeated to convert the other quaternary salts of formula (I) into the corresponding radiopharmaceutical compounds, e.g. for conversion of compound 76 into complex 78, compound 8_3 into complex 8_5, etc.

Example 21; 5-aminomethyl-4,7-diaza-2,9-dimethyldecane-2,9-dithiol

(Compound 7_4 in Scheme 9)

To a slurry of 11 g of lithium aluminum hydride in 300 ml

dry tetrahydrofuran is added dropwise over a 2 hour period and under an argon atmosphere 13 g of the amide 7_2 in 150 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is heated under reflux for 30 hours,

and then saturated Na-K tartrate solution is 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 gives the desired amine, compound 7_4 in Scheme 9, as a viscous oil.

A sample of the thus obtained free amine is dissolved in diethyl ether and hydrogen gas is added. The white powder that separates is removed by filtration and purified from ethanol/water to give the corresponding hydrochloride salt melting at 225 - 228°C. -""H NMR (D2O) 3 , 3-4 , 2 (m, 9H, HCl, NH2CH2 ,

-HC1 NHCH_2) , 1, 5 [m, 12H, c (CH3) 2]. Theoretical analysis for<C>11<H>30<C1>3N3S2-

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 22: Compound 19_2 in scheme 24

A mixture of 1 g of the amine 74, 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, aqueous 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 (CHCl^/methanol, 2:1) indicates two main components with Rf values 0.13

and 0.73. The component with the lowest Rf value shows a positive ninhydrin test confirming that it is the desired primary amine 192, while the component with the higher Rf value is negative.<1>H NMR of the Rf 0.73 component (CDC1.J : δ 2.9, 2.5, 1.3-1.5.H NMR of the Rf 0.13 component (CDCl 3 ): δ 3.0, 2.8, 2.3. 1.2-1.7 The desired bisthiazolidine primary amine, compound 192 in Scheme 24 is thus obtained.

Example 23: Compounds 193 and 7_6 in scheme 24

The reaction between bisthiazolidone primary amine 192 and quaternized activated ester 17 or 191 gives the corresponding bisthiazolidine quaternary compound, i.e. in compound 19_3 in scheme 24, 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 76 in Scheme 24.

Example 24: Compound 8_1 in scheme 10

A solution of 7 g (3 mmol) of the ester 71 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, compound 81 in Scheme 10.<X>H NMR (CDCl1) 6 2.2-2.8, 3.5, 2.3, 1.5.

Example 25: Compound 8_3 in scheme 10

By following the general procedure in Example 22, but by

using an equivalent amount of the alcohol 8_1 in place of the amine 74 gives the bisthiazolidine alcohol, i.e. the protected counterpart of compound 81 in Scheme 10. This protected alcohol can then be subjected to the procedures detailed in Example 23 above to finally give the corresponding unprotected quaternary compound, compound 8_3 in Scheme 10.

Example 26: Compound 3_2 in form 5.

A solution of 17 ml of 2N lithium borohydride in tetrahydrofuran is added to 300 ml of dry tetrahydrofuran under an argon atmosphere. To this solution, add 10 g (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 a white powder that is very soluble in water, the corresponding primary alcohol, compound 3_2 in Scheme 5. Yield 2 g (24%); m.p. 85 - 90°C; 1 H NMR (acetone-d 6 ) δ 7-8, 4.15, 3.3-4.0.

Example 27: Compound 3_3 in form 5

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 10 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. and 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 5, is removed

by filtration and washed with water. Yield 1.2 g, m.p.

151 - 152°C; <1>H NMR (DMSO-dcb /acetone-dc) 6 7.4-8.3, 3.85, 3.1-3.6.

Example 28: Compound 168 in scheme 18

Cyanoacetic acid (8.5 g; 0.1 mol) and N-hydroxysuccinimide

(11.5 g; 0.1 mol) are combined in 150 ml of dry tetrahydrofuran. A solution of 20.6 g (0.1 mol) of dicyclohexylcarbodiimide in 50 ml of dry tetrahydrofuran is added dropwise to the cooled suspension over a period of 2 hours. The mixture is allowed to warm to room temperature overnight. The white precipitate that forms is removed by filtration and washed with 50 ml of tetrahydrofuran. The combined filtrates are concentrated to give 8 g (44% yield) of the ester 167. The product crystallizes from isopropyl alcohol as white needles, m.p. 140 - 142°C.

A solution of the ester 167 (0.62 g, 3.4 mmol) in 10 mL

dry dimethoxyethane is added dropwise to a stirred solution of the cyclic diamine 8_8 (0.8 g, 3.4 mmol) in 20 ml of dry dimethoxyethane at room temperature. The solution is stirred for a further 2 hours, after which it is allowed to stand for 16 hours. The dimethoxyethane is removed by rotary evaporation and the brown residue is suspended in water to remove a hydroxysuccinimide. The product 168 is removed by filtration and crystallized from toluene/hexanes as fine brown needles; yield 0.9 g (88%); m.p. 142 - 143°C; IR (thin film) 3450, 2250, 1675 cm"1;

<X>H NMR (CDCl 3 ): * 3.7, 2.4-3.6, 3.5, 1.3, 1.25. Analysis theoretical for C13H23N30S2: C, 51.79; H, 7.69; N, 13.94;

S, 21,27.

Found: C, 51.99; H, 7.12; N, 14.01; S, 21.34.

Example 29: Compound 169 in scheme 18

A solution of 3 g of the nitrile 168 in 50 ml of dry tetrahydrofuran is added dropwise over a period of 30 min. period to a stirred slurry of 1.2 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran under a nitrogen atmosphere. The pale yellow solution is heated under reflux for 7 hours and then stirred at room temperature for 50 hours. The slurry is hydrolysed with a saturated Na-K tartrate solution, the aqueous phase is extracted with dichloromethane and the combined organic extracts are dried over sodium sulphate. Rotary evaporation of the solution leaves the amine 169 as a viscous yellow oil.

Example 30: Compound 170 in scheme 18

A solution of the activated ester 16 (2 g, 9 mmol) in 30 mL of dimethoxyethane is added dropwise over a period of 1 hour to the amine 169 (2.6 g, 8.9 mmol) in 70 mL of dimethoxyethane. After one hour, thin layer chromatography (eluent: petroleum ether/acetone/dichloromethane/isopropyl alcohol, 10:5:5:1) indicates a major component with Rf 0.6. The solvent is removed by evaporation, the residue is treated with water and the mixture is extracted with chloroform and dried over sodium sulphate. Removal of the solvent leaves 170 as a viscous yellow mass, yield 2.1 g;<1>H NMR (CDCl3) 6 7.3-9.3,

2.6 - 3.6, 1.5.

Example 30: Compound 40 in scheme 19

To a mixture of 10 g of sodium bicarbonate in 50 ml of water and 200 ml of toluene, the ester TO (2 g, 0.01 mol) is added while cooling in an ice bath. Chloroacetyl chloride (5 g, 044 mol) solution is added dropwise and the solution is allowed to warm to room temperature. The organic phase is extracted with ethyl acetate, washed with ether and brine and then dried over magnesium sulfate. Removal of the solvent leaves 40 as a white mass; yield 2 g (70%); m.p. 85 - 87°C.<1>H NMR (CDCl3): δ 7.12, 7.6, 4.67, 4.2, 4.07, 3.75, 1.3.

Example 32: Compound 41 in scheme 19

A solution of the ester 40 (2 g, 9 mmol) in 20 ml of dry ethanol is prepared under argon. To this is added a solution of sodium thiobenzoate in dry ethanol (prepared from 0.45 g of Na in 20 ml of ethanol to form sodium ethoxide,

which is reacted with 2.5 g of 97% thiobenzoic acid). Precipitation takes place immediately. The reaction mixture is heated under reflux for 5 min. and then diluted with ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried over magnesium sulfate. Removal of the solvent leaves 4.1 g of a cream-colored white powder. Crystallization from toluene gives 2.4 g of white product, 41, m.p. 125 - 127°C

(Lit. 129.5 - 131°C). NMR is consistent with the structure.

Example 33: Compound 176 in scheme 19

A mixture of iodoethanol (7.5 g, 43 mmol), nicotinamide

(5.2 g, 43 mmol) and 150 ml of acetone are heated under reflux for 18 hours. The mixture is cooled and the product 176 is removed by filtration. Yield 1.5 g (12%); m.p. 87°C.

Example 34: Compound 127 in form 20

To a mixture of 10 g of potassium carbonate in 20 ml of water and

5 g (32 mmol) of 3,4-diaminobenzoic acid are added to 200 ml of toluene. To the cooled mixture is added 14.4 g (127 mmol) of chloroacetyl chloride in 10 ml of toluene over a period of 1 hour. After the addition is complete, the mixture is stirred at room temperature for 30 min. The brown product is removed by filtration and crystallized from ethanol. Yield 8 g (82%) of 177, m.p. 240 - 241°C.

Example 35: Compound 178 in scheme 20.

0.17 g of sodium metal is added to 25 ml of ethanol, followed by 1.1 g (7.4 mmol) of thiobenzoic acid. To the resulting yellow-brown solution is added 1.16 g (3.7 mmol) of the acid 127. The mixture turns yellow immediately and thickens. The mixture is diluted to 200 ml with dry ethanol and

heated under reflux for 2 hours. The product is removed by filtration and crystallized from isopropyl alcohol/tetrahydrofuran.

Yield 1 g (53%) of 128, m.p. 244 - 245°C.

Example 36: Compound 129 in form 20

500 ml of dry tetrahydrofuran are added to 15.2 g (0.03 mol) of the acid 128 and 3.45 g (0.03 mol) of N-hydroxysuccinimide. To the resulting suspension is added 6 g (0.03 mol) of dicyclohexylcarbodiimide in 50 ml of dry tetrahydrofuran over a period of 1 hour. The resulting mixture is stirred at room temperature for 16 hours. The white precipitate of dicyclohexylurea that forms is removed by filtration and the filtrate is concentrated under vacuum to give a brown product. Flash chromatography of a small sample (eluent: dichloromethane/acetone, 3:1) gives the ester

129, mp. 117 - 118°C.

Example 37: Compound 1.83 in scheme 21

A solution of 2-bromomethylamine hydrobromide (10.2 g,

0.05 mol) and nicotinamide (6 g, 0.05 mol) in 150 ml of dry dimethylformamide are heated at 140°C for 16 hours. The precipitate that forms is removed by filtration and washed with ether.

Yield 14 g (88%), m.p. 280°C (cleavage) of 183.

Example 38: Compound 75 in Scheme 9

A solution of the amine 7-4 (2 g, 7.5 mmol) and the activated ester 16 (1.65 g, 7.5 mmol) in 100 ml of dry dimethoxyethane is stirred at room temperature for 24 hours. The solvent is removed by rotary evaporation and the residue is treated with water. The viscous product is extracted with chloroform and dried over magnesium sulfate. Removal of the solvent leaves 75 as a viscous mass. NMR is consistent with the structure. The compound is used without further purification.

Example 39: Compound 7_6 in scheme 9

A solution of the amide 75 (0.5 g), 5 ml of methyl iodide and

20 ml nitromethane is stirred at room temperature for 7 days under argon. After the second day, a precipitate begins to form. The precipitate is removed by filtration and treated with acetone. Yield 150 mg of the quaternary salt 7_6, m.p. 210 - 215°C (dec) 1HNMR (DMSO-dg) 8.3-9.5, 4.5, 3.0-4.0, 1.2-1.5.

Example 40: Compound 7_7 in scheme 9

To a solution of 0.5 g (1 mmol) of the quaternary salt

76 in 10 ml of water, 0.25 g (3 mmol) of sodium bicarbonate and 0.61 g (3 mmol) of sodium dithionite are added. Ether

(50 ml) is added and the mixture is stirred under a nitrogen atmosphere for 30 min. while cooling in an ice-water bath. The aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate. In this way, the dihydro-derivative TJ is obtained.

Example 41: Compounds 8_1 and 8_la in scheme 10

A solution of the ester 7_1 (10 g, 35 mmol) in 100 ml of dry tetrahydrofuran is added dropwise over a period of 30 min. to a slurry of lithium aluminum hydride (4 g, 94 mmol) in 300 mL of tetrahydrofuran while cooling in an ice bath. The slurry is then heated under reflux for 24 hours. The reaction is stopped with saturated Na-K tartrate solution and then 3N hydrochloric acid and finally sodium carbonate are added. The aqueous phase is extracted with chloroform. The combined organic phase is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent leaves the alcohol 81 as a viscous mass. The product is taken up in ether saturated with hydrogen chloride, while cooling in an ice bath. Yield 6 g of the salt 8_la, m.p. 190 - 191°C.

NMR and elemental analysis are consistent with the structure.

Example 42: Compound 19.0 in form 2 3

To 24.6 g (0.17 mol) of nicotinic acid and 32 g (0.19 mol) of N-hydroxyphthalimide in 300 ml of tetrahydrofuran is added 41 g of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran over a period of 2 hours. The reaction mixture is stirred at room temperature for 24 hours. The white precipitate of dicyclohexylurea that forms is removed by filtration. The filtrate is concentrated leaving a white mass which is crystallized twice from ethyl acetate, once from isopropyl alcohol and again from ethyl acetate. The different portions of 190 obtained in this way melt at 132 - 135°C and 148 - 150°C. <1>H NMR (CDCl3)6 8.4 - 9.5 (m, 3H, Py-H); 7.95 (s, 4H, Ar-H); 7.5 - 7.7 (m, 1H, Py-H).

Example 43: Compound 191 in form 2 3

A solution of the ester 190 (5 g, 18.6 mmol) and methyl iodide (6 g, 42.4 mmol) in 40 ml of acetone is placed in a pressure bottle and heated in an oil bath (bath temperature 65°C) for 12 hours. The product is removed by filtration. Yield 4.5 g (59%) of the quaternized activated ester 191. The product darkens at 175°C and melts at 185°C.<1>H NMR (DMSO-dg) 6

8.2-9.9 (m, 4H, Py-H); 8.1 (s, 4H, Ar-H); 4.52 (s, 3H, N_CH 3 ).

Example 44: Compound 180 in form 21

To the activated ester 129 (9 g, 14.9 mmol) in 100 ml of dimethoxyethane is added ethanolamine (0.918 g, 15.4 mmol) in 50 ml of dimethoxyethane. The reaction mixture is stirred at room temperature for 48 hours. The white precipitate formed is then removed by filtration. Evaporation of the solvent gives a further 2 g of product. Yield 4 g (49%) of 180, which melts at 205 - 210°C. 1 H NMR (DMSO-dg): δ 7.5-10, 4.8, 3.3-3.7, 3.3.

Example 45: Compound 129 in form 25

The acid 128 (8g) and N-hydroxysuccinimide (1.8g) are combined

in 200 ml of tetrahydrofuran. To this suspension is added dicyclohexylcarbodiimide (3.16 g) in 25 ml of tetrahydrofuran over a period of 2 hours. The mixture is then stirred at room temperature for 16 hours. The white precipitate is removed by filtration and the filtrate is evaporated under vacuum. The product, the activated ester 129, is crystallized from toluene.

Example 46: Compound 1.94 in form 25

A solution of 0.14 g (8 mmol) of ammonia in 150 ml of dimethoxymethane is added to 4.7 g (8 mmol) of the activated ester 129. The reaction mixture is stirred at room temperature for 16 hours. The solution is concentrated under vacuum to give

3 g of the amide 194 as a white product.

Example 47: Compound 76 in scheme 23

To 6.12 g (23 mmol) of the amine 74 in 100 ml of anhydrous dimethylformamide is added dropwise over a period of 4 hours, 2.2 g (6 mmol) of the activated ester 17 in 80 ml of anhydrous dimethylformamide. The reaction is carried out at -47°C (acetonitrile/carbonic acid ice) under an argon atmosphere. The reaction mixture is stirred for a further 2 hours at -47°C and then placed in a deep freezer (approximately -20°C) overnight. The dimethylformamide is removed under vacuum. 150 ml of xylene is added to the residue and the solvent is removed again under vacuum. The residue is taken up in 75 ml of benzene and triturated with petroleum ether, after which a gummy product is separated. This process is repeated twice. The resulting gummy residue is suspended in the same solvent. High pressure liquid chromatography HPLC data indicates a major peak with some amine present. Flash chromatography (eluent-ethanol) of a small sample of the reaction mixture gives a product which by HPLC indicates two components, the remaining amine and the desired quaternary salt 16.

Example 48: Compound 16 in form 23

To 1.5 g (5.7 mmol) of the amine 74 in 20 ml of dimethylformamide is added 0.5 g (1.4 mmol) of the quaternary compound 19.1 in 20 ml of dimethylformamide. The reaction is carried out at -47°C over a 2 hour period under an argon atmosphere. The solvent is removed under vacuum and the residue is treated five times with benzene/petroleum ether. HPLC data again indicate that most of the amine has been removed leaving the desired quaternary salt 16.

Example 49: 1-methyl-3-[N-{£3-{4-[1',2'-bis(4''-methyl-thiosemicarbazono)prop-1'-yl]-phenyl)ethyl 1" J] carbamoylJpyridinium-j odid hemihydrate

(Compound 2.22 in Scheme 32)

Amino-PTS hydrochloride monohydrate (100 mg, 0.238 mmol) i

dry pyridine (15 mL) with the quaternized activated ester 19.1 (200 mg, 0.488 mmol) is heated under gentle reflux. After 2 hours no amino-PTS remains and the mixture is set aside to cool. Volatile components are removed under vacuum and the residue is washed with water (10 ml) and taken up in chloroform (40 ml). The aqueous layer is re-extracted with chloroform (20 ml) and the combined, dried (mg SO 3 ) organic layers are evaporated to dryness leaving an orange colored oil. The oil is absorbed in a minimum quantity while warm

ethanol. Trituration treatment results in the precipitation of a pale yellow powder. Yield 75 mg (51%) of the quaternary salt 222, which melts at 214 - 216°C. IR (KBr) 3000-3600, 1670, 1535, 1470 cm<-1>;<1>H NMR (DMSO-doc)6 9.5, 8.1-9.4, 7.1-7.6, 4.5, 2.3-3.8. Analysis calculated for C22H29N8IOS<*>1/2H2O: C, 42.51: H, 4.86; Mon, 18.01, Sat, 10.31.

Found: C, 42.70; H, 4.77; N, 17.74; S, 10.42.

Example 50: 1-{{ 4'-{3-[N-(1"-methyl-1", A"-

dihydropyridin-3" -yl)carbonylamino]-ethyl)phenyl))propane-1,2-dione-bis(4-methylthiosemicarbazone), hydrated with 1/4 mol H2O

(Compound 222 in form 32)

The quaternary salt 222 (104 mg, 0.17 mmol) in ice-cold deaerated water (30 mL) is treated with sodium bicarbonate

(140 mg, 1.7 mmol) and sodium dithionite (30 mg, 1.7 mmol). Ethyl acetate (50 mL) is added to the stirred solution

and nitrogen gas (washed free of oxygen by passing through a basic pyrogallol solution) is bubbled through the reaction mixture. After 45 min. the organic and aqueous layers are separated and the aqueous layer is re-extracted with ethyl acetate (30 ml). The combined organic layers are dried over magnesium sulfate and the volume of solvents is reduced to half by evaporation under vacuum. The product is eluted through a short column of neutral alumina (Aldrich, 150 mesh, Brockman 1). Evaporation of the solvent gives the dihydro derivative 22.3 as a yellow powder. Yield 57 mg (70%). The product darkens at 130°C and decomposes at 185°C. H NMR (CDCl 3 /DMSO-d 6 ) 8.0-8.3, 7.1-7.5, 6.95, 6.0-6.4, 5.6-5.8, 4.5-4.8, 3.4-3.7, 3.2, 2.8-3.4, 2.3. Analysis calculated for C22H30N8OS2'1/4H2°:C'53'80; H'6'41; N, 22.82; S, 13.04. Found: C, 53.80; H, 6.27; N, 22.63; S, 13.02.

The preceding reaction schemes and examples illustrate the preparation of a wide range of derivatives in accordance with the invention in which the dihydropyridine pyridinium salt redox carrier moieties can be one of the [DHC]/[QC<+>] groups depicted on pages 17 to 36 in the preceding wherein p is zero. The preparation of further derivatives of this type will be readily apparent to one skilled in the art from the foregoing teachings, particularly in light of the illustrative synthetic methods detailed in PCT/US83/00725. Furthermore, it is possible to adapt the methods of PCT/US83/00725 and of the present preparation to prepare the present derivatives containing the carrier moieties depicted on pages 17 to 36 above where p is equal to one or two.

Some illustrative methods of making compounds

in accordance with the invention in which the carrier comprises a

-group as depicted in the preceding

where p = 1 or 2 is indicated below. It should be noted that just as the p = 1 or 2 derivatives can be prepared by methods analogous to those depicted in the 1 reaction schemes for the p = 0 derivatives, so can

The p = 0 derivatives are prepared by methods analogous to those specifically described below for the p = 1 or 2 derivatives. The methods described in the following must of course be adapted to the particular chelating agent chosen for the derivatization, in an analogous manner to the reaction schemes depicted in the foregoing.

ILLUSTRATIVE SYNTHESIS METHODS

I. Methods for derivatization of -NH2 or -NH functions

METHOD A

The chelating agent or its protected counterpart (e.g. 74 in scheme 9 or 192 in scheme 24 or 2.21 in scheme 32) is reacted with nicotinuric acid chloride, with nicotinuric anhydride, or with nicotinuric acid in the presence of a suitable coupling agent such as e.g. dicyclohexylcarbodiimide, in a suitable organic solvent, to give the corresponding glycylnicotinamide, or nicotinuramide. The nicotine uramide is then typically quaternized by treatment with methyl iodide in a suitable organic solvent to give the quaternary derivative, which is then deprotected if necessary and reduced by treatment with sodium dithionite or sodium borohydride as generally described above.

Alternatively, glycine can first be reacted with a reagent which is

capable of introducing an amino protecting group such as e.g.

benzyloxycarbonyl or t-butoxycarbonyl and the N-protected glycine are then reacted with the chelating agent or its protected counterpart in the presence of a coupling agent such as dicyclohexylcarbodiimide, followed by removal of the N-protecting group, followed by reaction with nicotinyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or another suitable coupling agent, to give the nicotinuramide. The nicotine uramide can then be quaternized and the quaternary compound deprotected if necessary and reduced as described in the previous section.

The procedure in the second section of this method can be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, instead of the nicotinic acid or its acid chloride anhydride, respectively, to convert chelating agents or their protected counterparts to the corresponding glycyl picolinamides and glycylisonicotinamides and then to the corresponding quaternary and dihydro derivatives. The procedure in the first section of this method can be adapted accordingly. Furthermore, any of these procedures can be repeated, replacing the glycine or nicotinuric acid used in the preceding, with another amino acid or nicotinic acid derivative thereof, e.g. by replacing the glycine with alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine.

Alternatively, the chelating agent or its protected counterpart can be reacted with an activated ester of nicotinuric acid or the like, e.g. a succinimidyl ester such as

and the product is quaternized, deprotected if necessary and then reduced as described in the first section of this method to give the identical products. As an even further and highly desirable alternative, the activated ester, e.g. the succinimidyl ester depicted above is quaternized (eg, by treatment with methyl iodide) and the quaternized activated ester is then reacted with the active compound. The compound thus obtained can then be deprotected if necessary and reduced as described in the first section of this method.

METHOD B

This method is of particular use when the -NH function is part of an amide or imide or a primary or secondary amine with a very low pKa value.

The chelating agent (eg, 52 in Scheme 7) is first reacted with an aldehyde (eg, formaldehyde, benzaldehyde, acetaldehyde or chloral (Cl 3 CCHO)); e.g. in the case of formaldehyde, the -NH function is converted to a function

and thus forms a suitable bridging group. The resulting compound is then reacted with nicotinuric acid in the presence of a suitable dehydrating agent, or with nicotinuric acid chloride or nicotinuric anhydride to form the corresponding nicotinuric acid ester of partial formula

The resulting intermediate is then quaternized and reduced as under method A. The alternative process using an activated ester or quaternary derivative thereof described under method A can be used with advantage here as well.

Alternatively, the steps after the formation of the function can

is replaced by steps analogous to those detailed in the second section of method A.

The procedure in the previous section can be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, instead of the nicotinic acid or its acid chloride or anhydride respectively. (as referred to in the second section of method A) to convert chelating agents into the corresponding glycylpicolinic acid esters and glycylisonicotinic acid esters and then into the corresponding compounds in accordance with the invention. Derivatives of the amino acid other than glycine can be prepared in a similar way. See method A, last paragraph.

Alternatively, the intermediate compound may contain the group

or the like is reacted with thionyl chloride to give the corresponding compound containing a group or the like group. This derivative can then be reacted with a metal salt (especially a silver salt or tallous salt) of nicotinuric acid or the like (formed for example by reacting nicotinuric acid or the like with freshly prepared silver hydroxide or oxide or with tallous ethoxide. The resulting nicotinuric acid ester with the partial formula

or similar derivative is then quaternized and then reduced as under method A.

METHOD C

The procedure in the second section of Method A is followed, except that removal of the N-protecting group is followed by reaction with 3-quinolinecarboxylic acid or its acid chloride or anhydride instead of the nicotinic acid or its acid chloride or anhydride. The procedure in the first section of method A can be correspondingly adapted to the preparation of the 3-quinoline carboxylic acid derivatives. Furthermore, method C can be combined with a method to give the corresponding 3-quinoline carboxylic acid derivatives of the type of chelating agent used in this method.

The procedure in the first section of this method can be repeated using 4-isoquinoline carboxylic acid or its acid chloride or anhydride to convert chelating agents such as those mentioned with methods A and B into the corresponding 4-isoquinoline carboxylic acid derivatives.

The procedure in the first or third section of this method can be repeated, by replacing the glycine used in the first step with another amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine (see method A, second section).

The general procedures described above can be used to prepare the 1,2-dihydro derivatives as well as the 1,4-dihydro derivatives.

METHOD D

The procedure in the second section of method A is followed, with the exception that a reaction component of formula

is used instead of nicotinic acid. (This starting material can be prepared by reacting nicotinic anhydride, nicotinoyl chloride or nicotinic acid with glycolic acid. The preceding procedure can be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, instead of nicotinic acid or its acid chloride or anhydride, respectively, in the preparation of the reaction component depicted above. This variation gives a reaction component of formula

which can then be used instead of nicotinic acid for the production of the derivatives of chelating agents or their protected counterparts such as e.g. those mentioned with method A.

METHOD E

The procedure in the second section of method A is followed, with the exception that a reaction component of formula

in which n = 1-3, preferably 2, is used instead of nicotinic acid. (This reaction component can be prepared from nicotinamide, e.g. when n = 2, by reacting 3-iodopropionic acid with nicotinamide). The quaternary salt thus obtained can then be deprotected if necessary and reduced as described in

method A. See also form 26.

The procedure described above can be repeated using picolinamide or isonicotinamide in place of nicotinamide in the preparation of the reaction components depicted above. This variation gives a reaction component of formula

which can then be used instead of nicotinic acid for the procedure in the first section of this method.

II. Methods for the derivatization of -OH functions

METHOD F

The chelating agent or its protected counterpart

(e.g. 81 in scheme 10, or the corresponding bistiazoline)

is reacted with nicotinuric acid chloride, with nicotinuric anhydride, or with nicotinuric acid in the presence of a suitable coupling agent such as e.g. dicyclohexylcarbodiimide, in a suitable organic solvent, to give the corresponding glycyl nicotinate, or nicotinate. The nicotine urate is then quaternized, deprotected if necessary and then reduced as described above in method A. The alternative process using an activated ester or quaternary derivative thereof described in method A can be used with advantage here as well.

Alternatively, glycine can first be reacted with a reagent which is

capable of introducing an amino protecting group such as e.g. benzyloxycarbonyl or t-butylcarbonyl and the N-protected glycine is then reacted with the chelating agent or its protected counterpart in the presence of a coupling agent which

e.g. dicyclohexylcarbodiimide, followed by removal of the N-protecting group, followed by reaction with nicotinyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to provide the nicotinate urate. The nicotine urate can then be quaternized, deprotected if necessary and the quaternary compound reduced as described in the previous section.

The procedure according to the second paragraph of this method can be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, instead of nicotinic acid or its acid chloride respectively. anhydride, to convert chelating agents into the corresponding glycylpicolinic acid esters or glycylisonicotinic acid esters and then into the corresponding compounds in accordance with the invention. The procedure in the first section of this method can be adapted in a similar way. Furthermore, any of these procedures can be repeated, replacing the glycine or nicotinuric acid used in the preceding with another amino acid or nicotinic acid derivative thereof, e.g. that glycine is replaced by alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine.

METHOD G

The procedure in the second section of method F is followed,

with the exception of a reaction component of formula

in which n = 1-3, preferably 2 (prepared as described in method E), is used instead of nicotinic acid. The quaternary salt thus obtained can then be deprotected if necessary and reduced as described in method A.

Method G is of particular use in the preparation of derivatives of chelating agents in which the hydroxy function is hindered.

Alternatively, method G can follow method F, second paragraph, with the exception that it uses a reaction component with formula

(prepared as described in method E) instead of nicotinic acid.

The procedure in this method can be repeated, using the glycine

in the first step is replaced with another amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine (see method A, second section).

METHOD H

The procedure in Method F, second paragraph, is followed, except that the removal of the N-protecting group is followed by reaction with 3-quinolinecarboxylic acid or its acid chloride or anhydride instead of nicotinic acid or its acid chloride or anhydride.

The procedure in the first paragraph of method F can be adapted

in a similar manner to the preparation of the 3-quinolinecarboxylic acid derivatives.

The procedure in Method H can be repeated using 4-isoquinoline carboxylic acid or its acid chloride or anhydride in place of the 3-quinoline carboxylic acid or its acid chloride or anhydride.

3-quinolinecarboxylic acid or its acid chloride or anhydride or 4-isoquinolinecarboxylic acid or its acid chloride or

anhydride can also be used instead of nicotinic acid or its acid chloride in method B, fourth paragraph, to give the corresponding derivatives.

The general procedures described above can be used to provide the 1,2-dihydro derivatives as well as the 1,4-dihydro derivatives.

METHOD I

The procedure in the second section of method F is followed, with the exception that a reaction component of formula

is used instead of nicotinic acid.

A starting material with the formula stated immediately above can also be used instead of the nicotinic acid in method B, section four, to produce the corresponding derivatives.

Alternatively, method According to method F, second paragraph,

with the exception that it uses a reaction component of formula

(prepared as described in method D). These alternative starting materials in method I can be used instead of nicotinic acid in method B, fourth paragraph, to give de

corresponding derivatives.

The procedure in the first or third section of this method can remain, as another amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine are used instead of the glycine used in the first step (see method A, second section).

III. Methods for the derivatization of -COOH functions

METHOD J

Nicotinuric acid (N-nicotinoylglycine) or an activated ester thereof, is reacted with an aminoalkanol

wherein Z' is C 1 -C 8 straight chain or branched alkylene, e.g. 2-aminoethanol, to give the corresponding intermediate alcohol, e.g. in the case of 2-aminoethanol, an intermediate of formula

This alcohol is then reacted with a chelating agent containing one or more -COOH functions, in the presence of a suitable coupling agent such as e.g. dicyclohexylcarbodiimide. The compound thus obtained is then quaternized and then reduced as described above in method A.

Nicotinuric acid is commercially available. However, it and analogous starting materials can be easily prepared by reacting the chosen amino acid with the acid chloride of nicotinic acid, or picolinic acid, or isonicotinic acid, or 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic acid or the like to give the desired N-substituted amino acid, which can then is reacted with an amino alcohol as described above.

METHOD K

The chelating agent is first reacted with ethylene glycol (or other dihydroxyalkanol with up to 8 carbon atoms),

in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH function or functions into the corresponding group

(or other -OH group(s). Then an N-protected amino acid, such as N-benzyloxycarbonyl-glycine, which has been prepared as described in method A, is then reacted in the presence of dicyclohexylcarbodiimide or other suitable coupling agent. Removal of the protecting group, e.g. by catalytic hydrogenation, gives a derivative of the chelating agent in which the original group or groups -COOH, in the case of ethylene glycol or glycine being used, have been converted to the structure This intermediate is then reacted with a compound of formula

or similar, prepared as described in method E, in the presence of a coupling agent such as e.g. dicyclohexylcarbodiimide, to give the desired quaternary derivative. Subsequently

reduction to the corresponding dihydro-derivative takes place as described in method A.

The procedure in the preceding can be repeated using a reaction component of formula

or the like, prepared as described in method E, in the presence of the intermediate of formula

METHOD L

A chelating agent containing a -COOH function is reacted with an equivalent amount of inositol, in the presence of ... dicyclohexylcarbodiimide or other suitable coupling agent, to convert the -COOH function into a group of the structure

Reaction of this intermediate with nicotinuric acid, in the presence of a suitable coupling agent, or with an activated ester of nicotinuric acid, gives an intermediate in which the original group -COOH has been converted to in which each R is H or

the number of original hydroxy groups that were esterified varies with the amount of nicotinuric acid used. Subsequent quaternization and reduction are carried out as

in method A.

Alternatively, the above procedure can be repeated, replacing the nicotinuric acid with an analogous starting material, produced by reacting the selected amino acid with the acid chloride of nicotinic acid, or picolinic acid, or isonicotinic acid, 3-quinoline carboxylic acid, 4-isoquinoline carboxylic acid or the like.

Repeating the procedure in the first section of this method using a larger amount of the chelating agent (eg, 2 to 5 or more moles per mole of inositol) gives an intermediate containing from 2 to 5 acid residues and from 4 to 1 hydroxyl group. This intermediate is then reacted with nicotinuric acid to convert at least one hydroxyl group to the corresponding group

Subsequent formation of the quaternary compound and the reduction take place as in method A.

METHOD M

The chelating agent is first reacted with 1,2-propylene glycol (or other dihydroxyalkanol of up to 8 carbon atoms), in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH function or functions into the corresponding group(s)

(or other group(s) The resulting intermediate is then reacted with nicotinuric acid, in the presence of a suitable coupling agent, or with an activated ester of nicotinuric acid, to give an intermediate of partial formula

Subsequent quaternization and reduction are carried out as

in method A.

Alternatively, the above procedure can be repeated replacing nicotinuric acid with an analogous starting material, prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, or picolinic acid, or isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic acid or the like.

METHOD N

Glucosamine, with structural formula

is reacted with nicotinuric acid using equimolar amounts of the reaction components in the presence of a suitable coupling agent such as e.g. dicyclohexylcarbodiimide, or with an activated ester of nicotinuric acid. The resulting intermediate of formula

is then reacted with a chelating agent containing a reactive -COOH function, in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, one or more of the hydroxy groups being replaced by one or more acid residues, the number of groups being replaced varying with the relative amounts of used reaction components.

Alternatively, the above procedure can be repeated, replacing the nicotinuric acid with an analogous starting material, produced by reacting the selected amino acid with the acid chloride of nicotinic acid, picolinic acid, isonicotinic acid, 3-quinoline carboxylic acid, 4-isoquinoline carboxylic acid or the like.

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 the invention will vary with the size and nature of the research object, the purpose for which the complex is supplied, the particular dosage form used and the like, as discussed below. The amount of added dosage form required to deliver the desired dose of the radiopharmaceutical compound will of course depend on the concentration of the complex in any given pharmaceutical preparation form/dosage form thereof,

and its radioactivity.

As an example, a 5-50 mg/kg dose of the radiopharmaceutical compound of formula (III) injected into the tail vein or carotid vein of rats will, due to the "lock-in" mechanism, show a very clear difference between radioactivity levels in the brain and the periphery, resulting in light radio imaging of the brain. Imaging at approximately 60 to 90 min. after delivery will be most effective, as it will take advantage of this brain/periphery differentiation

The present radiopharmaceutical compounds are generally administered intravenously. Sustained-release delivery, typically by slow intravenous infusion, will further improve the site-specificity of the present redox system. The release rate of the radiopharmaceutical compound 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 in specificity .

In a further aspect, the 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 penetrant form, of 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 amount.

The production of the radio-pharmaceutical compound can be carried out in the hospital or in a similar place where the patient is in order to reduce the loss of radioactivity caused by the splitting of the radioactive metal to a minimum. As the preparation for visualization can be injected, 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 technetium-99m, is used.

The kit comprises a collecting bottle to receive and/or contain, an aqueous medium in which the complexation reaction can be carried out. The kit further includes the chelating agent of formula (II) or chelating agent precursor of formula (I) and a pharmaceutically acceptable reducing agent to reduce the radioactive element to a suitable oxidation state for complexation with the chelating agent

(and also to reduce the pyridinium carrier moiety to the corresponding dihydropyridine form, when a chelating agent precursor of formula (I) is present).

In the case of technetium-99m, the radioactive element is received from a radionuclide generator as an aqueous pertechnetate (TcO^) solution such as an eluate in isotonic salt solution, as is well known in the art. The amount of Tc-99m necessary to produce an amount of radiopharmaceutical compound of formula (III) sufficient for diagnostic purposes is generally from 0.01 millicurie (mCi) to 500 mCi per ml 99m-pertechnetate solution. The reducing agent for the pertechnetate can be a thiosulphate 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 radio-pharmaceutical compound, e.g. for complexation with an organ-specific agent labeled with a radioactive metal, includes in separate containers: (1) a biologically compatible, sterile aqueous medium suitable for complexation with a radioactive metal, (2) a dihydropyridine ^==^ pyridinium salt carrier complexing agent of formula (I) or (II) compatible therewith, and (3) a pharmaceutically acceptable reducing agent for the radioactive metal.

The dihydropyridine ^ 1 pyridinium salt carrier moiety may be present in the kit in either its oxidized or its reduced state as desired. The reducing agent for the radioactive metal may be selected to also reduce the oxidized carrier moiety, if present, when the radioactive metal is reduced to form the complex prior to the injection of the radiopharmaceutical compound into a companion animal or patient. In a preferred embodiment of the invention is selected

a reducing agent capable of reducing both the oxidized form of the carrier moiety and the radioactive metal and chelating agent precursor of formula (I) is present in the kit. In a particularly preferred embodiment, the kit comprises in separate containers (preferably aseptically and hermetically sealed bottles of approximately 5-25 ml volume), (1) a biologically compatible, sterile aqueous medium, (2) a chelating agent precursor of formula (I) , (3) a pharmacologically tolerable reducing agent capable of reducing the chelating agent precursor of formula (I)

to a chelating agent of formula (II) and also capable of reducing 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 preferably the reducing agent is sodium dithionite and most preferably the radioactive metal technetium. The dithionite reduction is preferably carried out in a basic medium. This can be accomplished by ensuring that the aqueous medium (1) above has a basic pH, or by adding a suitable base (e.g. NaOH, ^200^) when the kit components are combined with

the pertechnetate solution. As a further alternative, the kit may comprise only two separate components: (1) the biologically compatible sterile aqueous medium of substantially neutral pH containing the chelating agent precursor of formula (I), and (2) the reducing agent and base, e.g. sodium dithionite and sodium carbonate.

Radioactive metal ions are typically not supplied with the kit due to the relatively short half-lives of commonly used radionuclides. Rather, the radionuclide is provided separately as described earlier and mixed with the components of the kit shortly before use, as is known for other delivery systems of radiopharmaceutical compounds. In the case of technetium-99m, the pertechnetate solution and the basic aqueous medium may first be combined and then heated, e.g. from 40 to 95°C for 10 to 20 min. in the presence of the reducing agent and then cooled to about room temperature or below before the addition of the precursor of formula (I). In this case the technetium will be reduced before the reduction of the quaternary part of the corresponding dihydroform and in this case a substantial part of the quaternary salt (I) will probably chelate with the reduced technetium to form the quaternary complex (IV) in the reaction mixture which 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 to 9, it can be added as it is after 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. 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) with respect to the radionuclide to be complexed therewith, e.g. a molar excess of 1:2. The reducing agent is present in a large excess in relation 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.

In order to carry out visualization, the diagnostic agent is administered to a patient, typically intravenously, with or without further dilution with a carrier substance such as physiological saline, phosphate-buffered saline and plasma or the like. Generally, the dose to be delivered has a radioactivity of about 0.01 millicurie (mCi) to about 100 millicurie, preferably about 1 mCi to about 20 mCi. The solution that is injected into an adult patient per unit dose is about 0.01 milliliter (ml) to about 1 milliliter.

After intravenous administration, imaging of the organ in vivo can take place after a few minutes. If desired, 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. Imaging preferably takes 60 to 90 minutes. 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 be seen in the broadest sense to provide mixtures comprising: (1) the residue of a chelating agent with at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, the functional group not being essential for the complex-forming properties of the said chelating agent, the rest being characterized by the absence of a hydrogen atom from at least one of the said reactive functional groups in the chelating agent, the chelating agent being either (a) capable of chelating with a metal -radionuclide or (b) chelated with a metal radionuclide; and (2) a dihydropyridine - pyridinium salt redox carrier moiety, the chelating agent moiety and the carrier moiety being linked together to form a hydrolytically cleavable bond therebetween.

While the invention is described on the basis of various preferred embodiments, the person skilled in the art will realize that various modifications, substitutions, omissions and changes can be made without departing from the scope and it is consequently intended that the scope of the present invention should only be limited by the scope of the following patent claims .

Claims (138)

1. Substance mixture, characterized in that it includes: (1) the residue of a chelating agent with at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and amide, the functional group not being essential for the complexing properties of the chelating agent, the residue being characterized by absence of a hydrogen atom from at least one of said reactive functional groups in the chelating agent, the chelating agent either (a) being capable of chelating with a metal radionuclide or (b) being chelated with a metal radionuclide; and (2) a dihydropyridine pyridinium salt redox carrier moiety; the chelating agent residue and said carrier part being linked to each other to form a hydrolytically cleavable bond therebetween. 2. A salt, characterized by the fact that the structural formula wherein the residue is a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, the functional group is not essential for the complex-forming properties of the chelating agent, the rest being characterized by the absence of a hydrogen atom from at least one of the mentioned reactive functional groups of the chelating agent; y is 1 or 2; [QC <+> ] is the hydrophilic, ionic pyridinium salt form of a dihydropyridine ^==^ pyridinium salt redox carrier; X- is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; and m is a number that when multiplied by n equals y. 3. Salt as specified in claim 2, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one amino- or hydroxy1-reactive functional group in the chelating agent. 4. Salt as specified in claim 3, characterized by atyerl. 5. Salt as specified in claim 3, characterized in that [QC <+> ] is a radical with formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical o with the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 aralkyl; R 3 is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or C^-C^ alkyl, or X is -CH=NOR'" wherein R'" is H or C^-C^ alkyl; the carbonyl-containing groups in formulas (a) and (c) and the X substituent in formula (b) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (d) and (f) and the X-substituent in formula (e) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the carbonyl-containing groups in formulas (g) and (j) and the X substituent in formula (h) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. 6. Salt as specified in claim 5, characterized by atper zero. 7. Salt as stated in claim 5, characterized in that p is one, the alkylene is -CH2 - and Rq is H, -CH3 < -CH(CH3 )2 , CH3 -CH2 -CH(CH3 )2< -CH-C2 H5 , -(CH2 )2 -SCH3' -CH2 -CONH2 or -CH2 CH2 -CONH2 . 8. Salt as specified in claim 2, characterized in that the residue is characterized by the absence of a hydrogen atom from an -NH part which is part of an amide or imide functional group or which is part of a primary or secondary amino functional group with a low pKa value. 9. Salt as specified in claim 8, characterized by y being one. 10. Salt as specified in claim 8, characterized in that [OC <+> ] is a radical with formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms, R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the Rq radicals are the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 7 <-C> 10 aralkyl; R is hydrogen, C₁-C₁ alkyl, C₁ -C₃ cycloalkyl, C^-C^ haloalkyl, furyl, phenyl, or phenyl substituted with one or more halogens, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono lower alkylcarbamoyl, dilower alkylcarbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R~ is C 1 -C 4 alkylene; X is -CONR'R" in which R' and R" are the same or different and are each H or C 1 -C 4 alkyl or X is -CH=NOR"' in which R'" is H or C 1 -C 4 alkyl; the carbonyl-containing groups in formulas (k) and (m) and the X substituent in formula (I) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (n) and (p) and the X-substituent in formula (o) may each be linked to 2-, the 3- or 4-position of the quinolinium ring; and the carbonyl-containing groups in formulas (q) and (s) and the X-substituent in formula (r) may each be linked to 1-, 3- or 4- the position of the isoquinolinium ring. 11. Salt as stated in claim 10, characterized by atper zero. 12. Salt as stated in claim 10, characterized in that p is one, the alkylene is -CH2 - and Rq is H, - CH^, -CH(CH3 )2 , -CH2-CH( CB^)2, -(CH2 )2 _SCH3' -CH2 -CONH2 or -CH2 CH2 -CONH2 . 13. Salt as specified in claim 2, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one carboxyl-reactive functional group in the chelating agent. 14. Salt as stated in claim 13, characterized by atyerl. 15. Salt as stated in claim 13, characterized in that [OC <+> ] is a radical with formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; Z' is C 1 -C 8 straight chain or branched alkylene; Q is -O- or -NH-; R-1 is C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 aralkyl; R 1 is C 1 -C 4 alkylene; X is .CONR'R" wherein R' and R" which are the same or different are each H or C₁-C₁ alkyl, or X is -CH═NOR"' wherein R'" is H or C₁-C₁ alkyl; The X-substituent in formula (ii) and the carbonyl-containing groups in formulas (i) and (iii) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; The X substituent in formula (v) and the carbonyl-containing groups in formulas (iv) and (vi) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the X substituent in formula (viii) and carbonyl-containing groups in formulas (vii) and (ix) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. 16. Salt as specified in claim 14, characterized in that [QC <+> ] is a radical with formula where ^ j is the skeleton of a sugar molecule; n <iv> is a positive integer equal to the total number of -OH functions in the sugar molecule from which the skeleton is derived; nv is a positive number one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of the structures (xii), (xiii) and (xiv) can independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group, the residue being characterized by the absence of a hydrogen atom from said -COOH functional group in the chelating agent; and each R 4 ' in each of structures (x) and (xi) may independently be hydroxy, wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R o is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; D' is defined as having the structure (xii), (xiii) and (xiv); R 1 is C 1 -C 6 alkyl, C 1 -C 6 -, haloalkyl or C 1 -C 6 aralkyl; and the depicted carbonyl-containing groups may be attached at the 2-, 3- or 4-position of the pyridinium or quinolinium ring, or at the 1-, 3- or 4-position of the isoquinolinium ring; with the condition that at least one R^ ' in each of the structures (x) and (xi) is wherein the alkylene, R , p and R 1 and the position of the carbonyl-containing groups are as defined above; and with the further condition that when more than one of the R^' radicals in a given compound are the aforementioned carbonyl-containing groups, all these carbonyl-containing groups in the compound are the same. 17. Salt as stated in claim 15, characterized by atperO. 18. Salt as stated in claim 16, characterized by atperO. 19. A salt as stated in claim 15 or 16, characterized by atperl, the alkylene is 20. A connection characterized in that it has the structural formula <" ller a non-toxic pharmaceutically acceptable salt thereof, wherein the remainder is a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, the functional group not being essential for the complex-forming properties of the chelating agent, the remainder being characterized by the absence of a hydrogen atom from at least one of the aforementioned reactive functional groups in the chelating agent; y is 1 or 2; and [DHC] is the reduced, biooxidizable, blood-brain barrier-penetrating form of the dihydropyridine pyridinium salt redox carrier. 21. Compound as stated in claim 20, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one amino- or hydroxyl-reactive functional group in the chelating agent. 22. A compound as stated in claim 21, characterized by atyerl. 23. A compound as stated in claim 21, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; Ro is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; the dotted line in formulas (a'), (b') and (c') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (d'), (e') and (f') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 q aralkyl; R 3 is C to alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C 1 -C 4 alkyl, or X is -CH=NOR"' wherein R'" is H or C 1 -C 1 alkyl ; the carbonyl-containing groups in formulas (a') and (c') and the X-substituent in formula (b') may each be linked to 2-, the 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (d') and (f') and the X-substituent in formula (e') can each be linked to 2-, 3- or 4- the position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas (g') and (j') and the X-substituent in formula (h') may each be attached to the 1-, 3- or 4-position of the dihydroisoquinoline ring. 24. A compound as stated in claim 23, characterized by atperO. 25. A compound as stated in claim 23, characterized by atperl, the alkylene is -CH2 - and RQ is H, - CU^, -CH(CH3)2 26. A compound as stated in claim 20, characterized in that the residue is characterized by the absence of a hydrogen atom from a -NH part which is part of an amide or imide functional group or which is part of a primary or secondary amino functional group with a low pKa value. 27. A compound as stated in claim 26, characterized by atyerl. 28. A compound as stated in claim 26, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; R is hydrogen, C^-C-j alkyl, C-j-Cg cycloalkyl, C^-C^ haloalkyl, furyl, phenyl or phenyl substituted with one or more halogen, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl Jcarbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl, or lower alkylsulfonyl; the dashed line in formulas (k'), (1') and (m') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (n'), (o') and (p') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 7 -C 10 aralkyl; R, is C to C"3 alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or C1-C7 alkyl, or X is -CH-NOR'" wherein R'" is H or C 1 -C 7 alkyl; the carbonyl-containing groups in formulas (k') and (rn') and the X substituent in formula (1') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (n') and (p') and the X substituent in formula (o') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas (q') and (s') and the X-substituent in formula (r') may each be attached to the 1-, 3- or 4-position of the dihydroisoquinoline ring. 29. A compound as stated in claim 28, characterized by atperO. 30. A compound as stated in claim 28, characterized by atperl, the alkylene is 31. A compound as stated in claim 20, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one carboxyl-reactive functional group in the chelating agent. 32. A compound as stated in claim 31, characterized by atyerl. 33. A compound as stated in claim 31, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical o with the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formulas (i'), (ii') and (iii') indicates the presence of a double bond at either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (iv'), (v') and (vi') indicates the presence of a double bond at either the 2- or 3-position of the dihydroquinoline ring; Z' is C 1 -C 8 straight or branched alkylene; Q is -O- or -NH; R is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 7 -C 10 aralkyl; R 1 is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or -C^-C^ alkyl, or X is -CH=NOR"' wherein R'" is H or C^ -C ^ alkyl; The X-substituent in formula (ii') and the carbonyl-containing group in formulas (i') and (iii') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; The X-substituent in <:> formula (v') and the carbonyl-containing group in formulas (iv') and (vi') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the X substituent in formula (viii') and the carbonyl-containing groups in formulas (vii') and (ix') may each be attached to the 1-, 3- or 4-position of the dihydroisoquinoline ring. 34. A compound as stated in claim 32, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formula (xii') indicates the presence of a double bond at either the 4- or 5-position of the dihydropyridine ring; the dashed line in formula (xiii') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; • * is the skeleton of a sugar molecule; n <iv> is a positive integer equal to the total number of -OH functions in the sugar molecule from which the skeleton is derived; nv is a positive integer one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of structures (xii'), (xiii'), (xiv') and (xiv" ) may independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group , the residue being characterized by the absence of a hydrogen atom from the said -COOH function or group in the chelating agent; and each R. in each of the structures (x') and (xi') may independently be hydroxy, wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical o with the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line is defined as structures (xii') and (xiii'); D' is defined as the structures (xii'), (xiii'), (xiv') and (xiv" ); R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 aralkyl; and the depicted carbonyl groups may be attached to the 2-, 3-, or 4-positions of the pyridinium or quinolinium ring, or when not otherwise indicated at the 1-, 3-, or 4-position of the isoquinolinium ring; with the condition that at least one R^ in each of the structures (x') and (xi') is wherein the alkylene, R , p, R , the dashed lines and the position of the carbonyl-containing groups are defined as above; and with the further proviso that when more than one of the R^ radicals in a given compound are the said carbonyl-containing groups, all such carbonyl-containing groups in the compound are the same. 35. Connection as stated in claim 33, characterized by atperO. 36. Compound as stated in claim 34, characterized by atperO. 37. Compound as stated in claim 33 or 34, characterized by atperl, the alkylene is -CH„- and R is H, -CH-,,2 ^ o 3 38. Radio-pharmaceutical compound, characterized in that it has the structural formula or a non-toxic pharmaceutically acceptable salt thereof, wherein ^^ -is the residue of a chelating agent capable of chelating with a metal radionuclide, the chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, being functional group is not essential for the complex-forming properties of the chelating agent, the remainder being characterized by the absence of a hydrogen atom from at least one of the mentioned reactive functional groups in the chelating agent; y is 1 or 2; [DHC] is the reduced, biooxidizable, blood-brain barrier-penetrating form of dihydropyridine pyridinium salt redox carrier and M is a metal radionuclide, the radiopharmaceutical compound of formula (III) being a chelate of said metal -radionuclide with a compound of formula wherein fOHC] and y has the above meaning. 39. Radio-pharmaceutical compound as stated in claim 38, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one amino- or hydroxyl-reactive functional group in the chelating agent. 40. Radio-pharmaceutical compound as stated in claim 39, characterized by atyerl. 41. Radio-pharmaceutical compound as stated in claim 39, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; the dotted line in formulas (a'), (b') and (c') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (d'), (e') and (f') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; R 1 is C 1 -C 1 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; R 1 is C to C alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or C1-C? alkyl, or X is -CH=NOR'" wherein R'" is H or C₁ -C₁ alkyl; the carbonyl-protected groups in formulas (a') and (c') and the X-substituent in formula (b') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (d') and (f') and the X-substituent in formula (e') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas (g') and (j') and the X-substituent in formula (h') may each be attached to the 1-, 3- or 4-position of the dihydroisoquinoline ring. 42. Radio-pharmaceutical compound as stated in claim 41, characterized by atperO. 43. Radio-pharmaceutical compound as stated in claim 41, characterized in that p is one, the alkylene is -CH2 - and RQ is H, - CH^, 44. Radio-pharmaceutical compound as stated in claim 38, characterized in that the residue is characterized by the absence of a hydrogen atom from an -NH part which is part of an amide or imide functional group or which is part of a primary or secondary amino functional group with a low pKa value. 45. Radio-pharmaceutical compound as stated in claim 44, characterized by atyerl. 46. Radio-pharmaceutical compound as stated in claim 44, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and may contain 1 to 3 carbon atoms; RQ is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the R 2 radicals are the same or different; R is hydrogen, C 1 -C 4 alkyl, C 1 -C cycloalkyl, C 1 -C haloalkyl, furyl, phenyl or phenyl substituted with one or more groups halogen, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy , lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; the dashed line in formula (k'), (1') and (m') indicates the presence of a double bond according to the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (n'), (o') and (p') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; is C₁ - C₁ alkyl, C₁ - C₁ haloalkyl or C₁ -C₁ q aralkyl; R 1 is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or C^-C^ alkyl, or X is —CH-NOR'" wherein R'" is H or C^C^ alkyl ; the carbonyl-containing groups in formulas <f> k' ) and (m') and the X-substituent in formula (1') can each be linked to the 2-, 3- or 4-position of the dihydropyridine ring; the carbonyl-containing groups in formulas (n') and (p') and the X-substituent in formula (o') can each be linked to 2-, the 3- or 4-position of the dihydroquinoline ring; and the carbonyl-containing groups in formulas (q') and (s') and the X-substituent in formula (r') may each be linked to 1-, The 3- or 4-position of the dihydroisoquinoline ring. 47. Radio-pharmaceutical compound as stated in claim 46, characterized by atperO. 48. Radio-pharmaceutical compound as stated in claim 46, characterized in that perl, the alkylene is -CH„ and R is H,2 o 49. Radio-pharmaceutical compound as stated in claim 48, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one carboxyl-reactive functional group in the chelating agent. 50. Radio-pharmaceutical compound as stated in claim 49, characterized by atyerl. 51. Radio-pharmaceutical compound as stated in claim 49, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; RQ is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formulas (i'), (ii') and (iii') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formulas (iv'), (v') and (vi') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; Z' is c±~ cq straight chain or branched alkylene; Q is -O- or -NH-; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 7 -C 10 alkyl; R - is C 1 -C 4 alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C₁-C₁ alkyl, or X is -CH=NOR'" wherein R'" is H or C 1 -C alkyl; The X-substituent in formula (ii') and the carbonyl-containing group in formulas (i') and (iii') may each be attached to the 2-, 3- or 4-position of the dihydropyridine ring; The X-substituent in formula (v') and the carbonyl-containing group in formulas (iv') and (vi') may each be attached to the 2-, 3- or 4-position of the dihydroquinoline ring; and the X-substituent in formula (viii') and the carbonyl-containing groups in formulas (vii') and (ix') may each be attached to the 1-, 3- or 4-position of the dihydro-isoquinoline ring. 52. Radio-pharmaceutical compound as stated in claim 50, characterized in that [DHC] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms, R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 then the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line in formula (xii') indicates the presence of a double bond in either the 4- or 5-position of the dihydropyridine ring; the dashed line in formula (xiii') indicates the presence of a double bond in either the 2- or 3-position of the dihydroquinoline ring; i iv v-' is the skeleton of a sugar molecule; n is a positive integer equal to the total number of -OH functions in the sugar molecule from which the skeleton is derived; nv is a positive integer one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of the structures (xii'), (xiii'), (xiv') and (xiv" ) can each independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group , the remainder being characterized by the absence of a hydrogen atom from the said -COOH functional group in the chelating agent; and each R 4 in each of the structures (x') and (xi') can independently be hydroxy, wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; the dashed line is defined as with structures (xii') and (xiii'); D' is defined as having the structures (xii'), (xiii'), (xiv') and (xiv"); R.^ is C1-C7 alkyl, C1-C-J haloalkyl or C7-C1Q aralkyl; and the depicted carbonyl groups may be attached to the 2-, 3-, or 4-position of the pyridinium or quinolinium ring or, unless otherwise indicated, at the 1-, 3-, or 4-position of the isoquinolinium ring, provided that at least one R4 in each of the structures (x') and (xi') is wherein the alkylene, R, p, R^, the dashed lines and the position of the carbonyl-containing groups are as indicated above; and with the further condition that when more than one of the R^ radicals in a given compound are the above-mentioned carbonyl-containing groups, then all such carbonyl-containing groups in the compound are the same. 53. Radio-pharmaceutical compound as stated in claim 51, characterized by atper zero. 54. Radio-pharmaceutical compound as stated in claim 52, characterized by atper zero. 55. Radio-pharmaceutical compound as stated in claim 51 or 52, characterized by atperl, the alkylene is -CH0 - and R is H,2 ^ o 56. Radio-pharmaceutical compound as stated in claim 38, characterized by atMer technetium-99m. 57. Radio-pharmaceutical compound characterized in that it has 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 reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, the functional group not being essential for the complex-forming properties of the chelating agent, the remainder being characterized by the absence of a hydrogen atom from at least one of the aforementioned reactive functional groups in the chelating agent; y is 1 or 2; [QC <+> ] is the hydrophilic ionic pyridinium salt form of a dihydropyridine pyridinium salt redox carrier; X- is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m is a number which when multiplied by n 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 of formula where , y, [QC <+> ] , X , n and y are as defined above. 58. Radio-pharmaceutical compound as stated in claim 57, characterized in that the residue is characterized by the absence of a hydrogen atom from at least one amino- or hydroxyl-reactive functional group in the chelating agent. 59. Radio-pharmaceutical compound as stated in claim 58, characterized by atyerl. 60. Radio-pharmaceutical compound as stated in claim 58, characterized in that [QC <+> ] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 7 -C 10 aralkyl; R 3 is C 1 to C 3 alkylene; X is -CONR'R" wherein R' and R" are the same or different and are each H or C1 -C7 alkyl, or X is -CH=NOR'" wherein R'" is H or C1 -C7 alkyl; the carbonyl-containing groups in formulas (a) and (c) and the X substituent in formula (b) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (d) and (f) and the X substituent in formula (e) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the carbonyl-containing groups in formulas (g) and (j) and the X substituent in formula (h) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. 61. Radio-pharmaceutical compound as stated in claim 60, characterized by atperO. 62. Radio-pharmaceutical compound as set forth in claim 60, characterized by atperl, the alkylene is -CHn - and R is H,2 ^ o 63. Radio-pharmaceutical compound as stated in claim 57, characterized in that the residue is characterized by the absence of a hydrogen atom from an -NH part which is part of an amide or imide functional group which is part of a primary or secondary amino functional group with a low pKa value. 64. Radio-pharmaceutical compound as stated in claim 63, characterized by atyerl. 65. Radio-pharmaceutical compound as stated in claim 63, characterized in that [QC <+> ] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R o is a radical identical to the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; R 1 is C 1 -C 4 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; R is hydrogen, C^-C^ alkyl, C^- CQ cycloalkyl, C1~ C7 haloalkyl, furyl, phenyl, or phenyl substituted with one or more halogen groups, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 3 is to the alkylene; X is -CONR'R" in which R' and R" are the same or different and are each H or C-1-C4 alkyl, or X is CH=NOR"' in which R'" is H or C1-C7 alkyl; the carbonyl-containing groups in formulas (k) and (m) and the X substituent in formula (1) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; the carbonyl-containing groups in formulas (n) and (p) and the X-substituent in formula (o) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the carbonyl-containing groups in formulas (q) and (s) and the X substituent in formula (r) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. 66. Radio-pharmaceutical compound as stated in claim 65, characterized by atperO. 67. Radio-pharmaceutical compound as stated in claim 65, characterized by atperl, the alkylene is -CH2 - and RQ is H, 68. Radio-pharmaceutical compound as stated in claim 57, characterized in that the residue is characterized by the absence of a hydrogen atom which is at least a carboxyl-reactive functional group in the chelating agent. 69. Radio-pharmaceutical compound as stated in claim 68, characterized by atyerl. 70. Radio-pharmaceutical compound as stated in claim 68, characterized in that [QC <+> ] is a radical of formula wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical o with the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2, the alkylene groups are the same or different and the RQ radicals are the same or different; Z' is C₁-CQ straight chain or branched alkylene; Q is -O- or -NH-; 1^ is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 aralkyl; is to CU alkylene; X is -CONR'R" wherein R' and R" are the same or different and each is H or C^C^ alkyl, or X is —CH=NOR"' wherein R'" is H or C^-C^ alkyl; The X substituent in formula (ii) and the carbonyl-containing groups in formulas (i) and (iii) may each be attached to the 2-, 3- or 4-position of the pyridinium ring; The X substituent in formula (v) and the carbonyl-containing groups in formulas (iv) and (vi) may each be attached to the 2-, 3- or 4-position of the quinolinium ring; and the X substituent in formula (vii) and the carbonyl-containing groups in formulas (vii) and (ix) may each be attached to the 1-, 3- or 4-position of the isoquinolinium ring. 71. Radio-pharmaceutical compound as set forth in claim 69, characterized in that [QC <+> ] is a radical of formula *■ v i v where \ ) is the skeleton of a sugar molecule; n is a positive integer equal to the total number of -OH functions in the sugar molecule from which the skeleton is derived; n v is a positive integer one less than the total number of -OH functions in the sugar molecule from which the skeleton is derived; each A in each of the structures (xii), (xiii) and (xiv) can each independently be hydroxy or D', D' being the residue of a chelating agent containing a reactive -COOH functional group, the residue being characterized by the absence of a hydrogen atom from said -COOH functional group in the chelating agent; and each ' in each of structures (x) and (xi) may independently be hydroxy, wherein the alkylene group is straight chain or branched and contains 1 to 3 carbon atoms; R is a radical identical o with the corresponding part of a natural amino acid; p is 0, 1 or 2, with the proviso that when p is 2 the alkylene groups are the same or different and the RQ radicals are the same or different; D' is defined as having structures (xii), (xiii) and (xiv); R 1 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 4 aralkyl; and the depicted carbonyl-containing groups may be attached to the 2-, 3-, or 4-position of the pyridinium or quinolinium ring, or at the 1-, 3-, or 4-position of the isoquinolinium ring; with the condition that at least one R^ ' in each of the structures (x) and (xi) is wherein the alkylene, Rq, p and R^ and the position of the carbonyl-containing groups are as indicated above; and with the further condition that when more than one of the R 4 ' radicals in a given compound is the above-mentioned carbonyl-containing groups then all such carbonyl-containing groups in the compound are the same. 72. Radio-pharmaceutical compound as stated in claim 70, characterized by atperO. 73. Radio-pharmaceutical compound as stated in claim 71, characterized by atperO. 74. Radio-pharmaceutical compound as stated in claim 70 or 71, characterized by atperl, the alkylene is -CH~ - and R is H,2 * o 75. Radio-pharmaceutical compound as stated in claim 57, characterized by atMer technetium-99m. 76. Chemical compound as stated in claim 5, 23, 41 or 60, characterized in that Rj is methyl. 77. Chemical compound as stated in claim 5, 23, 41 or 60, characterized in that R, is -Cr^CE^-. 78. Chemical compound as specified in claim 5, 23, 41 or 60, characterized in that X is -CONI^ . 79. Chemical compound as stated in claim 5, 23, 41 or 60, characterized in that X and the carbonyl-containing groups whose ring positions can vary are located in the 3-position of the pyridinium or dihydropyridine rings, in the 3-position of the quinolinium or dihydroquinoline ring systems, or in the 4-position of the isoquinolinium or dihydroisoquinoline ring systems. 80. Chemical compound as stated in claim 5, 23, 41 or 60, characterized in that the carrier part is a radical with formula (a) or (a'). 81. Chemical compound as stated in claim 80, characterized in that the carrier part is a radical with the formula 82. Chemical compound as specified in claim 10, 28, 46 or 65, characterized in that R. is methyl. 83. Chemical compound as specified in claim 10, 28, 46 or 65, characterized in that X and the carbonyl-containing groups whose ring positions can vary are located in the 3-position of the pyridinium or dihydropyridine rings, in the 3-position of the quinolinium or dihydroquinoline ring systems, or in the 4-position of isoquinolinium- or the dihydroisoquinoline ring esters. 84. Chemical compound as specified in claim 10, 28, 46 or 65, characterized in that R is hydrogen, C₁ -C₁ alkyl, C₁ -C₂ cycloalkyl, C₁ - C₁ haloalkyl, furyl or phenyl. 85. Chemical compound as specified in claim 15, 33, 51 or 70, characterized in that Z' is C1-C3 straight-chain or branched alkylene. 86. Chemical compound as stated in claim 85, characterized in that Z' is C2-C3 straight-chain or branched alkylene. 87. Chemical compound as specified in claim 15, 33, 51 or 70, characterized in that X and the carbonyl-containing groups whose ring positions can vary are located in the 3-position of the pyridinium or dihydropyridine rings, in the 3-position of the quinolinium or dihydroquinoline ring systems, or in the 4-position of isoquinolinium- or the dihydroisoquinoline ring esters. 88. Chemical compound as specified in claim 16, 34, 52 or 71, characterized in that the carbonyl-containing groups covered by the definitions for and R^' are located in the 3-position of the pyridinium or dihydropyridine rings, in the 3-position of the quinolinium or dihydroquinoline ring systems, or in the 4-position of isoquinolinium - or the dihydroisoquinoline ring esters. 89. A salt as specified in claim 5, 6 or 7, characterized in that it has the structural formula wherein each R^ is independently selected from the group consisting of H and C"1~C7 alkyl, or one R^ may be combined with neighboring ^ C_R5 such that represents ^C=0; each Rg is independently selected from the group consisting of H and C-.C- alkyl, or an R, may be combined with neighboring <v> C-Rc such that represents ^C=0; is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 - C 7 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being adjacent to each other nor adjacent to -A^ -' X- is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; rn' is a number which when multiplied by n is equal to one; s is zero or one; -A^ - is -NH-, -O- or wherein Rg is C₁-C₁ alkyl, and [QC <+> ] is as defined in claim 5, 6 or 7. 90. A salt as specified in claim 10, characterized in that it has the structural formula wherein each R,, is independently selected from the group consisting of H and C^-Cy alkyl, or one R^ may be combined with neighboring ^C-R^ such that represents^ C=0 , each Rg is independently selected from the group consisting of H and C 1 -C 6 alkyl, or an R, may be combined with l / o neighboring ^ C- R6 r such that represents ^C=0; is a radical with formula wherein each R 7 is independently selected from the group consisting of H and C 1 -C 4 alkyl; (alk is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other and also not being in a neighboring position to -A2~ ; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n equals one; s is zero or one; -A2~ is -CONH- or wherein R 8 is C 1 -C 4 alkyl; and [QC <+> ] is as defined in claim 10. 91. A salt as specified in claim 15 or 16, characterized in that it has the structural formula wherein each R,- is independently selected from the group consisting of H and C 1-C_ alkyl, or an R- may be combined with neighboring ^C-R^ so that each R, is independently chosen represents ^ C=0; from the group consisting of H and C1-C„ alkyl, or an R,, may be combined with neighboring ^C-R^ such that D represents is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A^ -; X is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to 1; s is zero or one; -A^ - is -C00-; and [QC <+> ] is as set forth in claim 15 or 16. 92. A salt as specified in claim 5, 6 or 7, characterized in that it has the structural formula wherein R 1 and R 2 are each H or C^ -C^ alkyl, n' is an integer from 0 to 3 and [QC <+> ] is as stated in claim 5, 6 or 7. 93. A salt as specified in claim 5, 6 or 7, characterized in that it has the structural formula wherein [QC <+> ] is as set forth in claim 5, 6 or 7. 94. A compound as stated in claim 23, 24 or 25, characterized in that it has the structural formula in which each FU is independently selected from the group consisting of H and C.-C- alkyl, or an Rj- can be combined with neighboring ^. C-R^ so that represents ^C=0; each R6 is independently selected from the group consisting of H and C~-Cn alkyl, or one R,, may be combined with neighboring«C-R^ such that represents _^C=0; is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 7 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A-^-; s is zero or one; -A^ - is -NH-, wherein R 8 is C 1 -C 4 alkyl; and [DHC] is as defined in claim 23, 24 or 25. 95. A compound as stated in claim 28, characterized in that it has the structural formula in which each R,- is independently selected from the group consisting of H and C..-C- alkyl, or an R^ can be combined with neighboring ^ C-Rj. so that represents ^ C=0; each R^ is independently selected from the group consisting of H and C 1 -C 2 alkyl, or one R 2 may be combined with neighboring ^ C-R& such that represents ^ C=0; is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other, nor in a neighboring position to -A2 -; s is zero or one; -A2~ is -CONH- wherein R 8 is C 1 -C 4 alkyl; and [DHC] is as stated in claim 28. 96. A compound as stated in claim 33 or 34, characterized in that it has the structural formula in which each R 5 is independently selected from the group consisting of H and C 1 -C 4 alkyl, or an R 5 can be combined with x/ neighboring ^ C <_>R 5 such that represents C=0; each R 6 is independently selected from the group consisting of H and C 1 -C 6 alkyl, or one R 6 may be combined with neighboring ^C-R^ such that represents^ C=0; is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A^ -; s is zero or one; -A^ - is -C00-; and [DHC] is as set forth in claim 33 or 34. 97. A compound as stated in claim 23, 24 or 25, characterized in that it has the structural formula in which R 1 and R 2 are each H or C^ -C^ alkvl, n' is an integer 0 to 3 oq [DHC] is as stated in claim 23, 24 or 25. 98. A compound as claimed in claim 23, 24 or 25, characterized in that it has the structural formula wherein [DHC] is as claimed in claim 23, 24 or 25. 99. A radio-pharmaceutical compound as set forth in claim 41, 42 or 43, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a compound of the structural formula wherein each R^ is independently selected from the group consisting of H and C1-C7 alkyl, or an R^ may be combined with neighboring ^C-Rbc such that represents ^C=0; each R^ is independently selected from the group consisting of H and C^ -C-, alkyl, or one R^ may be combined with neighboring ^c_Rg such that represents ^C=0; is a radical with formula wherein R 1 is independently selected from the group consisting of H and C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A^ -; s is zero or one; -A^ - is -NH-,-O- or wherein R 8 is C 1 -C 4 alkyl; and [ DEC] is as set forth in claim 41, 42 or 43. 100. Radio-pharmaceutical compound as stated in claim 46, characterized in that the radio-pharmaceutical compound is a chelate of a metal radionuclide with a compound of structural formula wherein R^ is independently selected from the group consisting of H and C.sub.-C.sub.3 alkyl, or an R.sub.- may be combined with the neighboring ^ C-R^ such that represents ^.C=0; each R& is independently selected from the group consisting of H and C^-C^ al kvi. pl lpr en R. can be combined with neighboring ^C- R^ such that represents ^C=0; is a radical with formula wherein each R 7 is independently selected from the group consisting of H and C 1 -C 7 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A,,-; s is zero or one; -A2~ is -CONH- wherein R 8 is C 1 -C 8 alkyl; and [DHC] is as set forth in claim 46. 101. Radio-pharmaceutical compound as stated in claim 51 or r 52, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a compound of structural formula wherein each R^ is independently selected from the group consisting of H and C 1 -C alkyl, or an R r may be combined with neighboring ^C-R^ such that represents ^C=0; each R^ is independently selected from the group consisting of H and C^-C7 alkyl, or one R^ may be combined with adjacent is a radical with formula wherein each R 7 is independently selected from the group consisting of H and C 1 -C 7 alkyl; (alk) is a straight-chain or branched lower alkylene group which may further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being themselves in a neighboring position to each other and also not in a neighboring position to -A^ -; s is zero or one; -A^ - is -C00-; and [DHC] is as set forth in claim 51 or 52. 102. Radiopharmaceutical compound as stated in claim 99, characterized in that the metal radionuclide is the oxotechnate-99m ion. 103. Radio-pharmaceutical compound as stated in claim 99, characterized in that the metal radionuclide is the oxotechnate-99m ion. 104. Radio-pharmaceutical compound as stated in claim 101, characterized in that the metal radionuclide is the oxotechnate-99m ion. 105. Radio-pharmaceutical compound as stated in claim 41, 42 or 43, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a compound of structural formula wherein R 1 and R 2 are each C 1 -C 2 alkyl, n' is an integer 0 to 3 and [DHC] is as stated in claim 41, 42 or 43. 106. Radio-pharmaceutical compound as stated in claim 105, characterized in that the metal radionuclide is the oxotechnate-99m ion. 107. Radio-pharmaceutical compound as stated in claim 41, 42 or 43, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a compound of structural formula wherein [DHC] is as set forth in claim 41, 42 or 43. 108. Radio-pharmaceutical compound as stated in claim 107, characterized in that the metal radionuclide is the oxotechnate-99m ion. 109. Radio-pharmaceutical compound as stated in claim 60, 61 or 62, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a salt with the structural formula wherein each R 5 is independently selected from the group consisting of H and C 1 -C alkyl, or an R 5 may be combined with neighboring ^C-R^ such that represents ^ C=0; each Rg is independently selected from the group consisting of H and C^ -C-, alkyl, or one R^ may be combined with neighboring ^C-Rg such that represents ^.C=0; is a radical with formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 7 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -A-^ -; X~ is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to one; s is zero or one; -A^ - is -NH-, -O- or wherein R 8 is C 1 -C 4 alkyl; [QC <+> ] is as stated in claim 60, 61 or 62. 110. Radio-pharmaceutical compound as stated in claim 65, characterized in that the radio-pharmaceutical compound is a chelate of a metal radionuclide with a salt of structural formula wherein each Rj- is independently selected from the group consisting of H and C,-C alkyl, or an R,- may be combined with neighboring >C-R^ such that represents ^C=0 ; each R 8 is independently selected from the group consisting of H and C 1 -C 2 alkyl, or one R 2 may be combined with neighboring ^ C-RD, so that represents ^C=0; a radical with formula wherein R 1 - is independently selected from the group consisting of H and C 1 -C 4 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other nor in a neighboring position to -& 2~' ^ the anion is in a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to one; s is zero or one; -A2~ is -CONH- or wherein R 8 is C 1 -C 4 alkyl; t and [0C <+> ] are as stated in claim 65. 111. Radio-pharmaceutical compound as stated in claim 70 or 71, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a salt of structural formula wherein each R,, is independently selected from the group consisting of H and Cj-Cy alkyl, or an R^ may be combined with neighboring ^C-R,- such that represents ^.C=0; each R^ is independently selected from the group consisting of H and C-C, alkyl, or an R, may be combined with neighboring ^C-R^ such that represents ^C=0; o is a radical of formula wherein each R 1 is independently selected from the group consisting of H and C 1 -C 1 alkyl; (alk) is a straight-chain or branched lower alkylene group which can further contain 1, 2 or 3 oxygen atoms in the chain, the oxygen atoms not being in a neighboring position to each other and also not in a neighboring position to -A^ -; X- is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to one; s is zero or one; -A^ - is -C00-; and [QC <+> ] is as set forth in claim 70 or 71. 112. Radio-pharmaceutical compound as stated in claim 109, characterized in that the metal radionuclide is the oxotechnate-99m ion. 113. Radio-pharmaceutical compound as stated in claim 110, characterized in that the metal radionuclide is the oxotechnate-99m ion. 114. Radio-pharmaceutical compound as stated in claim 111, characterized in that the metal radionuclide is the oxotechnate-99m ion. 115. Radio-pharmaceutical compound as stated in claim 60, 61 or 62, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a salt of structural formula wherein R 1 and R 2 are each H or C 1 -C 2 alkyl, n' is an integer 0 to 3 and [QC ] is as stated in claim 60, 61 or 62. 116. Radio-pharmaceutical compound as stated in claim 115, characterized in that the metal radionuclide is the oxotechnate-99m ion. 117. Radio-pharmaceutical compound as stated in claim 60, 61 or 62, characterized in that the radiopharmaceutical compound is a chelate of a metal radionuclide with a salt of structural formula wherein [QC <+> ] is as set forth in claim 60, 61 or 62. 118. Radio-pharmaceutical compound as stated in claim 117, characterized in that the metal nuclide is the oxotechnate-99m ion. 119. A salt as specified in claim 2, characterized in that it has the structural formula 120. A compound as set forth in claim 20, characterized in that the structural formula 121. Radio-pharmaceutical compound as stated in claim 38, characterized in that the radio-pharmaceutical compound is a complex of the oxotechnate-99m ion with a compound of formula 122. Radio-pharmaceutical compound as stated in claim 57, characterized in that the radio-pharmaceutical compound is a complex of the oxotechnate-99m ion with a salt of the formula 123. Method for radio-imaging of the brain, characterized in that a patient is administered a radio-pharmaceutical compound as stated in claim 38 in an amount sufficient to deliver an effective radio-imaging amount of a radionuclide to the brain after which the brain is imaged by radiation imaging devices. 124. A kit for the preparation of an injectable radio-pharmaceutical preparation, characterized in that it comprises in separate containers: (1) a compound of formula (II) as stated in claim 20; (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); and (3) a biologically compatible sterile aqueous medium. 125. A kit for the manufacture of an injectable radio-pharmaceutical preparation, characterized in that it comprises in separate containers: (1) a salt of formula (I) as stated in claim 2; (2) a pharmaceutically acceptable reducing agent capable of reducing the salt of the corresponding compound of formula wherein C^}~°9^ is as3 -^ itt in claim 2 and [DHC] is the reduced, biooxidizable blood-brain barrier-penetrating form of a dihydropyridine ■«, * pyridinium salt redox carrier, the reducing agent also being capable of reducing a radioactive metal to an oxidation state in which the metal is capable of complexing with the compound of formula (II); and (3) a biologically acceptable, sterile aqueous medium. 126. Set as claimed in claim 125, characterized in that the radioactive metal which the reducing agent is able to reduce is technetium. 127. Kit as stated in claim 125, characterized in that the reducing agent is sodium dithionite. 128. Set as stated in claim 125, characterized in that the aqueous medium has a basic pH. 129. Kit for the production of an injectable radio-pharmaceutical preparation, characterized in that it comprises in separate containers: (1) a salt of formula (I) as stated 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 wherein (^)~°9 Y is as set forth in claim 2 and [DHC] is the reduced, biooxidizable, blood-brain barrier-penetrating form of a dihydropyridine v * pyridinium salt redox carrier, 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). 130. Seen as claimed in claim 129, characterized in that the radioactive metal which the said reducing agent is able to reduce is technetium. 131. Set as in claim 129, characterized in that the reducing agent is sodium dithionite. 132. Seen as in claim 129, characterized in that the aqueous medium has approximately neutral pH. 133. Kit as set forth in claim 129, characterized in that (2) contains a base in addition to the said reducing agent. 134. Process for producing a salt with formula (1) as stated in claim 2, characterized in that a chelating agent or protected derivative thereof with at least one reactive functional group, selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, and where the functional group is not essential for the complexing properties of the chelating agent, is reacted with a reagent capable of replacing a hydrogen atom from at least one of said reactive groups with a [QC <+> ] radical, or with a radical capable of being quaternized to give a [QC ] -radical, followed by quaternization when the hydrogen atom has been replaced by a radical capable of being quaternized to give a [QC <+> ] radical, since when the protected derivative has been used as starting material this is followed by removal of the protecting group(s) to give the corresponding salt of formula (I). 135. Process for producing a compound of formula (II) as set forth in claim 20, characterized in that the process comprises reduction of a salt of formula (I) as set forth in claim 2. 136. Process for the production of a radiopharmaceutical compound of formula (III) as stated in claim 38, characterized in that the process comprises complex formation of a metal radionuclide with a compound of formula (II) as stated in claim 20. 137. Process for the production of a radio-pharmaceutical compound of formula (III) as stated in claim 38, characterized in that the process comprises the reduction of a radio-pharmaceutical compound of formula (IV) as stated in claim 57. 138. Process for the production of a radio-pharmaceutical compound of formula (IV) as stated in claim 57, characterized in that the process comprises (a) complexation of a metal radionuclide with a salt of formula (I) as stated in claim 2, or (b) oxidation of a radiopharmaceutical compound of formula (III) as set forth in claim 38. A redox or chemical delivery system of the dihydropyridine ^ZZZ ^pyridinium salt type for site-specific and/or site-enhanced delivery of a radionuclide to the brain. A chelating agent capable of chelating with a radionuclide and with a reactive hydroxyl, carboxyl, amino, amide or imide group is coupled to a support moiety comprising a dihydropyridine^pyridiniumsa 11-k nucleus and then complexed with radionuclide to provide a new radionuclide preparation which, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BBB") and allows increased levels of radionuclide concentrations in the brain, particularly as the oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt delays clearance from the brain while clearance from the general circuit is accelerated. This radionuclide delivery system is suitable for use in scintigraphy and similar radiographic methods.