EP0187832A1 - Compounds for site-enhanced delivery of radionuclides and uses thereof - Google Patents

Compounds for site-enhanced delivery of radionuclides and uses thereof

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Publication number
EP0187832A1
EP0187832A1 EP85903633A EP85903633A EP0187832A1 EP 0187832 A1 EP0187832 A1 EP 0187832A1 EP 85903633 A EP85903633 A EP 85903633A EP 85903633 A EP85903633 A EP 85903633A EP 0187832 A1 EP0187832 A1 EP 0187832A1
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EP
European Patent Office
Prior art keywords
formula
alkyl
radiopharmaceutical
group
alkylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP85903633A
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German (de)
English (en)
French (fr)
Inventor
Nicholas S. Bodor
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University of Florida
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University of Florida
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

  • the present invention relates to a dihydropyridine pyridinium salt type of redox, or chemical, delivery system for the site-specific and/or site- enhanced delivery of a radionuclide to the brain and other organs. More particularly, this invention relates to the discovery 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 pyridinium salt nucleus and then complexed with a radionuclide to provide a new radiopharmaceutical that, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BSB”) and allows increased levels of radionuclide concentration in the brain, particularly since oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt retards elimination from the brain while elimination from the general circulation is accelerated.
  • BBB blood-brain barrier
  • the present radionuclide delivery system is well suited for use in scintigraphy and similar radiographic techniques.
  • Radiographic techniques such as scintigraphy, and the like, find application in biological and medical procedures for diagnosis as well as research.
  • Scintigraphy Involves the use of radiopharmaceuticals; i.e., compounds containing (or labeled with) a radioisotope (i.e. radionuclide) which upon introduction into a mammal become localized in specific organs, tissue, or skeletal material that are sought to be Imaged.
  • traces, plates, or sdntlphotos of the existing distribution of the radionuclide may be made by various radiation detectors known in the art. The observed distribution of the localized radionuclide can then be used to detect the presence of pathological conditions, abnormalities, and the like. Radiopharmaceuticals are thus often referred to as radiodiagnostics.
  • radiopharmaceuticals are prepared using target-specific chelating agents which provide a bridge connecting a radionuclide, such as a radioactive metal like technetium-99m, or the like, and a material which will temporarily localize in the organ, tissue, or skeletal material which is to be Imaged.
  • Typical chelating agents for such purposes are: polydentate ligands that form a 1:1 or 2:1 ligand:radioactive metal complex; macrocyclic ligands of appropriate ring size and preferably where all coordinating atoms are in a planar configuration; and blcyclic or polycyclic ligands that can encapsulate the radioactive metal.
  • the Science publication outlines a scheme for specific and sustained delivery of drug species to the brain, as depicted in the following Scheme 1: According to the scheme in Science, a drug [D] is coupled to a quaternary carrier [QC] + and the [D-QC] + which results is then reduced chemically to the lipoidal dlhydro form [D-DHC]. After administration of [D-DHC] in vivo. 1t is rapidly distributed throughout the body, including the brain.
  • the dihydro form [D-DHC] is then in situ oxidized (rate constant, k 1 ) (by the NAD NADH system) to the ideally inactive original [D-QC] quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k 3 » k 2 ; k 3 » k 7 ).
  • Enzymatic cleavage of the [D-QC] + that is "locked” in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k 5 ). metabolism.
  • a properly selected carrier [QC] + will also be rapidly eliminated from the brain (k 6 » k 2 ).
  • N-methyl derivative in vivo supported the criteria set forth in Scheme 1.
  • Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and Indicated that use of N-methyl nicotinic acid esters and amides and their pyridine ring-substituted derivatives was being studied for delivery of araino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed.
  • a drug (typically having a reactive -OH, -COOH or -NH 2 group) can be coupled to a dihydropyridine pyridinium carrier; the lipoidal dihydro form of the drug-carrier system readily crosses the blood-brain barrier; the dihydropyridine moiety is then oxidized in vivo to the ideally inactive quaternary form, which Is "locked in” the brain, while it Is facllely eliminated from the general circulation; enzymatic cleavage of the "locked in” quaternary effects a sustained delivery of the drug itself to the brain, to achieve the desired biological effect.
  • Diagnostic agents such as radiopharmaceuticals are generally disclosed in the PCT application as possible candidates for the carrier system, but the synthetic approach of that application, which utilizes the drug itself as the starting material, is not desirable when radioactive materials, especially relatively short-lived radionuclides, are involved. Moreover, in the case of radionuclides, the earlier objective of an ideally inactive form locked in the brain would not achieve the desired result. Thus, a serious need still exists for an effective general method for the site-spedflc and/or sustained delivery of a desired radionuclide to the brain.
  • a chemical delivery system based upon a dihydropyridine pyridinium salt type redox carrier is uniquely well suited for an effective site-specific and/or sustained and/or enhanced delivery of a radionuclide to the brain or like organ, via novel carrier-containing radiopharmaceuticals, and novel carrier-containing chelating agents and novel carriercontaining precursors thereto, useful in the preparation of said radiopharmaceuticals.
  • the present invention thus provides novel carrier-containing chelating agent precusors having the formula
  • a chelating agent capable of chelating with a metallic radionuclide, said chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and tmide, said functional group being not essential for the complexing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said 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 which when multiplied by n is equal to y .
  • the present invention provides novel carrier-containing chelating agents having the formula
  • the present invention provides, as an effective radionuclide delivery system, novel carrier-containing radiopharmaceuticals of the formula
  • (III) is the chelated, or complexed, counterpart of (II), formed by complexing the novel carrier-containing chelating agent of formula (II) with a radioactive metal.
  • a radiopharmaceutical of formula (III) When a radiopharmaceutical of formula (III) is administered, it readily penetrates the BBB. Oxidation of (III) in vivo affords the corresponding pyridinium salt of the formula
  • the formula (IV) substance is "locked-in” the brain, thus allowing radiographic imaging of the radionuclide present in the complex (IV). While the quaternary "locked-in” form will gradually cleave to release the carrier moiety and the chelate portion of the molecule, such cleavage will generally occur after the most desirable period for radiographic imaging has already passed. It is generally considered most desirable, from the standpoint of patient and technician safety, to image the target area as soon as possible after administration and to use relatively short-lived radio- isotopes.
  • the present invention does not in fact provide a system for delivery and imaging of previously known radiopharmaceuticals; by the time the present delivery system degrades to a chelate of a known chelating agent and a radioactive metal, said chelate will generally no longer be sufficiently radioactive for practical Imaging. Moreover, once such degradation occurs, the known chelate may not be retained in the brain in sufficient amounts to allow imaging thereof.
  • the present invention provides, and indeed requires, an active quaternary form locked in the brain in order to allow effective radionuclide imaging.
  • the present chelate/carrier system for radionuclides is characterized by enhanced efficacy and decreased toxicity. Indeed, consistent herewith systemic toxicity is significantly reduced by accelerating the elimination of the quaternary carrier system from. the general circulation.
  • Technetium-99m is a preferred radionuclide for diagnostic purposes because of its favorable radi ation 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 herein in a chelated form are cobaIt-57, gallium-67, gallium-68, indium-111, indium-111m. and the like.
  • drug as used herein means any sub- stance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animal.
  • non-toxic pharmaceutically acceptable salts generally includes the non-toxic salts of products of the invention of structures (II) and (III) hereinabove formed with non-toxic, pharmaceutically acceptable inorganic or organic adds of the general formula HX.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, sucdnic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetlc, glutamic, benzole, salicylic, sulfanilic, fumaric, methanesulfonic, toluenesul fonic and the like.
  • organic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, sucdnic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetl
  • a compound of formula (III) may be administered 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 the formula
  • amino means any primary or secondary amino function, i.e. -N H2 or -NHR where R is typically C 1 -C 7 alkyl or is a portion of the chelating agent residue itself.
  • the secondary amino function is also represented herein as -NH-, particularly since the exact identity of the R portion of -NHR is immaterial, just so long as it does not prevent the formation of the chelating agent residue and its linkage to the carrier moiety or otherwise interfere with the objects o ⁇ f this invention.
  • hydroxyl means an -OH function
  • amide means a carbamoyl (-CONH 2 ) or substituted carbamoyl (-CONHR, where R is typically C 1 -C 7 alky! functional group.
  • the -CONHR group may also be represented herein as -CONH-, since the exact identity of the R portion of -CONHR is immaterial, just so long as it does not prevent the formation of the chelating agent residue and its linkage to the carrier moiety or otherwise interfere with the objects of this invention.
  • imide means a functional group having the structure
  • the sustained delivery of a radionuclide to the brain in sufficient concentrations for radioimaging can be. effected with much lower concentrations in the peripheral circulation afld other tissues.
  • the present invention o f course will allow such imaging of any other organs or glands in which sufficient radioactivity accumulates.
  • the quaternary form (IV) which is locked in the brain will be locked in the testes as well. See the aforementioned PCT application.
  • the novel radionuclide delivery system of this invention begins with the preparation of the novel carrier-containing chelating agent precursors of formula (I).
  • the preparation of those precursors will be tailored to the particular chelating portion and carrier portion to be combined, and especially to the nature of the chemical bond between them, e.g. whether the linkage is an ester or amide linkage, as well as to the presence or absence of other reactive functional groups (amino, mercapto, carboxyl, Tiydroxy) in either the chelating or carrier portion. Typically, if such other reactive groups are present, they are found in the chelating portion.
  • a step that introduces appropriate protecting groups can be Incorporated at a suitable stage of the synthetic pathway.
  • Protective groups are well known in the art and Include t-butoxycarbonyl for amino groups, N-methyleneacetamldo for mercaptans, and N-hydroxysuccinimidyl for carboxyl groups. Acyl or carbonate groups are typically utilized to protect alcohol hydroxyls.
  • the step of introducing the protecting groups will involve reacting the alcohol with a halocarbonate of the type ROCOCl or ROCOBr (formed by reaction of ROH with COCl 2 or COBr 2 , R typicaliy being lower alkyl).
  • acyl protecting groups For acyl protecting groups, the alcoholic hydroxyl is reacted with an acyl halide RCl or RBr, R being -COCH 3 or -COC(CH 3 ) 3 .
  • R being -COCH 3 or -COC(CH 3 ) 3 .
  • At least one -COOH, -OH, primary or secondary amino, amide or imide group in a chelating agent will be bonded to [QC + ], the hydrophilic, ionic pyridinium salt form of a dihydropyridine pyridinium salt redox carrier.
  • any non-toxic carrier moiety comprising, containing or including the pyridinium nucleus, whether or not a part of any larger basic nucleus, and whether substituted or unsubstituted, the only criterion therefor being capacity 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 ].
  • the Ionic pyridinium salt radiopharmaceutical/carrier entity of formula (IV) which res.ults from in vivo oxidation of the dihydropyridine form (III) is prevented from efflux from the brain, while elimination from the general circulation is accelerated.
  • Radioimaging of the radionuclide present in the "locked in” formula (IV) quaternary allows observation of the distribution of the localized radionuclide for diagnosis of pathological conditions, abnormalities, etc. Subsequently, the coupling between the particular radioactive species and the quaternary carrier [QC] + is likely raet abolically cleaved which results in facile elimination of the carrier moiety [QC + ] .
  • Coupling between the chelate moiety and the quaternary carrier can be a simple direct chemical bond, e.g., an amide bond or ester bond, or any other like bond, or same can even be comprised of a linking group or function as is illustrated in the Examples or the ethylenediamine group illustrated in Schemes 3 and 4.
  • Eventual cleavage of the formula (IV) quaternary with facile elimination of the carrier moiety [QC + ] is characteristically an enzymatic or chemical cleavage, e.g., by an amidase, albeit any type in brain cleavage which might result, whether enzymatic, metabolic or otherwise, of course remains within the ambit of this Invention.
  • dihydropyridine pyridinium salt redox carrier moieties illustrated for use hereinbelow are merely exemplary of the many classes of carriers contemplated by this invention. While the following list of carrier classes is not meant to be exhaustive (and, indeed yet other carrier classes are illustrated hereinbelow as well as in the aforementioned PCT application, PCT/US83/00725), the following major classes of quaternaries and the corresponding dihydro forms are prime examples of the moieties encompassed hereby: (1) For linkage to a chelating agent having at least one -NH 2 , -NH- or -OH functional grouping, replacing a hydrogen atom from at least one of said functional groupings with one of the following [QC + ] groupings:
  • alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R o is a radical identical to the corresponding portion of a natural amino acid;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • R 1 is C 1 -C 7 alkyl, C 1 - C 7 haloalkyl or C 7 -C 10 aralkyl;
  • R 3 is C 1 to C 3 alkylene;
  • the carbonyl-containing groupings in formulas (a) and (c) and the X substituent in formula (b) can each be attached at the 2, 3 or 4 position
  • the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical identical to the corresponding portion of a natural amino acid;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • Z' is C 1 -C 8 straight or branched alkylene, preferably C 1 -C 3 straight or branched alkylene;
  • Q is -0- or -NH-;
  • R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl;
  • R 3 is C 1 -C 3 alkylene;
  • the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical identical to the corres pondi ng porti on of a natural ami no add;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radi cal s can be the same or di f ferent ;
  • alkylene, R 0 , p and R 1 and the position of the carbonyl-containing groupings are defined as above; and with the further proviso that when more than one of the R' 4 radicals in a given compound are the aforesaid carbonyl-containing groupings,, then all such carbonylcontaining groupings in said compound are identical;
  • alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical identical to the corresponding portion of a natural amino acid;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl;
  • R is hydrogen, C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower al koxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl) carbamoyl, di(lower alkyl
  • C 1 -C 7 haloalkyl means C 1 -C 7 alkyl substituted by one or more halogen atoms.
  • alkyl radicals including alkyl and alkylene portions of other radicals, can be straight or branched unless otherwise specified.
  • R 0 is a radical identical to the corresponding portion of a natural amino acid" is believed to be self-explanatory.
  • R 0 can be hydrogen, as in glycine; methyl, as in alanine; -CH(CH 3 ) 2 . as ⁇ n valine; -CH 2 -CH(CH 3 ) 2 , as in leucine;
  • - as in phenyl alanine; , as in tryptophan; -CH 2 OH, as in serine; -CHOH-CH3, as in threonlne; -(CH 2 ) 2 -SCH 3 , as in methionine; -CH2-CONH 2 , as in asparagine; -CH 2 CH 2 -CONH 2 , as in glutamine;
  • amino acids encompassed by the R 0 term include glycine, alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine and glutamine.
  • the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical identical to the corresponding portion of a natural amino acid;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be 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 dotted 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 7 haloalkyl or C 7 -C 10 aralkyl;
  • R 3 is C 1 to C 3 alkylene;
  • X is -CONR'R'', wherein R'
  • alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical Identical to the corresponding portion of a natural amino add;
  • p is 0, 1 or 2, provided that, when p Is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • the dotted line in formulas (i'), (i') and (iii') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring;
  • the dotted 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;
  • V is C 1 -C 8 straight or branched alkylene, preferably C 1 -C 3 straight or branched alkylene;
  • Q is -0- or -NH-;
  • 9. ⁇ is C 1 -C 7 alkyl, C
  • the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1 s a radical identical to the corresponding portion of a natural araino add; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line in formula (xii') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (xiii') Indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinollne 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 said skeleton is derived; n v 1s a positive integer one less than the total number of -OH functions in the sugar molecule from which said skeleton is derived; each A
  • the alkylene group can be straight or branched and can-contain 1 to 3 carbon atoms;
  • R 0 is a radical Identical to the corresponding portion of a natural amino acid;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • the dotted line is defined as with structures (xii') and (xiii');
  • 0' is defined as with structures (xii'), (xiii'), (xiv') and (xiv");
  • R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; and the depicted carbonyl groupings can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring or, except where otherwise specified, at the 1, 3 or 4 position of the isoquinolinium ring;
  • alkylene, R 0 , p, R 1 , the dotted lines and the position of the carbonyl-containing groupings are defined as above; and with the further proviso that when more than one of the R 4 radicals in a given compound are the aforesaid carbonyl-containing groupings, then all such carbonyl-containing groupings in said compound are identical;
  • alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;
  • R 0 is a radical identical to the corresponding portion of a natural amino add;
  • p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different;
  • R is hydrogen, C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, 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 dotted line in
  • dihydropyridine pyridinium salt redox carrier moieties are the quaternaries of
  • Group (1) structures (a), (b), (d), (e), (g) and (h); those of Group (2), structures (i), (ii), (iv), (v), (vii), (viii), (x) and (xii); and those of Group 3, structures (k), (1), (n), (o), (q) and (r); and the corresponding dihydro forms, most especially when they contain the preferred structural variables identified in the preceding paragraph.
  • Scheme 1 above Illustrates a typical synthetic route for compounds in which the linkage between the carrier and chelate portions Is through a -COOH function in the chelating agent.
  • the alcohol reactant can be represented generally as HO-Z'-I wherein Z' Is C 1 -C 8 straight or branched alkylene;
  • the depicted reactant, nicotinamide could be readily replaced with plcoHnamlde, isonlcotlnamlde, 3-quinolinecarboxamide, 4-isoquinolinecarboxamide or the like.
  • (3-Quinolinecarboxamide and 4-isoquinolinecarboxamide can be prepared in known manner, e.g. by treating the corresponding adds with ammonia.)
  • Other process variations will be apparent to those skilled in the art, particularly from the teachings of the aforementioned International Application PCT/US83/00725.
  • n 1-8, preferably 1-3, can be reacted with or other -COOH-containing chelating agent or pre- cursor thereof.
  • Still other varlatlons would include reacting nicotinic acid or other suitable pyridine-ring containing add with an appropriate di- or polyhydroxy compound such as ethylene glycol, propyl ene glycol, inositol or a simple sugar, linking the resultant intermediate via its free hydroxy group(s) to the carboxyl ic acid function of the chelating agent or the precursor thereof, and then quaternizlng that Intermediate.
  • an appropriate di- or polyhydroxy compound such as ethylene glycol, propyl ene glycol, inositol or a simple sugar
  • esters e.g. an ester in which the is replaced with
  • Scheme 6 illustrates a method of particular use when the linkage between the carrier and chelate portions is through an -NH- function which is part of an amide or imide or a very low pKa primary or secondary amine. Conversion of an ester group to the corresponding amide is accomplished with excess ammonium. Then the chelating agent precursor 42 having a -CONH 2 funtlonal group is subjected to N-hydroxyalkylation, e.g. by reaction with an aldehyde [e.g. formaldehyde, benzaldehyde, acetaldehyde or chloral(Cl 3 CCHO)]; thus, for example, in the case of chloral, the CONH 2 group becomes a
  • Scheme 7 is Illustrative of a process in which the -NH- group to which the carrier is to be linked is part of an Imide structure. The earliest steps of this Scheme are described in the aforementioned Fritzberg patent. Then, 51 is reacted with excess ammonia to form the corresponding succinamide which, when heated, loses ammonia to give the succinimide 52. That intermediate is then reacted with an aldehyde, as generally described in the preceding paragraph. and the resulting -OH containing group then derivatized, also as described previously.
  • Scheme 8 illustrates yet another alternate to Schemes 1 and 2; 3,4-dlarainobenzoic acid is disclosed as a starting material for chelating agents in the Fritzberg patent.
  • Scheme 8 follows the reaction sequence of Scheme 2 and could be varied in any of the many ways described in conjunction with Scheme 2 hereinabove. Moreover, 59 could alternatively be subjected to the reactions shown in Schemes 5 and
  • Schemes 10 and 15 above illustrate typical conversion of an alcohol (-CH 2 OH), which may be obtained from the corresponding carboxyl 1c acid ester, to the corresponding nicotinoyl ester; reaction of the ester derivative with methyl iodide to afford the desired formula (I) quaternary; and reduction to the corresponding formula (II) dihydro or conversion directly to the corresponding formula (III) radiopharmaceutical.
  • an alcohol -CH 2 OH
  • reaction of the ester derivative with methyl iodide to afford the desired formula (I) quaternary
  • reduction to the corresponding formula (II) dihydro or conversion directly to the corresponding formula (III) radiopharmaceutical For process variations, see the discussion of Schemes 3, 4 and 5 hereinabove.
  • Scheme 11 above there is shown a typical method for introducing a longer alkylene chain between an atom which is involved in forming the chelate structure and a pendant NH 2 group which is to be coupled to the carrier moiety.
  • a secondary amino group is reacted with a haloalkamide, e.g. BrCH 2 CONH 2 , replacing the hydrogen of the with -CH 2 CONH 2 Reduction of the amide affords the corresponding CH 2 CH 2 NH 2 compound.
  • That amine can then be reacted with an activated ester of nicotinic acid, followed by quaternization and reduction as in the other schemes.
  • a haloalkamide e.g. BrCH 2 CONH 2
  • Schemes 13 and 16 illustrate yet other methods for lengthening the alkylene chain, the chain here being interrupted by one or more oxygen atoms.
  • a -CHgOH group is typically converted to the corresponding lithium salt and then reacted with an iodoalkanol, e.g. ICH 2 CH 2 OH, to convert the -CH 2 O-Li + group to a -CH 2 OCH 2 CH 2 OH group.
  • an iodoalkanol e.g. ICH 2 CH 2 OH
  • Scheme 18 above shows another typical method for introducing a longer alkylene chain between the nitrogen atoms.
  • the secondary amino group is converted to the corresponding group.
  • the resultant amine can then be reacted with an activated ester of nicotinic acid, followed by quaternization and reduction as in the other schemes.
  • the quaternary chelating agent precursor of the invention can be prepared directly from reaction of the corresponding amine with a quaternized activated ester of nicotinic acid.
  • Schemes 3, 4 and 5 above will be apparent, e.g. from Schemes 3, 4 and 5 above.
  • Scheme 19 represents an alternate approach to the derivatives resulting from Scheme 1.
  • this scheme could be varied in a number of ways, most notably in the fourth step, where nicotinamide could be replaced with another amide (e.g. one of those dis- cussed in Scheme 1) and where ICH 2 CH 2 OH could be replaced with another compound of the type I-Z'-OH where Z' is C 1 -C 8 straight or branched alkylene.
  • Scheme 20 illustrates an alternate route to the derivatives of Scheme 8. This scheme represents a particularly attractive synthetic route to the protected quaternary derivative 62. Moreover, the intermediate 176 can be varied as discussed in conjunction with Scheme 19; also, this process can be adapted to the preparation of derivatives of other -COOH-containing chelating agents, e.g. those of Schemes 1 and 2.
  • Scheme 22 is illustrative of yet another variation in the procedure of Scheme 8.
  • Scheme 22 can be readily adapted to the preparation of other derivatives of this invention; see, for example, the discussions of Schemes 8 and 20 above.
  • reaction with acetone protects both the secondary amino and thiol functions by formation of thiazolidine structures so that those functions do not interfere during addition of the carrier moiety.
  • the secondary amino and mercapto groups are regenerated by reacting the protected intermediate with mercuric chloride in an organic solvent such as methanol, conveniently at room temperature, and then decomposing the resulting complex with hydrogen sulfide. See, for example, British Patent Specification No. 585,250, which utilizes such a procedure for the production of esters of penicillamine.
  • the process of Scheme 9 can be used to prepare the other derivatives of this invention. Variations in the procedure used, e.g. as discussed in connection with Scheme 23, can be used to obtain yet other derivatives of the invention.
  • Scheme 25 represents an alternate route to the compounds obtained via Scheme 14.
  • the route uses the preferred route of introducing the carrier moiety in its quaternary form and can be readily adapted to the preparation of derivatives of other -COOH containing chelating agents and/or introduction of other carrier moieties disclosed herein.
  • Scheme 26 there is illustrated a process for
  • Scheme 27 depicts a process for preparing carriercontaining derivatives of yet another type of chelating agent.
  • the desired chelating agent in this instance contains oxime functions, which are introduced after the quaternary form of the carrier has been attached. Formation of derivatives of yet another type of chelating agent is deplcted'in Scheme 29.
  • Reduction of the quaternary salt of formula (I) to the corresponding dihydro derivative of formula (II) can be conducted at a temperature from about -10°C to room temperature, for a period of time from about 10 minutes to 2 hours, conveniently at atmospheric pressure.
  • a large excess of reducing agent is employed, e.g., a 1:5 molar ratio of reducing agent to starting compound of formula (I).
  • the process is conducted 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 conveniently carried out in an aqueous solution; the dihydro product of formula (II) is usually insoluble in water and thus can be readily separated from the reaction medium.
  • an organic reaction medium e.g., a lower alkanol such as methanol, an aqueous alkanol or other protic solvent.
  • the quaternary of formula (I) is reduced in the same reaction mixture as the reduction of technetium to an appropriate oxidation state, affording the formula (III) radiopharmaceutical in one step from the formula (I) quaternary. Further details of the one-step reduction are given hereinbelow.
  • each R 5 is independently selected from the group consisting of H and C 1 -C 7 alkyl, or an R 5 can
  • HN NH is a radical Q' of the formula
  • each R 7 is independently selected from the group consisting of H and C 1 -C 7 alkyl;
  • (alk) is a straight or branched lower alkylene group (C ⁇ -C «) which additionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A'-;
  • X" and n are as defined with formula (I);
  • m' is a number which when multiplied by n is equal to one; s is zero or one;
  • -A- is -NH-, -CO0-, -0-, -CONH-, wherein
  • R 8 is C 1 -C 7 alkyl, or wherein R 9 is C 1 -C 7 alkyl;
  • [QC + ] is a radical of any one of formulas (a) through (j) hereinabove; when -A- is -CONH- or or when has the imide structure dep cted above, en [QC + ] is a radical of any one of formulas (k) through (s) hereinabove; and when -A- is -COO-, then [QC + ] is a radical of any one of formula (i) through (xiv) hereinabove.
  • the salts of formula (la) have the partial structure
  • each R 7 is preferably H and (alk) is preferably a C 1 -C 7 al kyle ne group, or a C 1 -C 6 alkylene group interrupted by an oxygen atom in the chain; and that when
  • (alk) is preferably a C 1 -C 6 alkylene group, or a C 1 -C 6 alkylene grou ⁇ p inte/rrupted by an oxygen atom in the chain.
  • the presently preferred values for -(alk) s -A- are -COO-, -CH 2 O-, -CONH-, -CH 2 NH- and -CH 2 OCH 2 CH 2 O-, Preferred values for [QC + ] in formula (la) are as given in conjunction with formula (I) hereinabove.
  • R 5 and R 6 are as defined with formula (la) and is a radical of the formula
  • R 7 , (alk), s and -A- ar defined with formula (la); when -A- is -NH-, -0- or wherein R 8 is C 1 -C 7 alkyl, then [DHC] is a radical of any one of formulas (a') through (j'' ) hereinabove; when -A'- is -CONH- or wherein R 9 is C 1 -C 7 alkyl or when has the imide structure depicted above, then [DHC] is a radical of any one of formulas ( k ) through (s'' ⁇ hereinabove; and when -A- is -COO-, then [DHC] is a radical of any one of formulas (i') through (xiv'') hereinabove.
  • Preferred compounds of formula (Ila) are the dihydro derivatives corresponding to the preferred compounds of formula (la).
  • novel radiopharmaceuticals in which a formula (Ila) compound is chelated with a radioactive metal, especially with technetium.
  • a formula (Ila) compound is chelated with a radioactive metal, especially with technetium.
  • Especially preferred radiopharmaceuticals have the formula
  • R 7 , alk, s and -A- are as defined with formula (la) and [DHC] is as defined with formula (Ila) above; and the corresponding quaternaries, "locked in” the brain, especially those of technetium, which have the formula
  • R 5 , R 6 , m', X- and n are as defined with formula (la) and is a radical of the formula
  • R 1 , R 2 , R 3 and R 4 are each H or C 1 -C 3 alkyl can be first converted to the corresponding esters (e.g. replacing -COOH with -COOC 2 H 5 ), which can then be reduced to the corresponding alcohols (replacing -COOC 2 H 5 with -CH 2 OH) or converted to the corresponding amides; the alcohols or amides can then be converted to the corresponding carrier-containing derivatives; see, for example, the discussion of Schemes 9-16 above. Other process variations will be apparent from the many reaction schemes depicted hereinabove.
  • Another bifunctional chelating agent which can be readily converted to the redox system-containing chelating agent precursors, chelating agents and radiopharmaceuticals of this invention is a compound of the formula
  • Amino DTS can be readily converted to the derivatives of the present invention by reacting it with an activated ester of nicotinic acid or the like and quaternizing the resulting ester to afford the corresponding precursor of formula (I), which can then be utilized as generally described herein to prepare the corresponding compound of formula (II) and radiopharmaceuticals of formulas (III) and (IV). See, for example, Scheme 30 below.
  • Yet another group of known chelating agents which is particularly well-suited for conversion to the redox system-containing chelating agent precursors, chelating agents and radiopharmaceuticals of the present invention can be represented by the formula
  • R 1 , R 2 , R 3 and R 4 are each H or C 1 -C 3 alkyl and n' is an integer of 0 to 3.
  • n' is an integer of 0 to 3.
  • An especially preferred chelating agent encompassed by this group is known as amino-PTS, or AEPM, and has the structure
  • Amino-PTS can be converted to the derivatives of the present invention via the activated ester, as described supra in connection with amino-OTS. See, for example, Scheme 33 below.
  • One possible s t ruct u re for 224 is as follows:
  • the presently contemplated carrier system can be incorporated into the structure of a novel technetium-99m radiopharmaceutical whose chelate portion Is the residue of an amino- o r hydroxy-substituted iminodiacetic acid, e.g., N-[3-(l-naphthyloxy)2- hydroxypropyl] iminodiacetic acid.
  • a novel technetium-99m radiopharmaceutical whose chelate portion Is the residue of an amino- o r hydroxy-substituted iminodiacetic acid, e.g., N-[3-(l-naphthyloxy)2- hydroxypropyl] iminodiacetic acid.
  • Such substituted iminodiacetic acid chelating agents are known and are described in Loberg et al U.S. Patent No. 4,017,596; such chelating agents can be protected to the extent necessary and then the trigonell inate or other carrier structure introduced through reaction
  • suitable chelating agents and their precursors that include a di hydropyridine 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-diaminopentyl phosphonic acid, and the like.
  • a chelating agent which is a substituted-alkyl monophosphonic acid such as aminobutylphosphonic acid, 1, 5-diaminopentyl phosphonic acid, and the like.
  • Chelating agents of this general type are also known and are illustrated by those described in K ⁇ hler et al U.S. Patent No. 3,976,762.
  • X is H or -COOH, and R and R' are H or lower alkyl, and. water-soluble salts thereof, used to prepare the corresponding radiopharmaceuticals of the formula
  • X is H or -COOH
  • R and R' are H or lower alkyl.
  • the Fritzberg chelating agents are prepared from the corresponding 2,3-diaminoalkanoic acids by esterification with a lower alkanol containing dry HCl, followed by treating the resultant alkyl ester with a chloroalkanoyl chloride to form the bis(chloro alkanoamide)ester, followed by treating that ester
  • Radiopharmaceuticals containing a dihydropyrldine pyridiniu ⁇ n salt carrier system can also be prepared using a novel chelating agent precursor obtained by reacting, in pyrldine as the solvent, the aforementioned Compound 29 with nitrilotrlacetic anhydride according to the known general procedure illustrated in Kunn et al U.S. Patent No. 4,418,208.
  • the dlcarboxyl pyridinium salt obtained from the above reaction is obtained in purified form as follows:
  • the volatile components of the reaction mixture are evaporated to an oily semisolid on a rotary evaporator.
  • a solution of 10 percent aqueous sodium hydroxide (w/v) is used to dissolve the oily semlsolid.
  • the resulting solution is extracted with methyl ene chloride to remove the remaining pyrldine from the aqueous phase.
  • the pH value of the aqueous phase is thereafter lowered to a value of about 6-8.
  • the resulting aqueous solution is then reduced in volume to about that of the original pyrldine solution, and about five times that volume of a saturated solution of picric acid is added to form a picrate derivative precipitate.
  • the plcrate precipitate Is washed with cold, distilled water, and is then dissolved in a 10 percent aqueous solution of hydrochloric acid (v/v).
  • the resulting solution Is extracted with methyl chloride until there is no more yellow color in the aqueous or methyl ene chloride phases.
  • the resulting, colorless aqueous phase is concentrated to about the volume of the original pyrldine solution, and is then lyophyllzed to provide the chelating agent in dry form.
  • the dried chelating agent is then dissolved in ethanol and precipitated using the diethyl ether flooding technique described in Example 4 hereinbelow.
  • Still another useful chelating agent precursor can be prepared by reacting equimolar quantities of ethylenediarainetetracetic acid and acetic anhydride in dry pyrldine following the teachings of Nunn et al U.S. Patent No. 4,418,208, and thereafter reacting a further equimolar amount of Compound (29) to form the monoamide adduct.
  • the tridentate chelating agent salt is obtained as described Immediately above.
  • the tridentate chelating agent precursor salt so obtained is thereafter reacted with the 99ra pertechnate ion as described in Example 5 below, which reduces both the technetium and the pyridinium salt, to form a 1:1 ligandcradioactive metal ion complex drug delivery system of this invention.
  • the complex so formed is ionically neutral inasmuch as the five valences of the reduced technetium-99m metal are taken up with one oxygen atom and three carboxylate oxygens, and the pyridinium ring is in its reduced, dihydropyridine form.
  • the preparation of the chelating agent precursors, chelating agents and radiopharmaceuticals of this invention must be tailored to the particular starting materials used, especially as regards the presence of reactive functional groups in addition to the group which is to be linked to the carrier radety.
  • the stage at which the carrier is introduced and the manner in which the carrier is Introduced will be determined accordingly. Often the carrier must be introduced in quaternary form at an early stage of the synthesis as illustrated hereinabove.
  • an appropriate starting material such as nicotinic anhydride with an NH 2 - or OH- containing ligand or ligand precursor, and quaternize at a later stage, after coupling the ligand (chelating agent) and the 3-pyridinecarbonyl group.
  • N-(t-butoxycarbonyl),N-(2-mercaptoethyl)glycyl homocysteine thiolactone (13) is prepared as described in Examples 1 and 2 of Byrne et al U.S. Patent No. 4,434,151, and is dissolved (1.0 gram; 3 raillimoles) in 25 mill iliters of tetrahydrofuran (THF). The resulting solution is then cooled to about 0°C, and ethylenediamine (1.8 grams; 30 millimoles) is added to form a new solution. The resulting new solution is maintained for about one hour. The volatile components of the solution are thereafter removed with a rotary evaporator.
  • n-Butanol (about 10 mill iliters) is added to the "dried” solution components and the liquid components of the resulting composition are again removed by rotary evaporation. The last step is repeated until the vapors remaining in the evaporation vessel do not cause a moistened pH-indicator paper to indicate a basic pH value, thereby also Indicating that the ethylenediamine has been substantially removed and that the N-(t-butoxycarbonyl),N-(2-mercaptoethyl)- glycyl N'-(2-aminoethyl)homocysteinamide so obtained Is substantially pure.
  • Example 2a Succinimidyl nicotinate (Compound 16 of Scheme 3)
  • Nicotinic acid (12.3g;.0.1 mole) and N-hydroxysucdnlmide (11.5g; 0.1 mole) are dissolved in 300 milliliters of hot dioxane.
  • Tfve mixture is cooled on an ice-bath and dicyclohexylcarbodi Imide (20.6g; 0.1 mole) In 30 mlliiliters of dioxane fs added.
  • the reaction mixture is stirred, with cooling, for approximately three hours, then refrigerated for at least 2 hours.
  • the precipitated dicyclohexylurea is removed by filtration, the solution is condensed under vacuum, and the yellowish solids which precipitate are recrystallized from ethyl acetate.
  • White crystals (14g) of succinimidyl nicotinate are obtained (Yield 63.6%). Structure of the product is confirmed by NMR.
  • Succinimidyl nicotinate 16 (3.3 g; 15 mmole) is dissolved in 50 milliliters of dioxane and 3.7 millliiters (8.2g; 60 mraole) of methyl iodide is added. The reaction mixture is refluxed for about 48 hours. The yellow crystals which precipitate during the reaction are removed by filtration, washed with ethyl ether and dried under vacuum at 40°C. Succinimidyl trigonell inate (5.2g) is obtained (Yield 96.3%). Structure of the product is confirmed by NHR. An improved method for preparing Compound 17 is as fol lows:
  • the pyridine is removed on a rotary evaporator using n-butanol as a "chaser” as described before for the ethyl enediamine removal.
  • the dried residue is triturated with THF and the solid is removed by filtration and washed several times with THF with care not to dry by air suction.
  • the solid so obtained is thereafter dried in vacuo to provide Compound 18, N(t-butoxycarbony 1), N-(2-mercaptoethyl)glycyl N'-[1-methyl-3-(2-N-ethyl) carbamoyl - pyridinium iodide]homocysteinamide.
  • Example 4 N-(2-mercaptoethyl)glycyl N'-[l-methyl-
  • the precipitate is filtered and washed with diethyl ether with care not to dry the precipitate by air suction.
  • the solid is then dried in vacuo to provide N-(2-mercaptoethyl)glycyl-N'- [1-methyl-3-(2-N-ethyl)carbamoylpyridinium iodide] homocysteinamide.
  • N-(2-mercaptoethyl)-glycyl-N'-[l-methyl- 3-(2-N-ethyl)carbaraoyl pyridinium iodide]homocysteinaraide Compound 19 — (89 milligrams; 0.17 millimole) is dissolved in 1.0 millillter absolute ethanol and 1.0 milliliter of 1N NaOH. A 1.0 milliliter generator eluant of 99m Tc (5 to 50 milliCuries) in saline is added.
  • 0.5 millillter of dithionite solution prepared by dissolving 336 milligrams of Na 2 S 2 O 4 per milliliter of 1.0 NaOH, is added and the mixture heated sufficiently to reduce both the technetium and the pyridinium salt and to form the complex between N- (2-mercaptoethyl) glycyl -N'-[l-methyl -3- (N-ethyl)caramoyl-l,4-dihydropyridyl]homocysteinamide and the oxotechnate-99m 1on.
  • the complex so prepared is buffered by the addition of 1.0 milliliter of 1N HCl and 4.0 milliliter of 0.1 molar NaH 2 PO 4 , pH 4.5 buffer.
  • Example 6 Complex Between N-(2-mercaptoethyl)glycyl- N'-Cl-methyl-3-(N-2-ethyl)carbamoyl-1,4- dihydroquinolyl]homocysteinamide and the 0xotechnate-99m ion
  • a radiopharmaceutical coupled to a carrier based upon a reduced, dihydroquinol ine carrier such as the title complex can be prepared following the steps outlined in Examples 1-5, but replacing the nicotinic acid in Example 2a with an equivalent quantity of 3- quinolinecarboxylic acid.
  • Example 9 Complex Between N-(2-mercaptopropionyl)- glycyl-N'-[l-raethyl-3-(2-N-ethyl)carbamoyl- 1,4-dihydropyrldine]homocysteinamide and the Oxotechnate-99m ion- (Compound 27 of Scheme 4)
  • Example 8 Compound 26 of Example 8 (0.17 millimole) is dissolved in 1.0 milliliter of absolute ethanol and 1.0 milliliter of IN NaOH.
  • the complex of this Example is thereafter prepared in a manner analogous to that described for the complex of Example 5.
  • the basic solution frees the 2-mercaptopropionyl group from its protective N-methylene acetamido group, while the dithionite reduces both the pyridinium and technetium salts
  • Example 10 3,4-dithia-2,2.5.5-tetramethylhexane- 1,6-dione (Compound 68 of Scheme 9)
  • a solution of 8 g of the ester 70 and 7 mL of pyridine in 200 mL of methanol is added dropwise over a two 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 the addition for 1 hour, then is allowed to remain at room temperature for 1 hour.
  • the reaction mixture is then placed in a freezer (-20°C) overnight.
  • 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.
  • a solution of 1.8 g of the amide 73 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 over a 30 minute period.
  • the mixture is then heated at the reflux temperature for 20 hours. At the end of that time, the reaction mixture is first cooled and then quenched with saturated Na-K tartrate solution. The aqueous phase is extracted with chloroform. The combined organic phase is then dried over sodium sulfate.
  • Example 5 The general procedure of Example 5 can be repeated to convert the other quaternary salts of formula (I) to the corresponding radiopharmaceuticals, e.g. to convert Compound 76 to Complex 78, Compound 83 to Complex 85 and so forth.
  • the component with the lower R f value shows a positive ninhydrin test, confirming that it is the desired primary amine 192, while the component with the higher R f value is negative.
  • Cyanoacetlc add (8.5 g; 0.1 mol) and N-hydroxysuccinimide (11.5 g; 0.1 mol) are combined in 150 mL of dry tetrahydrofuran.
  • To the cooled suspension is added dropwise a solution of 20.6 g (0.1 mol) of dicyclohexylcarbod ⁇ mide in 50 mL of dry tetrahydrofuran over a period of 2 hours. The mixture is allowed to warm to room temperature overnight. The white precipitate which 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 3 g of the nitrile 168 in 50 mL of dry tetrahydrofuran is added dropwise over a 30 minute 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 at reflux for 7 hours, 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 sulfate.
  • Rotary evaporation of the solution leaves the amine 1£9 as a viscous yellow oil.
  • a solution of the ester 71 (10 g, 35 mmol) in 100 mL of dry tetrahydrofuran is added dropwise over a priod of 30 minutes to a slurry of lithium aluminum hydride (4 g, 94 mmol) in 300 mL of dry tetrahydro- furan, with cooling in an ice-bath.
  • the slurry is then heated at reflux for 24 hours.
  • the reaction is quenched with saturated Na-K tartrate solution, then with 3N hydrochloric acid and finally with sodium carbonate.
  • the aqueous phase is extracted with chloroform.
  • the combined organic phase is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate.
  • the acid 178 (8 g) and N-hydroxysuccinimide (1.8 g) are combined in 200 mL of tetrahydrofuran. To that 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 concentrated in vacuo. The product, the activated ester 179, is crystallized from toluene.
  • Example 50 l- ⁇ 4'- ⁇ -[N-(1''-methyl-1'',4"- dihydropyridin-3''-yl)carbonylamino]- ethyl ⁇ phenyl ⁇ propane-1,2-dione bis(4- methylthiosemicarbazone), hydrated with 1/4 mole H 2 O (Compound 223 of Scheme 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).
  • the chelating agent or its protected counterpart e.g. 74 in Scheme 9 or 192 in Scheme 24 or 221 in
  • glycine may be first reacted with a reagent capable of introducing an amino protecting group such as benzyloxycarbonyl or t-butoxycarbonyl and the N-protected glycine 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 nicotinoyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to afford the nicotinuramide.
  • the nicotinuramide may then be quaternized and the quaternary de- protected if necessary and reduced as described in the preceding paragraph.
  • the procedure of the second paragraph of this method may be repeated using picolinlc add or its acid chloride or anhydride, or isonicotlnic add or its acid chloride or anhydride, in place of nicotinic acid or its acid chloride or anhydride, respectively, to convert chelating agents or their protected counterparts to the corresponding glycyl picol inamides and glycyl isonicotinamides and then to the corresponding quaternary and dihydro derivatives.
  • the procedure of the first paragraph of this method may be similarly adapted.
  • any of these procedures may be repeated, substituting a different amino acid or nicotinic acid derivative thereof for the glycine or nicotinuric acid used above, e.g. replacing glycine with alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine.
  • the chelating agent or its protected counterpart may be reacted with an activated ester of nicotinuric acid or the like, e.g. a sucinimidyl ester such as
  • the activated ester e.g. the siccinimidyl ester depicted above
  • the activated ester may be quaternized (e.g. by treatment with methyl iodide) and the quaternized activated ester then reacted with the drug.
  • the quaternary compound thus obtained may then be de-protected if necessary and reduced as described in the first paragraph of this method.
  • the chelating agent (e.g. 52 in Scheme 7) is first reacted with an aldehyde [e.g. formaldehyde, benzaldehyde, acetaldehyde or chloral (CI 3 CCHO)]; for example, in the case of formaldehyde, one converts the -NH- function to a
  • the resultant compound is then reacted with nicotinuric acid in the presence of a suitable dehydrating agent, or with nicotinuric acid chloride or nicotinuric acid anhydride, to form the corresponding nicotinuric acid ester of the partial formula
  • the procedure of the preceding paragraph may be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, in place of nitotlnic acid or its acid chloride or anhydride, respectively (as called for in the second paragraph of Method A), to convert chelating agents to the corresponding glycyl picolinic acid esters and glycyl isonicotinic acid esters and then to the corresponding compounds of this invention.
  • Derivatives of amino acids other than glycine may be similarly prepared. See Method A, last paragraph.
  • That derivative may then be reacted with a metallic salt (especially a silver or thallous salt) of nicotinuric acid or the like (formed, e.g. by reacting nicotinuric acid or the like with fresh silver hydroxide or oxide or with thallous ethoxide).
  • a metallic salt especially a silver or thallous salt
  • nicotinuric acid or the like formed, e.g. by reacting nicotinuric acid or the like with fresh silver hydroxide or oxide or with thallous ethoxide.
  • Method A may be similarly adapted to the production of the 3- quinolinecarboxylic acid derivatves.
  • Method C may be combined with Method to afford the corresponding 3-quinol inecarboxylic acid derivatives of the type of chelating agent used in that method.
  • the procedure of the first paragraph of this method may be repeated using 4-isoquinol inecarboxylic acid or its acid chloride or anhydride to convert chelating agents such as those mentioned with Methods A and B to the corresponding 4-isoquinol inecarboxylic acid derivatives.
  • the procedure of the first or third paragraph of this method may be repeated, substituting a different amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine, for the glycine used in the first step. (See Method A, second paragraph).
  • a different amino acid e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine
  • nicotinic acid is used place of nicotinic acid. (That starting material may be prepared by reacting nicotinic anhydride, nicotinoyl chloride or nicotinic add with glycolic acid.)
  • the quaternary salt thus obtained may then be de-protected if necessary and reduced as described in Method A. See also Scheme 26.
  • the chelating agent or its protected counterpart (e.g. 81 of Scheme 10, or the corresponding bisthiazolidine) is reacted with nicotinuric acid chloride, with nicotinuric acid anhydride, or with nicotinuric acid in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, in an appropriate organic solvent, to afford the corresponding glycyl nicotinate, or nicotinurate.
  • the nicotinurate is then quaternized, de-protected if necessary and subsequently reduced as described above in Method A.
  • the alternative process utilizing an activated ester or quaternary derivative thereof which is described in Method A may be utilized to advantage here as well.
  • glycine may be first reacted with a reagent capable of introducing an amino protecting group such as benzyl oxycarbonyl or t-butylcarbonyl and the N- protected glycine 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 nicotinoyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to afford the nicotinurate.
  • the nicotinurate may then be quaternized, de-protected if necessary and the quaternary reduced as described in the preceding paragraph.
  • the procedure of the second paragraph of this method may be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, in place of nicotinic acid or its acid chloride or anhydride, respectively, to convert chelating agents to the corresponding glycyl picolinic acid esters or glycyl isonicotinic acid esters and then to the corresponding compounds of the invention.
  • the procedure of the first paragraph of this method may be similarly adapted.
  • any of these procedures may be repeated, substituting a different amino acid or nicotinic acid derivative thereof for the glycine or nicotinuric acid used above, e.g. replacing glycine with alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine.
  • n 1-3, preferably 2 (prepared as described in Method E), is used in place of nicotinic acid.
  • the quaternary salt thus obtained may then be de-protected if necessary and reduced as described in Method A.
  • Method G is of particular use in preparing derivatives of chelating agents in which the hydroxy function is hindered.
  • Method G may follow Method F, second paragraph, except that it employs a reactant of the formula
  • Method F The procedure of the first paragraph of Method F may be similarly adapted to the production of the 3- quinolinecarboxylic acid derivatives.
  • Method H may be repeated using 4- isoqulnolinecarboxylic acid or its acid chloride or anhydride in place of 3-quinolinecarboxylic acid or its acid chloride or anhydride.
  • 3-Quinol inecarboxyl ic acid or its acid chloride or anhydride or 4-isoquinolinecarboxyl ic acid or its acid chloride or anhydride can also be substituted for nicotinic acid or its acid chloride in Method B, fourth paragraph, to afford the corresponding derivatives.
  • the general procedures described above may be utilized to provide the 1,2-dlhydro derivatives as well as the 1 ,4-dihydros.
  • a starting material of the formula set forth immediately above can also be substituted for nicotinic acid in Method B, paragraph 4, to afford the corresponding derivatives.
  • Method I may follow Method F, second paragraph, except that it employs a reactant of the formula
  • Method I (prepared as described in Method D).
  • Method I starting materials may be substituted for nicotinic acid in Method B, fourth paragraph, to give the corresponding derivatives.
  • the procedure of the first or third paragraph of this method may be repeated, substituting a different amino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine, for the glydne used in the first step. (See Method A, second paragraph).
  • Nicotinuric acid N-nicotinoyl glycine
  • an activated ester thereof is reacted with an aminoal kanol
  • Z' is C 1 -C 8 straight or branched alkylene, e.g. 2-aminoethanol, to afford the corresponding intermediate alcohol, e.g. in the case of 2-aminoethanol, an intermediate of the formula
  • Nicotinuric acid is commercially available. However, it and analogous starting materials can be readily prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of picolinic acid, of isonicotinic acid, of 3-quinol Inecarboxylic acid, of 4-isoquinolinecarboxylic acid or the like to afford the desired N-substituted amino acid, which can then be reacted with an aminoal kanol as described above.
  • the chelating agent is first reacted with ethylene glycol (or other dihydroxyal kanol having up to 8 carbon atoms), in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH function(s) to the corresponding
  • N-protected amino acid such as N-benzyloxycarbonylglycine, which has been prepared as described in Method A, is reacted therewith in the presence of dicyclohexylcarbodiimide or other appropriate coupling agent. Removal of the protecting group, e.g. by catalytic hydrogenation, affords a derivative of the chelating agent in which the original -COOH group(s) has/have, in the case of utilizing ethylene glycol and glycine, been converted to the structure
  • a chelating agent containing one -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 to a group of the structure
  • each R is H or the number of original hydroxy groups esterified varying with the amount of nicotinuric acid employed. Subsequent quaternization and reduction are carried out as in Method A.
  • the above procedure may be repeated, replacing nicotinuric acid with an analogous starting material, prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of pico linlc acid, or isonicotlnic acid, of 3-quinolinecarboxylic acid, of 4-isoquinolinecarboxylic acid or the like.
  • the chelating agent is first reacted with 1,2- propylene glycol (or other dihydroxyalkanol having up to 8 carbon atoms), in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH function(s) to the corresponding
  • the above procedure may be repeated, replacing nicotinuric acid with an analogous starting material, prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of picolinic acid, of isonicotlnic acid, of 3-quinol inecarboxylic acid, of 4-isoquinolinecarboxlic acid or the like.
  • a chelating agent containing one reactive -COOH function is then reacted with a chelating agent containing one reactive -COOH function, in the presence of dicyclohexylcarbodiimide or other appropriate coupling agent, replacing one or more of the hydroxy groups with acid residue(s), the number of groups replaced varying with the relative amounts of reactants used.
  • the above procedure may be repeated, replacing nicotinuric acid with an analogous starting material, prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of picolinic acid, of isonicotinic acid, of 3-quinol inecarboxylic acid, of 4-isoquinolinecarboxylic acid or the like.
  • Suitable nontoxic pharmaceutically acceptable diluents or vehicles for use with the present complexes of formula (III) will be apparent-to those skilled in this art. See, for example, Remington's Pharmaceutical Sciences, 4th Edition (1970). Obviously, the choice of suitable diluents or vehicles will depend upon the exact nature of the particular dosage form selected.
  • the dosage ranges for administration of the complexes according to this invention will vary with the size and species of the subject, the objective for which the complex is administered, the particular dosage form employed, and the like, as discussed below.
  • the quantity of given dosage form needed to deliver the desired dose of the radiopharmaceutical depends upon the concentration of the complex in any given pharmaceutical composition/dosage form thereof and the radioactivity thereof.
  • a 5-50 mg/kg dose of formula (III) radiopharmaceutical injected into the tail vein or carotid vein of rats, due to the "lock in” mechanism will exhibit a very significant difference between brain and peripheral levels of radioactivity, with consequent ready radioimaging of the brain; imaging at approximately 60 to 90 minutes after administration will be most effective, since it will take advantage of this brain/peripheral differential.
  • the instant radiopharmaceuticals are generally administered intravenously. Sustained release administration, typically by slow intravenous Infusion, will further enhance the site-specificity of the instant redox system.
  • the rate of release of the formula (HI) radiopharmaceutical 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) in order to achieve the greatest degree of enhancement of specificity.
  • the present invention also provides a process for the manufacture of a diagnostic agent for the visualization of an organ such as the brain.
  • the blood-brain barrier penetrating form, formula (III) is admixed with an aqueous buffer medium having a pH value of about 4 to about 8 preferably of about 6.5 to about 7.5, in an effective radloimaging amount.
  • Preparation of the radiopharmaceutical can be carried out in the hospital or like location where the patient is found in order to minimize losses of radioactivity caused by the decay of the radioactive metal.
  • a so-called labeling kit can be provided that permits a simple, rapid and safe labeling of the solution to be injected with the radioactive metal, e.g., technetium-99m.
  • the radioactive metal e.g., technetium-99m.
  • kits are especially desirable when a short-lived radioisotope such as technetium 99-m is used.
  • the kit Includes a collecting vial for receiving and/or containing an aqueous medium in which the complexing reaction can be effected.
  • the kit includes the chelating agent of formula (II) or chelating agent precursor of formula (I) and a pharmacologically acceptable reducing agent for reducing the radioactive element to an appropriate oxidation state for complexing with the chelating agent [and also for reducing the pyridinium carrier moiety to the corresponding dihydropyridine form, when a chelating agent precursor of formula (I) is present].
  • the radioactive element is received from a radionuclide generator as an aqueous pertechnetate (Tc ) solution such as an eluate in isotonic saline, as is well-known in the art.
  • Tc aqueous pertechnetate
  • the amount of Tc-99m required to produce a quantity of formula (III) radiopharmaceutical sufficient for diagnostic purposes is generally from 0.01 milliCurie (mCi) to about 500 mCi per ml of 99m- pertechnetate solution.
  • the reducing agent for the pertechnetate can be a thiosulfate or dithionite if the reducing reaction is to be carried out in a basic medium, or a tin (II) salt such as SnCl 2 if the reducing reaction is to be carried out in an acid medium.
  • a kit for preparing an injectable radiopharmaceutical e.g., for complexing an organ-specific agent labeled with a radioactive metal, Includes, in separate containers: (1) a biologically compatible, sterile aqueous medium suitable for complex formation with a radioactive metal, (2) a dihydropyridin pyridinium salt carrier-containing complexing agent of formula (I) or (II) compatible therewith, and (3) a pharmaceutically acceptable reducing agent for the radioactive metal.
  • the dihydropyridine pyridinium salt carrier moiety may be present in the kit either in its oxidized or Its reduced state, as desired.
  • the reducing agent for the. radioactive metal can be selected to reduce also the oxidized carrier moiety, if present, as the radioactive metal is.
  • a reducing agent capable of reducing both the oxidized form of the carrier moiety and the radioactive metal is chosen and the chelating agent precursor of formula (I) is present in the kit.
  • the kit comprises, in separate containers (preferably aseptically and hermetically sealed vials of approximately 5-25 ml volume), (1) a biologically compatible, sterile aqueous medium, (2) a chelating agent precursor of formula (I), (3) a pharmacologically acceptable 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 formula (II) chelating agent to form a radiopharmaceutical of formula (III).
  • the reducing agent is sodium dithionite; also most preferably, the radioactive metal is technetium.
  • the dithionite reduction is preferably carried out in basic medium; this may be accomplished by providing that the aqueous medium (1) above is of basic pH, or by adding an appropriate base (e.g. NaOH, Na 2 CO 3 ) when combining the kit components and the pertechnetate solution.
  • the kit could comprise only two separate components: (1) the biologically compatible, sterile aqueous medium of essentially neutral pH containing the. chelating agent precursor of formula (I); and (2) the reducing agent and the base, e.g. sodium dithionite and sodium carbonate.
  • Radioactive metal ions are typically not provided with the kit due to the relatively short half-lives of commonly utilized radionuclides. Rather, the radionuclide is provided separately as described earlier and admixed with the components of the kit shortly before use, as is known for other radiopharmaceutical delivery systems.
  • the pertechnetate solution and the basic aqueous medium may be first combined and then heated, e.g. from 40 to 95°C. for 10 to 20 minutes, in the presence of the reducing agent, then cooled to about room temperature or below prior to addition of the formula (I) precursor.
  • the technetium will be reduced prior to reduction of the quaternary moiety to the corresponding dihydro form in which case a substantial portion of the quaternary salt (I) will likely chelate with the reduced technetium to form the quaternary complex (IV) in the reaction mixture as an intermediate to the dihydro complex (III), rather than the quaternary salt (I) being first converted to the dihydro chelating agent (II) and then to the dihydro complex (III).
  • the Precursor may be present in the initial mixture made from the kit, and it is likely in this instance that the formula (I) quaternary will be first reduced to the formula (II) dihydro, which will then chelate with the reduced technetium to form the complex (III).
  • the mixture is mildly basic, e.g. pH 8 to 9, it may be administered as is, after the reduction and chelation have occurred to form the formula (III) radiopharmaceutical, or the pH may be adjusted to about 7.
  • the mixture is more strongly basic, e.g. pH 13, it is generally desirable to adjust the pH to a slightly alkaline or neutral value.
  • the kit it is preferable for it to contain excess chelating agent precursor (I) or chelating agent (II) with respect to the radionuclide to be complexed therewith, e.g a 1:2 molar excess.
  • the reducing agent is present in a large excess with respect to the chelating agent precursor (I), e.g. 1:5 to 1:10.
  • the reducing agent is preferably present in a slight excess with respect to the radionuclide.
  • the diagnostic agent is administered to a patient, typically intravenously, with or without further dilution by a carrier vehicle such as physiological saline, phosphate-buffered saline, plasma, or the like.
  • a carrier vehicle such as physiological saline, phosphate-buffered saline, plasma, or the like.
  • the unit dose to be administered has a radioactivity of about 0.01 milliCurie (mCi) to about 100 milliCuries, preferably about 1 mCi to about 20 mCi.
  • the solution to be injected into an adult patient per unit dosage is about 0.01 millillter (ml) to about 1 milliliter.
  • 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 upon the half-life of the radioactive material that has been introduced into the patient and upon the amount of such material introduced Preferably, imaging takes place 60 to 90 minutes after intravenous administration.
  • compositions of matter comprising: (1) the residue of a chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, said functional group being not essential for the complexing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of said chelating agent, said chelating agent being either (a) capable of chelating with a metallic radionuclide or (b) chelated with a metallic radionuclide; and (2) a dihydropyridine pyridinium salt redox carrier moiety; said chelating agent residue and said carrier moiety being coupled to each Other to form a hydrolytically cleavable linkage between.

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US5079366A (en) * 1987-04-07 1992-01-07 University Of Florida Quarternary pyridinium salts
US4888427A (en) * 1987-04-07 1989-12-19 University Of Florida Amino acids containing dihydropyridine ring systems for site-specific delivery of peptides to the brain
DE3879024T2 (de) * 1987-07-31 1993-10-07 Takeda Chemical Industries Ltd Pyridinium-Derivate, ihre Herstellung und Verwendung.
DE4107570A1 (de) * 1991-03-07 1992-11-19 Diagnostikforschung Inst Chelate, deren metallkomplexe sowie ihre verwendung in diagnostik und therapie
JP4677863B2 (ja) * 2005-09-05 2011-04-27 堺化学工業株式会社 チオール系光硬化性モノマーおよび光硬化型樹脂組成物
US10864279B2 (en) * 2016-12-16 2020-12-15 Industrial Technology Research Institute Linker-drug and antibody-drug conjugate (ADC) employing the same

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