WO2017070752A1 - Agents d'imagerie - Google Patents

Agents d'imagerie Download PDF

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Publication number
WO2017070752A1
WO2017070752A1 PCT/AU2016/051033 AU2016051033W WO2017070752A1 WO 2017070752 A1 WO2017070752 A1 WO 2017070752A1 AU 2016051033 W AU2016051033 W AU 2016051033W WO 2017070752 A1 WO2017070752 A1 WO 2017070752A1
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Prior art keywords
substituted
unsubstituted
compound
independently selected
group
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PCT/AU2016/051033
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English (en)
Inventor
David C. REUTENS
Paul V. BERNHARDT
Rajiv Bhalla
Taracad K. Venkatachalam
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The University Of Queensland
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Priority claimed from AU2015904435A external-priority patent/AU2015904435A0/en
Application filed by The University Of Queensland filed Critical The University Of Queensland
Publication of WO2017070752A1 publication Critical patent/WO2017070752A1/fr

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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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the field of medical imaging. More particularly, the invention relates to imaging agents and the production thereof.
  • PET Positron emission tomography
  • the radioactive agent which has a radionuclide, is injected into the body where it undergoes positron emission decay to emit a positron which then collides with an electron in the tissue to form two photons.
  • a PET camera detects these protons in the form of light which is converted into an electrical signal to give an image which can be observed by an appropriate medical professional.
  • PET imaging can probe blood flow and oxygen consumption, and this is useful in oncology because tumour growths tend to be hypoxic because they are deprived of oxygen due to their rapid growth. These regions therefore have significantly lower blood flow which can be observed.
  • Radionuclides that are used in PET scanning are typically isotopes with short half-lives, and as such these PET imaging agents must be prepared and used shortly after preparation to detect the resultant decay. The short half- life also means that these imaging agents cannot be stored in the form in which they are administered.
  • the imaging agent In brain imaging it is essential that the imaging agent must be able to cross the blood-brain barrier (BBB). This requires low molecular mass, a neutral charge and moderate lipophilicity.
  • BBB blood-brain barrier
  • the imaging agent should be sufficiently lipophilic to cross the BBB, but also not so lipophilic that it will bind to proteins to an undesirable extent which can in itself prevent crossing of the BBB.
  • WO 2009/079024 discloses a method of reacting a 18 F atom with a metal to form a 18 F metal complex that can be administered to a patient.
  • WO 201 1/068965 discloses a method of labelling a molecule with 18 F or 19 F comprising the steps of attaching a complex of 18 F or 19 F and a group IMA metal to a chelating moiety, wherein the chelating moiety is conjugated to a targeting molecule or the chelating moiety is later attached to the targeting molecule.
  • This patent also discloses that aluminium, gallium, indium, and thallium are suitable for fluorine binding.
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • R 3 , R 4 , R 5 , R 6 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • Ei and E 2 are independently selected from S, O, or Se; F is 18 F or 19 F; and
  • M is a transition metal ion, or a radioisotope thereof.
  • Ri and R 2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1 -C6 alkoxy, substituted or unsubstituted C1 -C6 acyl, substituted or unsubstituted C3- C6 cycloalkyl, and substituted or unsubstituted C1 -C6 haloalkyl.
  • Ri and R 2 are independently selected from hydrogen, substituted or unsubstituted C1 -C6 alkyl, and substituted or unsubstituted aryl.
  • Ri and R 2 are independently selected from hydrogen, methyl, ethyl, or phenyl.
  • M is a transition metal ion with an oxidation state of +3.
  • M is a transition metal ion with an oxidation state of +3, then it may be selected from the group consisting of Al 3+ , Ga 3+ , ln 3+ , Sc 3+ , Y 3+ , Ho 3+ , Tm 3+ , Yb 3+ , and Lu 3+ .
  • M is Al 3+ , Ga 3+ or ln 3+ .
  • M is a radioisotope of a transition metal, then it may be selected from the group consisting of radioisotopes of gallium, and indium.
  • M is a radioisotope of a transition metal
  • it may be selected from the group consisting of 67 Ga, 68 Ga and 111 In.
  • at least one of M or F will be a radionuclide. Put another way, if F is 19 F then M is a transition metal radionuclide.
  • M and F are a radionuclide.
  • Ei and E 2 are independently selected from S and O. [0023] In one particular embodiment, Ei and E 2 are S.
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1 -C6 alkoxy, substituted or unsubstituted C1 -C6 acyl, substituted or unsubstituted C3- C6 cycloalkyl, and substituted or unsubstituted C1 -C6 haloalkyl.
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen and substituted or unsubstituted C1 -C6 alkyl.
  • R 3 , R 4 , R 5 and R 6 are H.
  • R 2 when Ri is hydrogen then R 2 may not be hydrogen.
  • the invention resides in an imaging complex comprising a compound of formula (I) linked to a biomarker:
  • l_n is a linker group
  • n 0 or 1 ;
  • BM is a biomarker
  • the compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.
  • the invention resides in a method of preparing a compound of formula (I) comprising the steps of: a. providing a compound of formula (II):
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • R 3 , R 4 , R 5 , R 6 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • Ei and E 2 are independently selected from S, O, or Se;
  • M is a transition metal ion, or a radioisotope thereof;
  • X is a leaving group; and b. substituting X with 18 F or 19 F.
  • Ri , R 2 , R3, R , R5, Re, Ei , E 2 and M may independently be as substantially described in any one or more embodiments of the first aspect.
  • the leaving group X is selected from the group consisting of chloride, bromide, iodide, nitrate, acetate, citrate, sulfonate, and triflate.
  • the leaving group X is a nitrate group.
  • M is a transition metal radionuclide
  • step b. comprises treating the compound of formula (II) with an appropriate fluorine salt.
  • the invention resides in a method of medical imaging of a patient comprising the steps of: a. administering a compound of formula (I) to the patient
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl, ;
  • R 3 , R 4 , R 5 , R 6 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • Ei and E 2 are independently selected from S, 0, or Se;
  • F is 18 F or 19 F;
  • M is a transition metal ion, or a radioisotope thereof; and b. detecting the radioactive decay from the 18 F or the transition metal radioisotope.
  • the compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.
  • the medical imaging is PET imaging.
  • the medical imaging is SPECT imaging.
  • FIG 1 shows a graphical representation of a time activity curve for a first mouse injected with 18 F thiosemicarbazone
  • FIG 2 shows a graphical representation of a time activity curve for a second mouse injected with 18 F thiosemicarbazone
  • FIG 3 shows an X-ray structure of the diphenylthiosemicarbazone gallium chloride complex
  • FIG 4 shows an X-ray structure of the diphenyl thiosemicarbazone gallium methoxide complex.
  • Embodiments of the present invention reside primarily in imaging agents. Accordingly, the method steps have been illustrated in concise schematic form describing those specific details that are necessary to understanding the embodiments of the present invention, but so as not to obscure the disclosure with excessive detail that will be readily apparent to those of ordinary skill in the art having the benefit of the present description.
  • substituted in each incidence of its use herein, and in the absence of an explicit listing for any particular moiety, refers to substitution of the relevant moiety, for example an alkyl chain or ring structure, with one or more more groups selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, CN, OH, oxo, NH 2 , CI, F, Br, I, aryl and heterocyclyl which latter two may themselves be optionally substituted.
  • alkyf refers to a straight-chain or branched alkyl substituent containing from, for example, 1 to about 12 carbon atoms, preferably 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, still yet more preferably from 1 to 2 carbon atoms.
  • substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, terf-butyl, pentyl, isoamyl, 2-methylbutyl, 3- methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the number of carbons referred to relate to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents, for example the carbon atoms of an alkoxy substituent branching off the main carbon chain.
  • cycloalkyl refers to optionally substituted saturated monocyclic, bicyclic or tricyclic carbon groups.
  • the cycloalkyl group may have a specified number of carbon atoms, for example, C3-C6 cycloalkyl is a carbocydic group having 3, 4, 5 or 6 carbon atoms.
  • Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.
  • alkoxy refers to an unsubstituted or substituted alkyl group linked by an oxygen atom (i.e., -O-Alkyl), wherein alkyl is described above.
  • alkoxy refers to oxygen-linked groups comprising 1 to 12 carbon atoms ("C1 -C12 alkoxy").
  • alkoxy refers to oxygen-linked groups comprising 1 to 8 carbon atoms ("C1 -8 alkoxy”), 1 to 6 carbon atoms (“C1 -6 alkoxy”), 1 to 4 carbon atoms ("C1 -4 alkoxy”), 1 to 3 carbon atoms (“C1 -3 alkoxy”), or 1 to 2 carbon atoms ("C1 -2 alkoxy”).
  • aryl refers to an unsubstituted or substituted aromatic carbocydic substituent, as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 ⁇ electrons, according to Huckel's Rule. C-5 or C-6 aryl is preferred.
  • heterocyclic and “heterocyclyl” as used herein refer to a non-aromatic ring having 5 to 7 atoms in the ring and of those atoms 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring wherein said heteroatoms are independently selected from O, N and S.
  • Heterocyclic includes partially and fully saturated heterocyclic groups. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated.
  • Non-limiting examples of heterocyclic may be selected from pyrazole, imidazole, indole, isoindole, triazole, benzotriazole, tetrazole, pyrimidine, pyridine, pyrazine, diazine, triazine, tetrazine, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl and thiapinyl, imidazolinyl, thiomorpholinyl, and the like. C-5 or C-6 heterocycles are preferred.
  • alkyl, etc. referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1 -2 carbon atoms, 1 -3 carbon atoms, 1 -4 carbon atoms, 1 -5 carbon atoms, 1 -6 carbon atoms, 1 -7 carbon atoms, 1 -8 carbon atoms, 1 -9 carbon atoms, 1 -10 carbon atoms, 1 -1 1 carbon atoms, 1 -12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-1 1 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-5
  • the terms "subject” or “individual” or “patient” may refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom diagnosis via medical imaging is desired.
  • Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g. , rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes).
  • a preferred subject is a human in need of diagnosis for a disease or condition.
  • indefinite articles “a” and “an” may refer to one entity or a plurality of entities (e.g. components) and are not to be read of understood as being limited to a single entity.
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • F is 18 F or 19 F.
  • M is a transition metal ion, or a radioisotope thereof.
  • a typical prior art imaging agent utilizes 99m Tc due to its half-life of 6.02 hours.
  • 99 Mo the parent isotope of 99m Tc and so many have turned to other radionuclides for their imaging agents.
  • the inventors postulate that the compounds of formula (I) can be used to efficiently cross the blood-brain barrier (BBB) and this is particularly useful in PET and SPECT imaging.
  • BBB blood-brain barrier
  • the BBB allows passage of water, some gases and lipid- soluble molecules by passive diffusion, as well as selective transport of molecules.
  • the compounds of formula (I) can be modified to change the lipophilic profile, and hence lipid- solubility, of the compound to allow for efficient transport across the BBB.
  • the compounds of formula (I) allow for the possibility of different radionuclides to be used.
  • the radionuclide can be present in the form of the 18 F radionuclide of fluorine.
  • the compound of formula (I) may comprise a radionuclide in the form of a radioactive isotope of the transition metal M. Suitable radioactive isotopes of the transition metal ion include 67 Ga, 68 Ga, and 11 1 ln. It will be appreciated by a person skilled in the art that the list of radioactive isotopes provided above is not an exhaustive list, but merely identifies some of the radioactive isotopes that may be utilized.
  • the compound of formula (I) can accommodate different radionuclides and therefore alleviate the reliance on any single radionuclide. Further to this, the compounds of formula (I) can be utilized with selected radionuclides tailored to different imaging techniques. For instance, when the metal ion is 67 Ga or 111 In then the modality would be SPECT.
  • the compounds of formula (I) are useful as imaging agents as they are stable, non-toxic, can be easily generated and safely administered. Further to this, the compounds of formula (I) lessen dependence on 99m Tc. It will also be appreciated by a person skilled in the art that either one of M or F can be the radionuclide, or, alternatively, both M and F can be radionuclides.
  • R H, Mc,Ph
  • R 2 H,Mc,Et,Ph
  • M Ga, Al, In
  • the compounds of formula (I) can be readily prepared without the need for any specialized equipment. This alleviates the problems associated with short half-life, and allows for radionuclides with shorter half-lives to be used because the compound can be generated in a basic laboratory or suitable preparation room and administered to a patient relatively quickly. Further to this, the preparation is simple and does not require any advanced synthetic knowledge or specialist tools or skills. [0062] It is believed that the molecular weight, log P value and overall charge of a compound of formula (I) are linked with the efficiency of the compound crossing the blood brain barrier. Advantageously, the compounds of formula (I) provide for desirable values in each of these areas of consideration.
  • the compound of formula (I) has a molecular weight suitably less than 1000 daltons, more suitably less than 800 daltons, preferably less than 700 daltons, and most preferably less than 600 daltons. Each of these values may be combined with a lower value selected from 50, 75 or 100 daltons.
  • the compound of formula (I) has a log P value of between about +0.5 and about +2.5.
  • the compound of formula (I) has an overall neutral charge.
  • the compound of formula (I) may be selected from the group consisting of:
  • metal ion may be 67 Ga or 68 Ga or may be replaced with 111 In. Each such analogue is considered to have been explicitly disclosed herein for each compound structure drawn above.
  • the invention resides in an imaging complex comprising a compound of formula (I) linked to a biomarker:
  • l_n is a linker group
  • n 0 or 1 ;
  • BM is a biomarker.
  • the compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.
  • the linker group can be any linker group that attaches to the compound of formula (I) to a biomarker.
  • Suitable linker groups include alkyl, amides, ethers, esters, alkenyl, acetyl groups, alkynyl groups, PEG, N-PEG, and amino acids. It will appreciated by a person skilled in the art that that the list provided is not an exhaustive list of linker groups, but merely demonstrate the types of linker groups that can be used to link the compound of formula (I) to a biomarker.
  • the biomarker can suitably be a naturally occurring molecule or gene which is capable of identifying a pathological or physiological process or disease.
  • the biomarker may be a compound comprised of moieties that recognize, bind or adhere to a target moiety of a target molecule or other biomarker located, for example, in an organism, tissue, cell or extracellular fluid, or any combination thereof.
  • Biomarkers include, but are not limited to, peptide targeting agents such as, for example, integrin targeting agents, proteins, antibodies, drugs, peptidomimetics, glycoproteins, glycolipids, glycans, lipids, nucleic acids, carbohydrates, phospholipids and the like.
  • Biomarkers include, but are not limited to, organic molecules comprised of a mass of 5,000 daltons or less.
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl,
  • R 3 , R 4 , R 5 , R 6 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • Ei and E 2 are independently selected from S, 0, or Se;
  • M is a transition metal ion, or a radioisotope thereof
  • X is a leaving group; and b. substituting X with 18 F or 19 F.
  • one advantage of the present invention lies in the ease of preparation of the compound of formula (I).
  • the compound of formula (I) is attractive since the radioactive isotope 18 F can be introduced at a late stage of the synthesis.
  • the simple preparation of the compound of formula (I) also alleviates the problem associated with using radionuclides with shorter half-lives, and the problem associated with the loss of efficacy due to a delay in administration. The reduced time between production and administration opens the possibility of using other radionuclides in imaging agents.
  • R-i, R 2 , R3, R 4 , R5 and R 6 are selected based on the starting material and the desired lipophilic profile. For example, if Ri and R 2 are phenyl moieties; R 3 , R 4 , R 5 and R 6 are hydrogens; Ei and E 2 are sulfur; and M is gallium, then the starting material is diphenylglyoxal.
  • Ri and R 2 are ethyl moieties; R 3 , R 4 , R 5 and R 6 are hydrogens, Ei and E 2 are sulfur, and M is gallium, then the starting material is diethylglyoxal.
  • a solution of a glyoxal in methanol and hydrochloric acid was treated with thiosemicarbazide to give a thiosemicarbazone.
  • a suspension of the thiosemicarbazone in methanol was then treated with sodium methoxide, and metal chloride to give a thiosemicarbazone-metal chloride complex.
  • the thiosemicarbazone-metal chloride complex was treated with silver nitrate, followed by treatment with potassium fluoride to give the thiosemicarbazone-metal fluoride complex.
  • the methoxide and ethoxide substituted metal complex are stable. This is advantageous as the methoxide and ethoxide precursor metal complex can be easily converted to the leaving group substituted metal complex. As such, these compounds can be stored prior to radiolabeling.
  • the leaving group will be understood by a person skilled in the art as a molecular fragment that can be substituted in a substitution reaction. A person skilled in the art will also understand that good leaving groups are generally weak bases and have a low or negative pKa value. Suitable leaving groups include chloride, bromide, iodide, nitrate, acetate, citrate, sulfonate, and triflate. It will be appreciated by a person skilled in the art that this list merely exemplifies the types of leaving groups that can be utilized and is not an exhaustive list.
  • a thiosemicarbazone-metal halogen complex can be converted to a thiosemicarbazone-metal nitrate complex by treating the halogen complex with silver nitrate.
  • the compound of formula (II) is treated with AgN0 3 .
  • the nitrate group in the thiosemicarbazone-metal nitrate complex can then be substituted with a radionuclide to give a compound of formula (I) by treating the nitrate complex with the potassium or sodium salt of 18 F or 19 F. These crude mixtures are then purified to give the compound of formula (I) that is ready for administration.
  • the halogen is 18 F. Suitable salts of the halogen are selected from the group consisting of K 18 F, Na 18 F, R 4 N 18 F, [K(kryptofix)] 18 F, Na(18-6-crown ether)] 18 F.
  • This vessel was sealed and heated under inert atmosphere, and allowed to dry. To this dry mixture was added the thiosemicarbazone-metal nitrate complex pre-dissolved in dimethylsulfoxide, and stirred and heated to form the thiosemicarbazone-metal fluoride complex.
  • the compound of formula (II) is treated with a fluoride salt and a base.
  • the compound of formula (II) is treated with K 2 C0 3 /Kryptofix 222/ 18 F.
  • the invention resides in a method of medical imaging of a patient comprising the steps of: a. administering a compound of formula (I) to the patient
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • R 3 , R 4 , R 5 , R 6 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;
  • Ei and E 2 are independently selected from S, 0, or Se; F is 18 F or 19 F;
  • M is a transition metal ion, or a radioisotope thereof; and b. detecting the radioactive decay from the 18 F or the transition metal radioisotope.
  • the compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.
  • the decay of the radionuclide allows the body to be imaged.
  • the compound should be administered quickly after production to ensure that any loss of efficacy is minimized.
  • the compound of formula (I) can also be linked to a biomarker so that a particular pathological or physiological process, or disease can be identified. The inclusion of a biomarker allows the imaging technique to probe a particular diseased state or another physiological state of the subject. The biomarker linked compound can then bind or adhere to a target area to improve the imaging ability of the compound.
  • Ri, R 2 phenyl. 6.8g, IR: 3415, 3226, 3136, 2950, 1584, 1474, 1442, 1240, 1 133, 1069, 1005, 922, 906, 865, 828, 763 cm- 1 ; 1 H NMR (d 6 -DMSO) ⁇ ppm: 9.84 (bs, 2H), 8.67 (bs, 2H), 8.38 (bs, 2H), 7.72 (m, 4H), 7.43-7.38 (m,6H); 13 C NMR (de-DMSO) ⁇ ppm: 179.1 , 140.5, 133.1 , 130.2, 128.4, 126.7; 15 NNMR (d 6 - DMSO):5 ppm 167.8,1 13.8.
  • Radio-HPLC of the crude reaction mixture confirmed formation of [ 18 F]diphenylthiosemicarbazone gallium fluoride which co-eluted at the same retention time as [ 19 F]diphenylthiosemicarbazone gallium fluoride (retention time of 15.6 minutes).
  • Diphenylthiosemicarbazone gallium fluoride complex [0093] Diphenylthiosemicarbazone gallium chloride (0. 0459g, 0.1 mmol) was suspended in methanol (15 ml) in a 20 ml vial. The blood red suspension was stirred (10 minutes) followed by the addition of silver nitrate (0.017g, 0.1 mmol), and shaken (2 minutes). The solution was then vigorously stirred (30 minutes), resulting in the formation of an orange solution and silver chloride precipitate. The contents were allowed to settle and the orange supernatant was transferred into another vial. Potassium fluoride (0.0058g, 0.1 mmol) was added to the supernatant and yielded a deep red solution.
  • the single crystal X-ray structure of the diphenyl thiosemicarbazone gallium chloride complex is shown in FIG 3, and the single crystal X-ray structure of the diphenyl thiosemicarbazone gallium methoxide complex is shown in FIG 4. Please note that a single methanol molecule co-crystallized in the diphenyl thiosemicarbazone gallium methoxide complex crystal.
  • the compound of formula (I) allows for different radionuclides to be utilized and it should be clear that the present invention alleviates the problems associated with the prior art imaging agents by lessening our dependency on 99m Tc. This is made possible by the simple synthetic route of the compounds of formula (I).
  • the synthetic route does not require lengthy purification steps and can be prepared in a standard laboratory to reduce the time between synthesis and administration.
  • Table 1 Snapshot of the uptake of [ 18 F]diphenylthiosemicarbazonegallium in a first mouse at 30 minutes

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Abstract

La présente invention concerne certains complexes métalliques de thiosemicarbazone qui présentent des propriétés avantageuses dans l'imagerie médicale. Les complexes métalliques de thiosemicarbazone peuvent être produits de façon sûre et aisée en temps réel, administrés rapidement après production, traverser facilement la barrière hématoencéphalique, et peuvent utiliser un certain nombre de radionucléides différents.
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Publication number Priority date Publication date Assignee Title
WO2019046761A1 (fr) * 2017-09-01 2019-03-07 Oregon State University Complexes de métal thérapeutiques et ligands, leurs procédés de fabrication et d'utilisation

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0024464B1 (fr) * 1979-08-29 1982-05-12 Nihon Medi-Physics Co., Ltd. Dérivés de 2-oxopropionaldéhyde bis(thiosemicarbazone), leur préparation et leur utilisation
WO2010066010A1 (fr) * 2008-12-12 2010-06-17 The University Of Melbourne Procédé de préparation de bis(thiosemicarbazones) asymétriques
WO2011068965A1 (fr) * 2009-12-04 2011-06-09 Immunomedics, Inc. Procédés et compositions de marquage f-18 amélioré de protéines, peptides et autres molécules

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Publication number Priority date Publication date Assignee Title
EP0024464B1 (fr) * 1979-08-29 1982-05-12 Nihon Medi-Physics Co., Ltd. Dérivés de 2-oxopropionaldéhyde bis(thiosemicarbazone), leur préparation et leur utilisation
WO2010066010A1 (fr) * 2008-12-12 2010-06-17 The University Of Melbourne Procédé de préparation de bis(thiosemicarbazones) asymétriques
WO2011068965A1 (fr) * 2009-12-04 2011-06-09 Immunomedics, Inc. Procédés et compositions de marquage f-18 amélioré de protéines, peptides et autres molécules

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VENKATACHALAM, T. K. ET AL.: "Heteronuclear NMR spectroscopic investigations of gallium complexes of substituted thiosemicarbazones including X-ray crystal structure, a new halogen exchange strategy, and 18F radiolabelling", AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 69, 2016, pages 1033 - 1048 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019046761A1 (fr) * 2017-09-01 2019-03-07 Oregon State University Complexes de métal thérapeutiques et ligands, leurs procédés de fabrication et d'utilisation
JP2020532538A (ja) * 2017-09-01 2020-11-12 オレゴン ステイト ユニバーシティー 治療用金属錯体およびリガンドならびにその作成および使用の方法
US11596651B2 (en) 2017-09-01 2023-03-07 Oregon State University Therapeutic metal complexes and ligands and methods of making and using the same

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