WO2021172030A1 - Composition, composition for dynamic nuclear polarization, highly polarized composition, method for highly polarizing substance, highly polarized substance, and nmr measurement method - Google Patents

Composition, composition for dynamic nuclear polarization, highly polarized composition, method for highly polarizing substance, highly polarized substance, and nmr measurement method Download PDF

Info

Publication number
WO2021172030A1
WO2021172030A1 PCT/JP2021/005096 JP2021005096W WO2021172030A1 WO 2021172030 A1 WO2021172030 A1 WO 2021172030A1 JP 2021005096 W JP2021005096 W JP 2021005096W WO 2021172030 A1 WO2021172030 A1 WO 2021172030A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
group
polarization
composition according
matrix material
Prior art date
Application number
PCT/JP2021/005096
Other languages
French (fr)
Japanese (ja)
Inventor
伸浩 楊井
君塚　信夫
智之 ▲濱▼地
朗生 山内
亘生 西村
宏徳 河野
才也 藤原
健一郎 立石
友洋 上坂
Original Assignee
国立大学法人九州大学
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 国立大学法人九州大学 filed Critical 国立大学法人九州大学
Priority to JP2022503252A priority Critical patent/JPWO2021172030A1/ja
Publication of WO2021172030A1 publication Critical patent/WO2021172030A1/en

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/50—NMR imaging systems based on the determination of relaxation times, e.g. T1 measurement by IR sequences; T2 measurement by multiple-echo sequences
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/30—Assessment of water resources

Definitions

  • the present invention relates to a composition useful as a polarization material for highly polarization the nuclear spin of a substance, a composition for dynamic nuclear polarization, a method for highly polarization a substance using the composition, and the high polarization thereof.
  • the present invention relates to a substance highly polarized by a polarization method and a method for NMR measurement of a substance using the composition.
  • NMR nuclear magnetic resonance
  • MRI magnetic resonance imaging
  • position information is given to the NMR signal and imaged
  • MRI magnetic resonance imaging
  • the energy state in which the spins are oriented parallel to the magnetic field and the spins are antiparallel to the magnetic field. It splits into a suitable energy state.
  • the value obtained by dividing the difference in the number of spins (occupancy number) having each energy state by the total number of spins is called the polarization rate, and the intensity of the NMR signal is said to be proportional to this polarization rate.
  • the polarization rate of nuclear spin is usually a very low value of 1 / tens of thousands or less at room temperature, which is a cause of limiting the sensitivity of NMR spectroscopy and MRI.
  • the spin polarization of the electrons is transferred to the surrounding nuclei by the solid effect induced by electromagnetic wave irradiation, the integral solid effect, etc., and the nuclear spin is highly polarized.
  • a dynamic nuclear polarization method has been proposed.
  • radicals and photoexcited triplet molecules are used as the source of electron spins (polarization source), and among them, the photoexcited triplet molecules have the number of electron spins occupied in a specific energy state regardless of the temperature. Since the state is largely biased, there is an advantage that the nuclear spin can be effectively highly polarized even at room temperature.
  • Patent Document 1 proposes to use a pentansen derivative having a specific hydrocarbon group as a photoexcited triplet molecule that serves as such a polarization source.
  • a pentansen derivative having a specific hydrocarbon group as a photoexcited triplet molecule that serves as such a polarization source.
  • the pentacene derivative using a polarized source was subjected to a dynamic nuclear polarization, as compared to the sample which was not subjected to the dynamic nuclear polarization, high 1 H spin signal is obtained It has been confirmed that
  • a photoexcited triplet molecule is known as a polarization source of dynamic nuclear polarization.
  • the photoexcited triplet molecule is an organic compound, it is generally hydrophobic. Therefore, when actually used for dynamic nuclear polarization treatment, a photoexcited triplet molecule serving as a polarization source is mixed with a hydrophobic base and applied to a polarization object.
  • the NMR measurement method is expected as a method for inspecting a living body and a method for analyzing a living body-related substance because it provides useful information on the bonding state of a hydrogen atom and a carbon atom. Many are hydrophilic.
  • the polarization material in which the polarization source is mixed with a hydrophobic base has low biocompatibility and affinity with bio-related substances, and it is difficult to utilize it for dynamic nuclear polarization in the fields of medicine and life science. There was a problem.
  • the present inventors have proceeded with studies for the purpose of providing a polarization material having higher biocompatibility than before and developing a technology that paves the way for dynamic nuclear polarization to bio-related substances.
  • the present inventors construct a polarization material by dispersing the polarization source in a water-soluble matrix material having a spin-lattice relaxation time T 1 of a certain value or more. By doing so, it was found that a polarization material having high biocompatibility and affinity with bio-related substances can be realized.
  • the present invention has been proposed based on these findings, and specifically has the following configuration.
  • a composition containing a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more and a polarization source dispersed in the water-soluble matrix [2] The composition according to [1], wherein the matrix material has a melting point of 30 ° C. or higher. [3] The composition according to [1] or [2], wherein the matrix material has a molecular weight of 300 or less. [4] The composition according to any one of [1] to [3], wherein the matrix material has a group capable of forming a hydrogen bond. [5] The composition according to any one of [1] to [4], wherein the matrix material has two or more hydroxy groups in the molecule.
  • the matrix material is composed of only hydrogen atoms, carbon atoms and oxygen atoms.
  • the matrix material is composed of only atoms selected from the group consisting of hydrogen atoms, carbon atoms, oxygen atoms and nitrogen atoms. ..
  • Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group.
  • Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group.
  • a composition for dynamic nuclear polarization comprising the composition according to any one of [1] to [23].
  • a highly polarized composition obtained by highly polarized the composition according to any one of [1] to [23].
  • a method for highly polarization a substance, which comprises a step of highly polarization the composition to obtain a highly polarized composition.
  • a step of bringing a substance into contact with the composition according to any one of [1] to [23] and then highly polarized the composition to obtain a highly polarized composition is included.
  • the highly polarized method according to [28] wherein the contact is performed by mixing and homogenizing the matrix material, the polarized source, and the substance.
  • An NMR measurement method comprising a step of measuring NMR of a substance using the composition according to any one of [1] to [23].
  • the composition of the present invention shows high affinity for bio-related substances and has high biocompatibility.
  • the nuclear spin of the matrix material can be easily highly polarized. Therefore, according to this composition, the nuclear spin polarization can be efficiently transferred to the nuclear spin of a biologically related substance, and the substance can be highly polarized. Therefore, the composition of the present invention is highly useful as a depolarizing material for highly depolarizing substances such as bio-related substances.
  • 9 is a time-resolved ESR spectrum of compositions 24-26. It is the attenuation curve of the ESR signal of compositions 24-26. 9 is a time-resolved ESR spectrum of compositions 27-29. 9 is an attenuation curve of the ESR signal of the compositions 27 to 29.
  • the numerical range represented by using "-" in the present specification means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
  • the isotope species of the hydrogen atom existing in the molecule of the compound used in the present invention is not particularly limited, and for example, all the hydrogen atoms in the molecule may be 1 H, or part or all of them may be 2 H. (Duterium D) may be used.
  • the “excitation light” in the present specification is light that causes excitation of an object to cause light emission, and light having a wavelength that matches the absorption wavelength of the object can be used.
  • composition of the present invention comprises a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more, and a polarization source dispersed in the water-soluble matrix.
  • the "matrix material” in the present invention means a base material that holds a polarization source in a dispersed state.
  • the matrix material refers to a material composed of a compound compounded in a molar number of 5 times or more the number of moles of the compound constituting the polarization source.
  • the number of moles may be, for example, in the range of 10 times or more, in the range of 50 times or more, or in the range of 100 times or more.
  • the matrix material may be composed of one kind of compound or two or more kinds of compounds. When the matrix material is composed of two or more kinds of compounds, the total number of moles thereof may be 5 times or more the number of moles of the polarization source.
  • the polarization source is dispersed by itself without being mixed or adsorbed by other materials, and it is preferable that the diameter of the dispersed polarization source is as small as possible. The most preferable case is that it is dispersed in a single molecule.
  • spin-lattice relaxation time T 1 means that the magnetization vector deviated from the Z-axis direction due to 90 ° pulse excitation is in the Z-axis direction when the direction of the total magnetization vector of the nuclear spin in the thermal equilibrium state is the Z-axis direction. It refers to the time it takes to recover. The longer the spin-lattice relaxation time T 1 , the easier it is to retain the spin polarization transferred from the polarization source, and the spin polarization can be accumulated to achieve high polarization. In the present invention, the “spin-lattice relaxation time T 1 " is measured by the saturation recovery method using a 90 ° pulse of 30 MHz at room temperature.
  • water-soluble in the present invention means a property of dissolving 1 mmol / L or more in water.
  • the “polarization source” in the present invention is the supply of spin polarization that generates spin-polarized electrons in the dynamic nuclear polarization that transfers the spin polarization from electrons to the nucleus to make the nuclear spin highly polarized. It is the source.
  • polarization or “spin polarization” refers to spins at an energy level between split energy levels when a static magnetic field is applied to an aggregate of spins to cause Zeeman splitting. It means that the occupancy number of is different. Also, when looking at a combination consisting of any two of the split energy levels, the difference between the spin occupancy N 1 in one energy level and the spin occupancy N 2 in the other energy level.
  • the ratio to the total number of spins is called the polarization ratio.
  • the polarization ratio in all the combinations of Zeeman-divided energy levels, those having a polarization rate of 0 are not spin-polarized, and at least one combination has an absolute value of the polarization rate of more than 0. (Positive or negative) can be said to be spin-polarized.
  • the larger the polarization ratio the more spin is present in one of the energy levels, and the larger the spin polarization is.
  • the composition of the present invention retains the polarization that has been transferred from the electron spin of the polarization source to the nuclear spin of the matrix material because the spin-lattice relaxation time T 1 of the matrix material is 2.5 seconds or more. It can be accumulated and easily put into a highly polarized state.
  • the matrix material since the matrix material is water-soluble, it exhibits high affinity for bio-related substances and has high biocompatibility. Therefore, this composition can efficiently transfer its nuclear spin polarization to the nuclear spin of a biologically related substance to highly polarize the substance. Therefore, the composition of the present invention can be suitably used as a polarization material for highly polarized bio-related substances, and can greatly contribute to the utilization of dynamic nuclear polarization in the medical field and the life science field. can.
  • the matrix material, the polarization source, and other materials constituting the composition of the present invention will be described.
  • the water-soluble matrix material used in the present invention has a spin-lattice relaxation time T 1 of 2.5 seconds or more.
  • the spin - Long matrix material lattice relaxation time T 1 As described above, the spin - Long matrix material lattice relaxation time T 1, by easily hold the polarized which has moved to the nuclear spins from electron spin Henkyokugen accumulates the nuclear spin polarization It can be easily highly polarized.
  • the spin-lattice relaxation time T 1 of the matrix material is preferably 10 seconds or longer, more preferably 14 seconds or longer, further preferably 30 seconds or longer, and even more preferably 60 seconds or longer. It is preferably 90 seconds or more, and particularly preferably 90 seconds or more. In the following description, the property of being able to retain nuclear spin polarization is referred to as "polarization holding ability".
  • the conditions for a compound having a relatively long spin-lattice relaxation time T 1 are (1) solid at the operating temperature, (2) relatively small molecular weight, and (3) alkyl group. There is no group that rotates around the bond hand as in (4), and there are factors that hinder the movement and vibration of the molecule, such as hydrogen bonds.
  • the matrix material preferably contains a compound having the following physical characteristics and structural characteristics.
  • the melting point of the compound constituting the matrix material is preferably 30 ° C. or higher, more preferably 50 ° C. or higher, further preferably 75 ° C. or higher, and even more preferably 100 ° C. or higher. Due to the high melting point of the compounds constituting the matrix material, the composition maintains a solid state and exhibits high polarization holding ability when performing dynamic nuclear polarization.
  • the upper limit of the melting point (decomposition temperature) is not particularly limited, but may be in the range of, for example, 350 ° C. or lower.
  • the molecular weight of the compound constituting the matrix material is preferably 1000 or less, more preferably 700 or less, further preferably 500 or less, and even more preferably 300 or less. Molecules with a relatively small molecular weight tend to have small intramolecular interactions due to the small number of proton nuclei, and tend to maintain the polarization of their proton spins.
  • the lower limit of the molecular weight is not particularly limited, but for example, it can be selected from a range of 50 or more, or can be selected from a range of 100 or more.
  • the compounds constituting the matrix material preferably have a group capable of forming a hydrogen bond.
  • Compound molecules having a group capable of forming a hydrogen bond, by the molecular motion or vibration to form a hydrogen bond is hindered, spin - lattice relaxation time T 1 is long, showing a high polarization holding capability.
  • the group capable of forming a hydrogen bond include an atom having a higher electronegativity than the hydrogen atom and a group containing a hydrogen atom covalently bonded to the atom.
  • Examples of atoms having a higher degree of electrical negativeness than hydrogen atoms include carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms, and halogen atoms.
  • oxygen atoms and sulfur atoms are preferable, and oxygen atoms are used.
  • the group capable of forming a hydrogen bond is preferably a hydroxy group (-OH) or a thiol group (-SH), and more preferably a hydroxy group.
  • the compound constituting the matrix material preferably has two or more hydroxy groups in the molecule, and preferably has an amino group and a group capable of forming a hydrogen bond with the amino group in the molecule.
  • An aminocarbonyl group can be mentioned as a preferable example of a structure having an amino group and a group capable of forming a hydrogen bond with the amino group.
  • the matrix material is preferably composed of only hydrogen atoms, carbon atoms and oxygen atoms, and is also preferably composed of only atoms selected from the group consisting of hydrogen atoms, carbon atoms, oxygen atoms and nitrogen atoms. .. If the matrix material contains hydrogen atoms, at least one of them may be deuterium atoms. Further, the matrix material preferably has no repeating units. Here, the repeating unit means, for example, a structural unit derived from a monomer in a polymer, and is a structural unit existing in two or more in the molecule. Furthermore, it is preferable that the compounds constituting the matrix material do not have an alkyl group. A compound having an alkyl group tends to be easily relaxed from a spin-polarized state to an equilibrium state by rotating the alkyl group around a bond (single bond).
  • the matrix material examples include sugar alcohols such as erythritol, xylitol and sorbitol, sugars such as fructose, glucose and maltose, compounds containing an aromatic ring such as ⁇ -estradiol, benzoic acid and carbamatepine, urea and triazole. Since the spin-lattice relaxation time T 1 is relatively long, erythritol, urea, and xylitol are preferable, and erythritol is more preferable. When sugar alcohol is used as a matrix material, it preferably has 3 to 8 carbon atoms. These spin-lattice relaxation times T 1 are shown in FIG.
  • one kind of compound may be used alone, or two or more kinds of compounds may be used in combination.
  • the polarization source of the composition is not particularly limited, but a molecule represented by the following general formula (1) or a porphyrin derivative can be preferably used.
  • the polarization source used in the present invention is preferably composed of a molecule represented by the following general formula (1).
  • the molecule represented by the general formula (1) used as the polarization source may be one kind or a combination of two or more kinds.
  • the molecule represented by the general formula (1) is a photoexcited triplet molecule capable of generating spin-polarized triplet electrons by photoexcitation, and serves as a polarization source for supplying the spin polarization of the triplet electrons to the nucleus. Can be used.
  • the molecule represented by the general formula (1) has a feature of having high oxygen resistance because it has an azaacene skeleton in which two nitrogen atoms are introduced into one benzene ring constituting the acene structure. Therefore, it is difficult to be oxidized even in an environment where air and light exist, such as a medical site or a research facility, and the function as a polarization source can be surely exhibited.
  • the reason why the molecule represented by the general formula (1) exhibits high oxygen tolerance is that the energy of LUMO (Lowest Unoccupied Molecular Orbital) is due to the introduction of a nitrogen atom with high electron attraction into the acene structure. It is presumed that this is because the level becomes low and the electron transfer from the molecule to the oxygen molecule is suppressed.
  • LUMO Local Unoccupied Molecular Orbital
  • n represents an integer of 1 to 4.
  • n is preferably 2 to 4, more preferably 2 or 3.
  • Z 1 to Z 10 existing in the general formula (1), 0 to 6 represent N, and the others represent CR. Therefore, all of Z 1 to Z 10 may be CR.
  • n 1, 0 to 6 of Z 1 to Z 10 represent N, and the other 4 to 10 represent CR.
  • n 2, 0 to 6 of Z 1 to Z 10 represent N, and the other 6 to 12 represent CR.
  • n is 3, 0 to 6 of Z 1 to Z 10 represent N, and the other 8 to 14 represent CR.
  • n is 4, 0 to 6 of Z 1 to Z 10 represent N, and the other 10 to 16 represent CR.
  • N represents a nitrogen atom
  • C represents a carbon atom
  • R represents a hydrogen atom or a substituent.
  • the plurality of Z 9s may be the same or different
  • the plurality of Z 10s may be the same or different.
  • two or more of Z 1 to Z 10 existing in the general formula (1) are N, for example, those satisfying at least one of the following three conditions can be mentioned as an example of a preferable group. .. ⁇ 1> Both Z 1 and Z 4 are N. ⁇ 2> Both Z 5 and Z 8 are N. ⁇ 3> Both Z 9 and Z 10 are N.
  • the number of N is preferably 2 to 2 n.
  • the number of N is preferably 2, and when n is 2, the number of N is preferably 2 to 4, and n is 3.
  • the number of N is preferably 2 to 6, and when n is 4, the number of N is preferably 2 to 8.
  • the plurality of Rs existing in the general formula (1) may be the same as or different from each other. Therefore, all of the plurality of Rs may be hydrogen atoms, or some of them may be hydrogen atoms and some of them may be substituents.
  • the substituent is a substituent containing one or more atoms selected from the group consisting of hydrogen atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom, boron atom, phosphorus atom, silicon atom, and halogen atom. It is preferable, and it is more preferable that it is a substituent composed of one or more atoms selected from the group consisting of these atoms.
  • the number of atoms constituting the substituent is preferably 1 to 50, more preferably 1 to 35, and even more preferably 1 to 20.
  • halogen atom, cyano group, carbonyl group, ester group, carboxyl group, sulfo group, boron atom, silicon atom, phosphorus atom, hydroxy group, thiol group, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring and Substituents containing an amino group can be mentioned.
  • the halogen atom, cyano group, carboxyl group, hydroxy group, thiol group, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring and amino group may be a substituent consisting of only these groups.
  • the hydrogen atom may be 1 H or 2 H (deuterium).
  • Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the amino group may or may not be substituted.
  • An acidic group such as a carboxyl group may have an anion group formed by ionizing the proton of the acidic group, or a salt of the anion group and a metal cation (for example, sodium ion or potassium ion) is formed. May be good.
  • the ester group include an alkyloxycarbonyl group and an aryloxycarbonyl group.
  • the substituted amino group include a dialkylamino group, a diarylamino group, a monoalkylamino group, and a monoarylamino group.
  • the alkyl group referred to here preferably has 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.
  • the aryl group preferably has 6 to 20 carbon atoms, and more preferably 6 to 10 carbon atoms.
  • the alkyl group and the aryl group may be substituted, and as the substituent, for example, those exemplified as the substituent of R can be referred to.
  • At least one of the plurality of Rs in the general formula (1) is a group containing an oligoalkylene oxy structure.
  • the oligoalkylene oxy structure By including the oligoalkylene oxy structure, the dispersibility of the molecule represented by the general formula (1) in an aqueous medium becomes extremely good.
  • a highly water-dispersible polarization source can efficiently transfer the polarization of its triplet electron spin to the proton spin of water molecules, and is therefore effective as a polarization source for NMR analysis of living organisms and biological materials. Can be used for.
  • the group containing an oligoalkylene oxy structure is preferably a group having an ion pair containing an ammonium ion having an oligoalkylene oxy structure, and more preferably C (carbon constituting a ring skeleton) of CR of the general formula (1). It is a group having an ion pair linked to an anion group (atom) and an ammonium ion having an oligoalkylene oxy structure.
  • the molecule represented by the general formula (1) is preferably an ion pair of an anion having a polycyclic condensed skeleton in the general formula (1) and an ammonium ion having an oligoalkylene oxy structure.
  • the ammonium ion having an oligoalkylene oxy structure constituting the ion pair is preferably an ammonium ion having an R 11- (OR 12 ) n- group.
  • R 11 represents a substituted or unsubstituted alkyl group
  • R 12 represents a substituted or unsubstituted alkylene group
  • n is an integer of 2 to 20.
  • n pieces of R 12 may be the same or different from each other.
  • the ammonium ion having an oligoalkylene oxy structure constituting the ion pair is more preferably an ammonium ion represented by [R 11 ⁇ (OR 12 ) n] 3- NH + .
  • [R 11 - (O-R 12) n] ammonium ion represented by 3 -NH + is that the by bulkiness, to further improve the dispersibility in the aqueous medium of the molecule represented by the general formula (1) Can be done.
  • the three R 11s may be the same or different from each other.
  • the 3n R 12 may be the same or different from each other.
  • the three ns may be the same or different from each other.
  • Particularly preferred as the ammonium ions constituting an ion pair, [R 11 - (O- R 12) n] is represented by 3 -NH +, 3 pieces of [R 11 - (O-R 12) n] are the same Is an ammonium ion.
  • the alkyl group in R 11 may be linear, branched or cyclic.
  • the alkyl group preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and even more preferably 1 or 2 carbon atoms.
  • a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like can be exemplified, and a methyl group is most preferable.
  • the alkylene group in R 12 may be linear, branched or cyclic.
  • the alkylene group preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and even more preferably 1 or 2 carbon atoms.
  • n is preferably an integer of 1 to 8, more preferably an integer of 1 to 4, and may be, for example, 1 or 2, or may be selected within the range of 2 to 4.
  • ammonium ions having oligoalkyleneoxy structure R 11 - (O-R 12) a plurality of ammonium ions having a n- group or,
  • R 11 - and ammonium has a (O-R 12) n- group ions other ammonium ion, R 11 s or, has a structure in which ends are bonded to each other of the substituents R 11 and other ammonium ions may be ammonium ions as multimers.
  • Ammonium ion having an oligoalkylene oxy structure constituting an ion pair is a precursor (ion pair) of a molecule represented by the general formula (1) before forming a salt with an amine having an oligoalkylene oxy structure and ammonium ion. It can be obtained by an acid-base reaction with a molecule having a proton donor group at the position corresponding to.
  • specific examples of amines having an oligoalkylene oxy structure that can be used to generate this ammonium ion will be illustrated. However, amines having an oligoalkylene oxy structure that can be used in the present invention should not be construed as being limited by these specific examples.
  • a represents an integer of 1 to 4
  • m and m1 to m3 represent an integer of 1 to 4.
  • m1 to m3 may be the same as or different from each other. For example, a case where a, m, and m1 to m3 are all 1 can be exemplified. As another example, the case where a, m, and m1 to m3 are all 2 can be exemplified.
  • ammonium ion represented by the following formula, which is produced by protonation of tris [2- (2-methoxyethoxy) ethyl] amine (MEEA).
  • the anion group forming an ion pair with the ammonium ion having an oligoalkylene oxy structure is a 1- to tetravalent anion group. It is preferably a monovalent anion group, and more preferably a monovalent anion group.
  • anionic groups are carboxy group (-COOH), phosphono group (-PO 3 H 2 ), phosphonoxy group (-OPO 3 H 2 ), sulfo group (-SO 3 H), sulfooxy group (-OSO 3 H).
  • anionic group proton from the acidic group is ionized etc., proton from the hydroxy group (-OH) may be able to include ionized anionic groups, among others -COO - group, -SO 3 - group, -PO 3 H - group, It is preferably an —O ⁇ group, and more preferably an —COO ⁇ group.
  • anionic groups may be introduced into any of Z 1 to Z 10. That is, CR which has an anion group linked to C may be any of Z 1 to Z 10.
  • the anion group may be bonded to C of CR with a single bond, or may be bonded via a linking group.
  • the linking group include a substituted or unsubstituted alkylene group and a substituted or unsubstituted arylene group.
  • the description and specific examples of the alkylene group can be referred to for the alkylene group in the above R 12.
  • the aromatic ring constituting the arylene group may be a monocyclic ring, a condensed ring in which two or more aromatic rings are condensed, or a linked ring in which two or more aromatic rings are linked. When two or more aromatic rings are connected, they may be linearly connected or may be branched.
  • the number of carbon atoms in the aromatic ring is preferably 6 to 22, more preferably 6 to 18, further preferably 6 to 14, and even more preferably 6 to 10.
  • Specific examples of the arylene group include a phenylene group, a naphthaleneylene group, and a biphenylene group.
  • substituents that can be introduced into the alkylene group and the arylene group for example, those exemplified as the substituent of R can be referred to.
  • the number of anion groups bonded to the linking group may be one or two or more. When two or more anion groups are attached to the linking group, the plurality of anion groups may be the same or different from each other.
  • the linking group is a phenylene group
  • the number of anion groups bonded to the phenylene group is 1 to 5, more preferably 2 to 4.
  • the bonding position of the anion group in the phenylene group is not particularly limited, but at least one of the anion groups is preferably bonded to the meta position or the para position with respect to the bonding position to the polycyclic condensed skeleton, and is bonded to the meta position. Is more preferable.
  • two or more anion groups are bonded to the phenylene group, it is preferable that at least two of them are bonded to each other at a meta position.
  • the number of ion pairs of anion groups and ammonium ions existing in the molecule is preferably 1 or more, more preferably 2 or more, still more preferably 3 or more, and even more. It is preferably 4 or more.
  • the group containing the oligoalkylene oxy structure in R is a group (substituent) in which the atomic group containing the oligoalkylene oxy structure is covalently bonded to C (carbon atom constituting the ring skeleton) of CR.
  • the "atomic group containing an oligoalkylene oxy structure” is a group containing an oligoalkylene oxy structure and in which all the bonds between atoms are covalent bonds (groups not containing an ion pair). means.
  • Atomic group containing oligoalkyleneoxy structure preferably R 11 - an atomic group having a (O-R 12) n- group.
  • R 11 and R 12 the above R 11 - has the same meaning as R 11 and R 12 of ammonium ions having a (O-R 12) n-group, for the preferred range and specific examples, the above R 11 and The description for R 12 can be referred to.
  • the R 11- (OR 12 ) n- group may be single-bonded to C of CR or to a covalently bonded linking group to C of CR. May be.
  • a represents an integer of 1 to 4
  • m and m1 to m3 represent an integer of 1 to 4.
  • m1 to m3 may be the same as or different from each other. For example, a case where a, m, and m1 to m3 are all 1 can be exemplified. As another example, the case where a, m, and m1 to m3 are all 2 can be exemplified.
  • the number of oligoalkylene oxy structures present in the molecule is preferably 1 or more, more preferably 3 or more, still more preferably 6 or more, still more preferably 9 or more, particularly. It is preferably 12 or more.
  • the group containing the oligoalkylene oxy structure and the ion pair of the anion group and the ammonium ion having the oligoalkylene oxy structure may be introduced into any of Z 1 to Z 10. That is, CR, in which R is a group containing an oligoalkylene oxy structure, preferably CR, and R is an ion pair of an anion group and an ammonium ion having an oligoalkylene oxy structure.
  • the group having the above may be any of Z 1 to Z 10.
  • At least one of the plurality of Rs in the general formula (1) is preferably a group having an ion pair of an anion group and an ammonium ion having no oligoalkylene oxy structure, and the oligoalkylene oxy structure is formed. It is also preferable that the atomic group (substituent) does not have.
  • the water dispersibility of the molecule represented by the general formula (1) can be improved, but instead of the group having this oligoalkylene oxy structure, another Molecules into which the group has been introduced may also exhibit excellent dispersibility in aqueous media.
  • a group having an ion pair of an anion group and an ammonium ion having an alkyl group substituted with a functional group, or a group having a substituted amino group containing an alkyl group substituted with a functional group can be used.
  • descriptions and specific examples of the alkyl group can be referred to for the alkyl group in the above R 11.
  • the functional group include a carboxy group, a hydroxy group, and a carbonyl group.
  • the description of the anion group in R can be referred to.
  • the composition is composed by combining the polarization source and the matrix material
  • the polycyclic condensed skeleton in the general formula (1) has atoms and atomic groups constituting the matrix material, and the matrix material contains ions. If included, it may be substituted with a group that interacts with the ion. As a result, it is possible to prevent the molecules of the polarization source from agglutinating to form an agglomerate, and the molecules can be easily dispersed in the matrix material.
  • the substituent (R) of the general formula (1) contains one or more atoms selected from the group consisting of halogen atoms, nitrogen atoms, oxygen atoms, sulfur atoms, boron atoms, phosphorus atoms, and silicon atoms. It is preferably a substituent. Specific examples include halogen atom, cyano group, carbonyl group, ester group, carboxyl group, sulfo group, phosphono group, phosphonoxy group, boron atom, phosphorus atom, silicon atom, hydroxy group, thiol group, pyridine ring, pyridazine ring and pyrimidine.
  • a substituent containing one or more selected from the group consisting of a ring, a pyrazine ring and an amino group can be exemplified.
  • Acidic group such as a carboxy group (-COOH), a sulfo group (-SO 3 H), a phosphono group (-P (O) (OH) 2), phosphonoxy group (-OP (O) (OH) 2) is a proton May be an ionized anion group, and examples thereof include a carboxylate anion group. These groups may be directly bonded to the polycyclic condensed skeleton or may be linked via a linking group.
  • At least one of Z 1 , Z 2 , Z 7 , Z 8 , Z 9 of the general formula (1) is CR 11
  • Z 3 , Z 4 , Z 5 , Z 6 , Z 10 is CR 12
  • R 11 and R 12 are independently composed of a halogen atom, a nitrogen atom, an oxygen atom, a sulfur atom, a boron atom, a phosphorus atom, and a silicon atom. It can be mentioned that it is one or more atoms to be selected.
  • the compound group represented by the following general formula (2) can be exemplified.
  • R 1 to R 8 independently represent a hydrogen atom or a substituent.
  • n1 and n2 each independently represent an integer of 0 to 4, and n1 + n2 is an integer of 2 to 5.
  • the plurality of R 5s may be the same or different, and the plurality of R 6s may be the same or different.
  • n2 is 2 or more, the plurality of R 7s may be the same or different, and the plurality of R 8s may be the same or different.
  • the description of the substituent represented by R in the general formula (1) can be referred to.
  • the molecule represented by the general formula (1) or the general formula (2) may have at least a part of its hydrogen atom substituted with a deuterium atom, and if it is substituted with a deuterium atom, it exists in the molecule. It is more preferable that 30 to 70% of the hydrogen atoms to be used are replaced with deuterium atoms. As a result, the spin-lattice relaxation time of the polarization source can be lengthened, and the nuclear spin can be effectively highly polarized.
  • the portion of the molecule substituted with the deuterium atom is a portion that is relatively easy to move.
  • an atomic group (substituent) bonded by a single bond is present in the polycyclic condensed skeleton, it is preferable that at least a part of the hydrogen atom of the substituent is substituted with a deuterium atom. It is preferable that all the hydrogen atoms are replaced with heavy hydrogen atoms.
  • a substituent preferable for substitution with a deuterium atom an alkyl group having 1 to 20 carbon atoms can be mentioned.
  • the polarization source used in the present invention may be a porphyrin derivative. That is, the composition of the present invention contains a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more, and a porphyrin derivative which is a polarization source dispersed in the water-soluble matrix. It may be a thing.
  • the porphyrin derivative used as the polarization source may be one kind or a combination of two or more kinds. Porphyrin derivatives are photoexcited triplet molecules capable of generating polarized triplet electrons and are highly biocompatible.
  • the dynamic nuclear polarization source composed of a porphyrin derivative can be effectively used as a dynamic nuclear polarization material for various substances including bio-related substances.
  • the porphyrin derivative include a porphyrin derivative represented by the following general formula (3) and a complex having the porphyrin derivative as a ligand.
  • Ar 1 to Ar 4 each independently represent a substituted or unsubstituted aryl group.
  • the aromatic ring constituting the aryl group in Ar 1 to Ar 4 is a connecting ring in which two or more aromatic rings are linked, whether it is a monocyclic ring or a condensed ring in which two or more aromatic rings are condensed. May be good. When two or more aromatic rings are connected, they may be linearly connected or may be branched.
  • the number of carbon atoms in the aromatic ring is preferably 6 to 22, more preferably 6 to 18, further preferably 6 to 14, and even more preferably 6 to 10.
  • the aryl group examples include a phenyl group, a naphthalenyl group, and a biphenylyl group.
  • substituent of the aryl group examples include a cationic group, an anionic group, an ion pair, and a halogen atom.
  • the cationic group may be a cationic group or a group that receives a proton and becomes a cationic group.
  • Specific examples of the cationic group include a substituted or unsubstituted amino group and an ammonium group.
  • the anionic group may be an anionic group or a group in which protons are ionized to become an anionic group.
  • the anionic group examples include a carboxy group (-COOH), a phosphono group (-PO 3 H 2 ), a phosphonoxy group (-OPO 3 H 2 ), a sulfo group (-SO 3 H), and a sulfooxy group (-OSO 3). H), a hydroxy group (-OH), and an anionic group in which a proton is ionized from these groups can be mentioned.
  • the cation group and the anion group may form an ion pair with the anion and the cation, respectively.
  • Examples of the anion include the above-mentioned compounds having an anion group, and examples of the cation include alkali metal ions such as ammonium ion, Na + , and K +.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is preferable.
  • an aryl group is substituted with an electron-attracting group such as a halogen atom (for example, a fluorine atom)
  • an electron-attracting group such as a halogen atom (for example, a fluorine atom)
  • the larger the number of substitutions of the electron-attracting group the larger the number of substitutions.
  • the number of substitutions is preferably 4 or less, more preferably 3 or less, and further preferably 2 or less. preferable.
  • the term "electron-attracting group” means a substituent having a positive Hammett ⁇ p value. For a description and numerical value of Hammett's ⁇ p value, refer to the description in Hansch, C.et.al., Chem.Rev., 91,165-195 (1991).
  • a porphyrin derivative may have at least a part of its hydrogen atoms substituted with deuterium atoms, and when it is substituted with deuterium atoms, 30 to 70% of the hydrogen atoms present in the molecule are substituted with deuterium atoms. It is more preferable that it is. As a result, the spin-lattice relaxation time of the polarization source can be lengthened, and the nuclear spin can be effectively highly polarized.
  • the portion of the molecule substituted with the deuterium atom is a portion that is relatively easy to move.
  • an atomic group (substituent) bonded by a single bond is present in the porphyrin skeleton, it is preferable that at least a part of the hydrogen atom of the substituent is substituted with a heavy hydrogen atom, and all of them are substituted. It is preferable that the hydrogen atom of the above is replaced with a heavy hydrogen atom.
  • a substituent preferable for substitution with a deuterium atom an alkyl group having 1 to 20 carbon atoms can be mentioned.
  • Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group.
  • M represents the central metal. Examples of the central metal include Zn, Mg, Fe, Ni, P, Sb, As, Si, Ge, Sn and the like.
  • the bias corresponds to the spin-lattice relaxation time in the electron spin as compared with the case of no substitution.
  • an electron-attracting group such as a halogen atom (for example, a fluorine atom)
  • the bias corresponds to the spin-lattice relaxation time in the electron spin as compared with the case of no substitution.
  • the aryl group in Ar 11 to Ar 14 is preferably substituted with an electron-attracting group such as a fluorine atom, and the number of substitutions is preferably 2 or more.
  • porphyrin derivatives that can be used as a polarization source will be illustrated.
  • the porphyrin derivative that can be used as a polarization source in the present invention should not be construed as being limited by these specific examples.
  • the porphyrin derivative may be an axially coordinated porphyrin derivative as shown below. These porphyrin derivatives can be synthesized according to the synthetic method described in IN. Meshkov, et al. Chem. Communi., 2017, 53, 9918. The following three porphyrin derivatives have high solubility, and triplet electron spin polarization has been observed.
  • the polarization source for the composition of the present invention. Since the water-soluble polarization source has a high affinity with the water-soluble matrix material, it can be easily dispersed in the matrix material. Further, from the viewpoint of affinity with the water-soluble matrix, the polarization source preferably has an ion pair, and preferably has a cationic group or an anionic group. For the definition of "water-soluble”, the definition of "water-soluble” in the above matrix material can be referred to.
  • the composition of the present invention may be composed of only a matrix material and a polarization source, or may contain other components.
  • a basic substance such as sodium hydroxide or potassium hydroxide
  • protons are ionized from the acidic group of the polarization source to form a conjugate base, which may improve the affinity with the matrix material.
  • the composition of the present invention may contain a polarized object such as a protein, a peptide or DNA, a solvent molecule, a template molecule or the like as other components.
  • the polarization target is a substance capable of transferring the nuclear spin polarization generated in the composition.
  • the preferable range, and specific examples, the corresponding description in the column of ⁇ Highly polarized method> can be referred to.
  • the content of the polarization source in the composition is preferably 10 mol% or less, more preferably 3 mol% or less, and for example, in the range of 1 mol% or less with respect to the number of moles of the compound constituting the matrix material. You may.
  • the content of the polarization source is preferably 0.01 mol% or more, preferably in the range of 0.1 mol% or more, and 0.5 mol, based on the total number of moles of the compounds constituting the matrix material. It may be within the range of% or more.
  • Examples of the method for producing the composition of the present invention include the following production methods (1) to (3). From these manufacturing methods, the optimum manufacturing method can be appropriately selected depending on the material used.
  • (3) A method for producing a solidified composition by heating and melting a mixed powder prepared by mixing a powder of a matrix material and a powder of an polarization source, and then quenching with liquid nitrogen.
  • the composition of the present invention can be highly polarized by performing dynamic nuclear polarization treatment.
  • the dynamic nuclear polarization treatment and the mechanism will be described with reference to FIG.
  • the dynamic nuclear polarization treatment performed on the composition of the present invention should not be construed as being limited by what is described below.
  • the dynamic nuclear polarization treatment can be performed by the following steps [1] and [2].
  • the composition is irradiated with excitation light to transition the polarized light source contained in the composition to the excited triplet state.
  • the polarization source molecule transitions from the basal singlet state S 0 to the excited singlet state S 1 , and further from the excited singlet state S 1 .
  • intersystem crossing is excited triplet state T n is happening.
  • the excited triplet state T n is gradually internally converted to a lower-order excited triplet state, and finally becomes the excited triplet state T 1 at the lowest energy level.
  • the polarization of the triplet electron spin generated by the polarization source is transferred to the nuclear spin of the matrix material, and the nuclear spin is highly polarized.
  • the composition in which the triplet electron spin of the polarization source is generated is irradiated with an electromagnetic wave in which the electron spin resonates, for example, to perform magnetic field sweeping. Then, due to the integral solid effect, the spin polarization of the electron is transferred to the nucleus of the matrix material, and the nuclear spin is highly polarized.
  • the conditions for high polarization are not particularly limited, but for example, the intensity of the external magnetic field should be appropriately selected from the range of 0.1 to 1 T, the frequency of the electromagnetic wave should be 2 to 20 GHz, and the intensity of the electromagnetic field should be appropriately selected from the range of 0.1 to 100 W. Can be done. From the composition in which the nuclear spin is highly polarized in this way, an NMR signal having high intensity can be obtained, and high measurement sensitivity in NMR spectroscopy and MRI can be realized.
  • the composition of the present invention exhibits a high affinity for biological substances because the matrix material is water-soluble.
  • the polarization is easily transferred to the nuclear spin of the bio-related substance via the nuclear spin of the matrix material in this high polarization step.
  • the bio-related substance can be highly polarized.
  • the nuclear spin polarization generated by this composition becomes a living body due to the high affinity between the composition and the bio-related substance.
  • the bio-related material can be highly polarized by easily transferring to the nuclear spin of the related material. Examples of nuclear spin polarization transfer from the matrix material into a biological substance, include, for example, spin-polarized transfer of the 1 H nucleus matrix material to 13 C nuclei biological substance.
  • the step [2] may be performed after the step [1] is performed, or the step [1] and the step [2] may be performed at the same time. good. In the latter case, while applying an external magnetic field to the composition, an electromagnetic wave in which excitation light and electron spin resonate are simultaneously irradiated.
  • composition for dynamic nuclear polarization of the present invention is characterized by comprising the composition of the present invention.
  • the description in the above section ⁇ Composition> can be referred to.
  • the composition of the present invention has a high affinity for a bio-related substance, and the nuclear spin of the matrix material can be easily highly polarized.
  • the biorelated material can be effectively highly polarized by easily translocating to nuclear spin.
  • the highly polarized composition of the present invention is a highly polarized composition of the present invention.
  • the method of high polarization (high polarization treatment) and the mechanism, the description in the above section ⁇ Composition> can be referred to.
  • the spin-lattice relaxation time T 1 of the matrix material is defined to be 2.5 seconds or more, the electron spin of the polarization source is used in the dynamic nuclear polarization process.
  • the polarization that has migrated to the nuclear spins of the matrix material is retained and accumulated in the nuclear spins, and the entire composition can be highly polarized.
  • this highly polarized composition shows a high affinity for biological substances, reflecting the water solubility of the matrix material. Therefore, when a bio-related substance is brought into contact with this highly polarized composition, the nuclear spin polarization of the highly polarized composition easily shifts to the nuclear spin of the bio-related substance, and the bio-related substance is highly polarized. Can be transformed into.
  • the present invention also includes the case where the bio-related substance itself is used as the matrix material.
  • the present invention also includes an embodiment in which the polarization is directly transferred from the electron spin of the polarization source to the nuclear spin of a biorelated substance (for example, sodium pyruvate).
  • a biorelated substance for example, sodium pyruvate.
  • the fact that the composition is a "highly polarized composition" of the present invention is confirmed by observing a peak (sensitized peak) having a higher intensity than the NMR spectrum of the composition in a thermal equilibrium state in the NMR spectrum. can do.
  • the intensity of the sensitized peak of the highly polarized composition is preferably 10 times or more, more preferably 100 times or more, more preferably 1000 times or more the corresponding peak intensity of the composition in thermal equilibrium. It is more preferable that the amount is double or more.
  • the first aspect of the highly polarized method of the present invention is a highly polarized method including a step of bringing a substance into contact with the highly polarized composition of the present invention.
  • the second aspect of the highly polarized method of the present invention includes a step of bringing a substance into contact with the composition of the present invention and then highly polarized the composition to obtain a highly polarized composition. This is a highly polarized method.
  • the highly polarized composition contains a water-soluble matrix material
  • a hydrophilic polarized object such as a biological substance is particularly compatible with the highly polarized composition. It can be made into good contact. Therefore, the polarization of the nuclear spins generated in the highly polarized composition can be easily transferred to the nuclear spins of the bio-related substance, and the bio-related substance can be highly polarized.
  • the temperature at which the highly polarized composition and the polarized object are brought into contact with each other is not particularly limited. For example, it may be carried out in a low temperature range of less than ⁇ 78 ° C. or in the range of ⁇ 78 ° C.
  • This highly polarized method may further include a step of transferring the nuclear spin polarization of the highly polarized composition to the polarized object.
  • the nuclear spin polarization of the highly polarized composition is transferred to and diffuses to the polarized object by bringing the polarized object into contact with the highly polarized composition without performing a separate step.
  • a step for inducing the transition of the nuclear spin polarization may be performed. Examples of such a method include a cross polarization method (CP method), a CP / MAS method in which cross polarization is used in combination with magic angle spinning and wideband decoupling, and adiabatic passage cross polarization.
  • the polarized object to be brought into contact with the highly polarized composition may be a solid, a gas, a liquid or a solution.
  • the spin polarization of the nucleus of the highly polarized composition shifts to the polarized object, and the nucleus of the polarized object is transferred.
  • the spin is highly polarized.
  • the method of contacting the gas, liquid or solution with the highly polarized composition is not particularly limited, and for example, these may be injected into the highly polarized composition, or the container may be filled with these. , A container may be placed therein and permeated.
  • the polarized object may be mixed with the highly polarized composition in a state of being dissolved or dispersed in the liquid.
  • the highly polarized composition may directly polarize the object to be polarized, or may polarize the object via a liquid.
  • the highly polarized method of the second aspect includes a step of contacting the composition of the present invention with an object to be polarized and then highly polarization the composition to obtain a highly polarized composition. ..
  • the contact is preferably performed by mixing and homogenizing the matrix material, the polarization source, and the polarization object.
  • the mixing is, for example, in the production method (1) or (2) in the above-mentioned [Method for producing composition] column, the polarization target is dissolved in water together with the matrix material and the polarization source and mixed.
  • the method can be carried out by the method of mixing the powder of the polarization target together with the powder of the matrix material and the powder of the polarization source in the production method of (3).
  • a bio-related substance as a polarization target can be uniformly mixed with other materials, and the polarization source and the polarization target are uniformly mixed in the matrix.
  • a dispersed composition can be prepared. Then, by performing a high polarization treatment on this composition, the polarization of the electron spin generated at the polarization source is transferred to the nuclear spin of the matrix material or the polarization target object, and further, the nuclear spin of the matrix material is transferred.
  • the polarization can be transferred to the nuclear spin of the polarization object to make the polarization object highly polarized.
  • the amount of the biological substance to be blended in the composition is preferably 0.1 to 50% by weight based on the total amount of the composition, and is 10 to 40% by weight because the detection sensitivity of the NMR signal is high. preferable.
  • the transition nuclear spin polarization may transition the 1 H high polarization poling the composition to 1 H of polarized object
  • the same nuclide may be a transition between each other, so that the 1 H high polarization poling the composition of 13 transition C into different nuclides polarized object, a transition between different nuclides with each other It may be both or both.
  • the nuclide of the polarization object that shifts the nuclear spin polarization can be used without particular limitation as long as the spin quantum number I is other than 0.
  • nuclides include 1 H, 2 H, 3 He, 11 B, 13 C, 14 N, 15 N, 17 O, 19 F, 29 Si, 31 P, 129 Xe, etc., which are naturally present. Since the ratio is high , it is preferably 1 H, 14 N, 19 F, and 31 P, and because the NMR signal intensity is high, it is more preferably 1 H, 19 F.
  • the object to be polarized is preferably a biological substance, but the object is not limited to this, and various substances to be analyzed by the NMR measurement method can be the object to be polarized.
  • the composition of the present invention tends to be highly polarized by itself, and the nuclear spin polarization is transferred to various substances.
  • the substance can be highly polarized.
  • the polarization target preferably contains a hydrocarbon and at least one compound selected from a derivative of a hydrocarbon in which at least one hydrogen atom is substituted with a substituent.
  • the hydrocarbon may be an acyclic compound (aliphatic compound) or a ring compound, may be a saturated hydrocarbon, an unsaturated hydrocarbon, or a low molecular weight compound. It may be a polymer compound.
  • the ring-based compound may be either an alicyclic-based compound or an aromatic-based compound.
  • the number of carbon atoms in the hydrocarbon is not particularly limited, and is usually in the range of 1 to 10. Further, the hydrocarbon may be one in which some carbon atoms in the molecule are replaced with heteroatoms. Heteroatoms are not particularly limited, and examples thereof include N, P, O, and S.
  • the substituent is not particularly limited, but at least one of the substituents is preferably a substituent containing an atom having a spin quantum number I other than 0, 13 C, 15 N, 19 F. , 29 Si, 31 P and the like are more preferable, and a group containing 13 C and a fluorine atom are further preferable.
  • specific examples of the polarized object will be illustrated. However, the polarized object that can be used in the highly polarized method of the present invention is not limitedly interpreted by this specific example.
  • a particularly preferable object to be polarized is a bio-related substance.
  • the term "living body-related substance” means a substance constituting a living body and a derivative of a substance constituting the living body.
  • substances constituting a living body include biopolymers (nucleic acids, proteins, polysaccharides), nucleotides, nucleosides, peptides, amino acids and sugars, and lipids, vitamins, hormones and the like, which are components thereof.
  • the red circle part in Fig. 2 (A) of Chem.Soc.Rev., 2014,43,1627-1659 cited here as a part of this specification is shown. 13 C-labeled molecules can be exemplified. By introducing such a molecule into a living body as a probe and using the present invention, MRI observation can be performed.
  • the highly polarized substance of the present invention is a highly polarized substance by the highly polarized method of the present invention.
  • the highly polarized method of the present invention the description in the above section ⁇ Highly polarized method> can be referred to.
  • the description of the highly polarized object described in the above section ⁇ Highly polarized method>, a preferable range, and a specific example can be referred to.
  • Polarization rate of the high polarization poled substance of the present invention is preferably 10 -4 or more, more preferably 10 -2 or more, further preferably 10 -1 or more.
  • the polarization ratio of a substance can be measured by comparing the NMR signal intensity when the high polarization is performed and the signal intensity when the high polarization is not performed.
  • the NMR measurement method of the present invention includes a step of measuring NMR (nuclear magnetic resonance) of a substance using the composition of the present invention. Further, the NMR measurement method of the present invention is a concept including the MRI method. For a description of the composition of the present invention, a preferable range, and specific examples, the above section ⁇ Composition> can be referred to.
  • NMR measurement method of the present invention an object to be measured by NMR is brought into contact with a highly polarized composition obtained by performing dynamic nuclear polarization on the composition of the present invention to increase the nuclear spin of the object to be measured.
  • polarization After polarization, it can be performed by observing the NMR of the measurement target using a known NMR signal detection method.
  • dynamic nuclear polarization is performed to highly polarize the nuclear spin of the measurement object, and then a known NMR signal detection method is used. This can be done by observing the NMR of the object to be measured. If the nuclide to be observed by NMR is 13 C or 19 F, the polarization is further transferred from the highly polarized 1 H to 13 C or 19 F before observing NMR.
  • the NMR signal can be detected by using a known method such as a continuous wave method or a pulse Fourier transform method.
  • a known method such as a continuous wave method or a pulse Fourier transform method.
  • an RF coil (probe), an amplifier or the like is provided for detecting an NMR signal by the pulse Fourier transform method.
  • Equipment can be used.
  • the nuclear spin of the object to be measured is highly polarized by using the composition of the present invention, the NMR signal from the object to be measured can be detected with high intensity. Therefore, by applying this NMR measurement method, it is possible to analyze the structure and physical properties of a compound by NMR spectroscopy and to inspect living organs by MRI with high sensitivity.
  • the features of the present invention will be described in more detail with reference to Examples below.
  • the materials, treatment contents, treatment procedures, etc. shown below can be appropriately changed as long as they do not deviate from the gist of the present invention. Therefore, the scope of the present invention should not be construed as limited by the specific examples shown below.
  • the light absorption spectrum is measured using a spectrophotometer (manufactured by JASCO Corporation: V-670, V-770), and the emission spectrum is measured using a spectrofluorescent photometer (manufactured by JASCO Corporation: FP-8700). ),
  • the NMR signal was measured using an NMR apparatus (manufactured by JASCO Corporation: JNM-ECA400).
  • the measurement of the time-resolved ESR spectrum and the dynamic nuclear polarization were performed by combining a 545 nm pulse laser, an electromagnet, a microwave generator (manufactured by Analog Devices, Inc .: HMC-T2220), and an ESR detector.
  • the compound used as the polarization source in this example was synthesized as follows.
  • the polarization source and matrix material used in each example are shown below.
  • Spin matrix material - lattice relaxation time T 1 was measured by saturation recovery method. Specifically, each matrix material to produce a solid sample to be measured by quenching after melting, using ECZ400S, spin at room temperature, 30 MHz pulse frequency - was measured lattice relaxation time T 1. Further, "mol%" indicating the ratio of the polarization source in each example is a molar percentage with respect to the number of moles of the matrix material.
  • Matrix material erythritol, sorbitol, fructose, urea, glucose, maltose spin - lattice relaxation time T 1 is as shown in FIG.
  • Other matrix materials spin - lattice relaxation time T 1 is 3 seconds ⁇ - estradiol, 80 seconds benzoic acid, 14 seconds carbamazepine.
  • D represents deuterium.
  • Example 1 Preparation of composition 1 using compound 1 as a polarization source and erythritol as a matrix material
  • the obtained powder was heated to 121 ° C. in an oil bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 1.
  • Example 2 Preparation of composition 2 using compound 9 as a polarization source and erythritol as a matrix material A solid composition in the same manner as in Example 1 except that compound 9 is used instead of compound 1. 2 was prepared.
  • Example 3 Preparation of composition 3 using compound 1 as a polarization source and urea as a matrix material An aqueous solution of urea (1 mM) and compound 1 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was dried by heating at 70 ° C. for 1 hour. The obtained powder was heated to 121 ° C. in an oil bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 3.
  • Example 4 Preparation of composition 4 using compound 1 as a polarization source and sorbitol as a matrix material Each powder of sorbitol (2.5 mmol) and compound 1 (1.25 ⁇ 10 -3 mmol) is prepared. Weighed and ground to prepare a mixed powder. This mixed powder was heated to 95 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 4.
  • compositions 5 and 6 Preparation of compositions 5 and 6 using compound 9 or compound 10 as a polarization source and sorbitol as a matrix material, except that compound 9 or compound 10 is used instead of compound 1. Solid compositions 5 and 6 were prepared in the same manner as in Example 4.
  • Example 7 Preparation of composition 7 using compound 10 as a polarization source and sorbitol as a matrix material An aqueous solution of sorbitol (1 mM) and compound 10 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was heated and dried at 70 ° C. for 1 hour. The obtained powder was allowed to stand in a desiccator for 1 day to obtain a solid composition 7.
  • composition 9 Preparation of composition 9 using compound 1 as a polarization source and fructose as a matrix material Weigh each powder of fructose (2.5 mmol) and compound 1 (1.25 ⁇ 10 -3 mmol). Grinded to obtain a mixed powder. This mixed powder was heated to 95 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 8.
  • composition 9 using compound 9 as a polarization source and fructose as a matrix material Weigh each powder of fructose (2.5 mmol) and compound 9 (1.25 ⁇ 10 -3 mmol). Grinded to prepare a mixed powder. This mixed powder was heated to 103 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 9.
  • composition 10 Preparation of composition 10 using compound 1 as a polarization source and glucose as a matrix material Weigh each powder of glucose (2.5 mmol) and compound 1 (1.25 ⁇ 10 -3 mmol). It was ground and a mixed powder was prepared. This mixed powder was heated to 146 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 10.
  • composition 11 Preparation of composition 11 using compound 10 as a polarization source and glucose as a matrix material An aqueous solution of glucose (1 mM) and compound 10 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was heated and dried at 70 ° C. for 1 hour. The obtained powder was allowed to stand in a desiccator for 1 day to obtain a solid composition 11.
  • Example 12 Preparation of composition 12 using compound 4 as a polarization source and ⁇ -estradiol as a matrix material
  • Compound 4 (0.1 mol%) and ⁇ -estradiol (200 mg, 0.73 mmol) were mixed.
  • a melt of ⁇ -estradiol in which compound 4 was dispersed was obtained by heating at 400 ° C.
  • the melt was rapidly cooled with liquid nitrogen to vitrify ⁇ -estradiol, and then the glass was crushed and placed in a capillary and heated again at 400 ° C. to melt it.
  • the composition 12 was obtained by quenching the melt with liquid nitrogen and vitrifying it.
  • compositions 13 and 14 Preparation of compositions 13 and 14 using compound 7 or compound 8 as a polarization source and ⁇ -estradiol as a matrix material Other than using compound 7 or compound 8 instead of compound 4. Obtained compositions 13 and 14 in the same manner as in Example 12.
  • compositions 15 to 21 Preparation of compositions 15 to 21 using compound 1 as a polarization source and deuterium substitution products of erythritol, xylitol, sorbitol, glucose, fructose, maltose, or erythritol as a matrix material.
  • Compositions 15 to 21 were prepared by the melt quench method. Specifically, the composition is prepared by dissolving 0.01 mol% of Compound 1 in each matrix material melted by heating to a temperature of melting point to (melting point +10) ° C., and then rapidly cooling to room temperature with liquid nitrogen. Obtained.
  • composition using erythritol or xylitol as the matrix material was rapidly recrystallized at room temperature, and the composition using maltose as the matrix material formed an amorphous solid at room temperature.
  • Compositions using sorbitol, glucose or fructose as the matrix material remained melted at room temperature but became solid upon cooling (solid at 100 K).
  • compositions 22 and 23 Preparation of compositions 22 and 23 using compound 2 as a polarization source and benzoic acid or carbamazepine as a matrix material Compound 2 is used instead of compound 1 and benzoic acid or benzoic acid is used instead of erythritol.
  • the compositions 22 and 23 were prepared in the same manner as in Example 15 except that carbamazepine was used.
  • compositions 24 to 29 Preparation of compositions 24 to 29 using compounds 3 to 8 as a polarization source and ⁇ -estradiol as a matrix material 0.1 mol of any of compounds 3 to 8 instead of compound 1.
  • Compositions 24-29 were prepared in the same manner as in Example 15 except that ⁇ -estradiol was used instead of erythritol.
  • Table 1 summarizes the polarization sources and matrix materials used in Examples 15 to 29.
  • compositions 15 to 20 in which the compound 1 is dispersed in the matrix material and the compositions 22 and 23 in which the compound 2 is dispersed in the matrix material almost the same spectral shape as that of the aqueous solution is observed. Compared with the solid, the long wavelength shift of the peak was suppressed. From this, it was confirmed that compounds 1 and 2 were dispersed and present in each matrix material.
  • FIG. 9 The ESR spectra of the compositions 15 to 20, 22, and 23 observed by this time-resolved ESR measurement are shown in FIG. 9, and the decay curve of the ESR signal observed at a specific magnetic field strength is shown in FIG. In FIG. 9, a peak falling in the direction of “ ⁇ E” represents microwave absorption, and a peak rising in the direction of “ ⁇ A” represents microwave emission.
  • FIG. 9 also shows a simulation curve sim (smooth curve) of the ESR spectrum obtained by calculation of the Easyspin toolbox (MATLAB) (registered trademark). The observed magnetic field strengths of the ESR signals used in FIG.
  • FIG. 10 shows a single exponential fitting curve of the attenuation curve. As shown in FIG. 9, in the ESR spectra of the compositions 15 to 20, 22 and 23, emission peaks and absorption peaks were observed, and the spectral shapes characteristic of triplet electron spins were shown. From this, it was confirmed that compounds 1 and 2 can transition to the excited triplet state in each matrix and take an electron spin polarization state.
  • FIG. 14 shows the results (1 H spin polarization build-up curve) plotted on the horizontal axis.
  • the 1 H NMR signal shown by the black line in FIG. 13 is a weak signal based on the 1 H spin observed in the thermal equilibrium state of the erythritol deuterium substituent.
  • the strong 1 H NMR signal observed after 100K dynamic nuclear polarization treatment is derived from the spin polarization transferred from compound 1 to the erythritol deuterium substituent.
  • the 1 H NMR signal intensity of the composition 21 was remarkably enhanced by repeating the dynamic nuclear polarization treatment, and after 15 minutes, the signal intensity was 120 times or more. From this, the composition 21 can efficiently transfer the polarization of the triplet electron spin of the compound 1 to the erythritol nuclear spin, and is a highly polarized composition or a composition for dynamic nuclear polarization. It turned out to be useful as. In addition, this result is significant in that it was confirmed that the polarization of triplet electron spins can be transferred to erythritol, which is a natural biomolecule.
  • the observed magnetic field strength of the ESR signal used for the attenuation curve was 328 mT for the composition 24, 332 mT for the composition 25, 338 mT for the composition 26, 290 mT for the composition 27, 287 mT for the composition 28, and 309 mT for the composition 29.
  • the time-resolved ESR spectra of the compositions 24-26 are shown in FIG. 15, and the attenuation curve of the ESR signal is shown in FIG.
  • the time-resolved ESR spectra of the compositions 27-29 are shown in FIG. 17, and the attenuation curve of the ESR signal is shown in FIG. As shown in FIGS.
  • the ESR spectra of the compositions 24-29 showed emission peaks and absorption peaks, and showed a spectral shape characteristic of triplet electron spins. From this, it was confirmed that compounds 3 to 8 also transition to the excited triplet state in the matrix material and can take electron spin polarization.
  • the polarization lifetime ⁇ of the attenuation curve shown in FIGS. 16 and 18 corresponds to the spin-lattice relaxation time of each composition.
  • the compositions 24 to 26 using a free porphyrin derivative (porphyrin derivative not forming a metal complex) as a polarization source the larger the number of substitutions of fluorine atoms in the porphyrin derivative (compositions 26, 25).
  • the composition of the present invention has a high affinity for bio-related substances, and can efficiently transfer the polarization of the triplet electron spin of the polarization source to the nuclear spin of the matrix material. Therefore, the composition of the present invention greatly contributes to the realization of dynamic nuclear polarization to bio-related substances, and has high industrial applicability.

Abstract

This composition includes a water-soluble matrix material having a spin-lattice relaxation time T1 of 2.5 seconds or higher, and a polarization source dispersed in the water-soluble matrix, the composition being usable as a composition for dynamic nuclear polarization. A composition for dynamic nuclear polarization in which this composition is used has higher biological compatibility than in the past, and therefore can contribute greatly to development of a feature for dynamic nuclear polarization to a biologically relevant substance.

Description

組成物、動的核偏極用組成物、高偏極化組成物、物質の高偏極化方法、高偏極化した物質およびＮＭＲ測定方法Composition, dynamic nuclear polarization composition, highly polarized composition, highly polarized substance, highly polarized substance and NMR measurement method
　本発明は、物質の核スピンを高偏極化する偏極材として有用な組成物および動的核偏極用組成物、並びに、その組成物を用いる物質の高偏極化方法、その高偏極化方法により高偏極化した物質、および、その組成物を利用する物質のＮＭＲ測定方法に関する。 The present invention relates to a composition useful as a polarization material for highly polarization the nuclear spin of a substance, a composition for dynamic nuclear polarization, a method for highly polarization a substance using the composition, and the high polarization thereof. The present invention relates to a substance highly polarized by a polarization method and a method for NMR measurement of a substance using the composition.
　磁気モーメントを有する原子核（核スピン）を静磁場中に置くと歳差運動を行うようになり、この状態で、その歳差運動と同じ周波数の電磁波を照射すると、核スピンが共鳴して電磁場のエネルギーを吸収する核磁気共鳴（ＮＭＲ）現象が現れる。このＮＭＲ現象における共鳴周波数は核種や原子核の置かれた化学的または磁気的環境に応じて差がでることから、有機化学や生化学の分野では、その共鳴によるエネルギー吸収量を電気信号に変換したＮＭＲ信号の周波数スペクトル（化学シフト値）を観測して、化合物の分子構造や物性を解析するＮＭＲ分光法が多く行われている。また、医療の分野においては、そのＮＭＲ信号に位置情報を与えて画像化する磁気共鳴撮像法（ＭＲＩ）が、脳などの生体器官の非侵襲的検査に応用されている。
　ここで、上記のような核スピンの集合体に、静磁場を印加すると、例えばプロトンの場合では、その磁場に対してスピンが平行に向いたエネルギー状態と、磁場に対してスピンが反平行に向いたエネルギー状態に***する。ここで、それぞれのエネルギー状態をもつスピンの数（占有数）の差をスピン総数で割った値は偏極率と称されており、ＮＭＲ信号の強度は、この偏極率に比例するとされている。しかし、核スピンの偏極率は、通常、室温では数万分の１以下と非常に低い値であり、このことがＮＭＲ分光法やＭＲＩの感度を制限する原因になっている。 When an atomic nucleus (nuclear spin) having a magnetic moment is placed in a static magnetic field, it will undergo aging motion. In this state, if an electromagnetic wave with the same frequency as the aging motion is irradiated, the nuclear spin will resonate and the electromagnetic field will resonate. A nuclear magnetic resonance (NMR) phenomenon that absorbs energy appears. Since the resonance frequency in this NMR phenomenon differs depending on the chemical or magnetic environment in which the nuclei and nuclei are placed, in the fields of organic chemistry and biochemistry, the amount of energy absorbed by the resonance is converted into an electric signal. Many NMR spectroscopy methods are used to analyze the molecular structure and physical properties of a compound by observing the frequency spectrum (chemical shift value) of the NMR signal. Further, in the medical field, magnetic resonance imaging (MRI), in which position information is given to the NMR signal and imaged, is applied to non-invasive examination of biological organs such as the brain.
Here, when a static magnetic field is applied to the aggregate of nuclear spins as described above, for example, in the case of protons, the energy state in which the spins are oriented parallel to the magnetic field and the spins are antiparallel to the magnetic field. It splits into a suitable energy state. Here, the value obtained by dividing the difference in the number of spins (occupancy number) having each energy state by the total number of spins is called the polarization rate, and the intensity of the NMR signal is said to be proportional to this polarization rate. There is. However, the polarization rate of nuclear spin is usually a very low value of 1 / tens of thousands or less at room temperature, which is a cause of limiting the sensitivity of NMR spectroscopy and MRI.
　そこで、核スピンを高偏極化する方法として、電子のスピン偏極を、電磁波照射にて誘起される固体効果や積分型固体効果等により、周囲の核に移行させて核スピンを高偏極化する動的核偏極法が提案されている。ここで、電子スピンの供給源（偏極源）には、ラジカルや光励起三重項分子が用いられ、このうち光励起三重項分子は、温度に関わりなく、電子スピンの占有数が特定のエネルギー状態に大きく偏った状態をとるため、室温においても、核スピンを効果的に高偏極化することができるという利点がある。
　例えば特許文献１には、こうした偏極源となる光励起三重項分子として、特定の炭化水素基を有するペンタンセン誘導体を用いることが提案されている。同文献では、試料管内において、そのペンタセン誘導体を偏極源に用いて動的核偏極を行ったところ、動的核偏極を行わなかったサンプルに比べて、高い１Ｈスピン信号が得られたことが確認されている。 Therefore, as a method of highly polarization the nuclear spin, the spin polarization of the electrons is transferred to the surrounding nuclei by the solid effect induced by electromagnetic wave irradiation, the integral solid effect, etc., and the nuclear spin is highly polarized. A dynamic nuclear polarization method has been proposed. Here, radicals and photoexcited triplet molecules are used as the source of electron spins (polarization source), and among them, the photoexcited triplet molecules have the number of electron spins occupied in a specific energy state regardless of the temperature. Since the state is largely biased, there is an advantage that the nuclear spin can be effectively highly polarized even at room temperature.
For example, Patent Document 1 proposes to use a pentansen derivative having a specific hydrocarbon group as a photoexcited triplet molecule that serves as such a polarization source. In this document, in a sample tube, the pentacene derivative using a polarized source was subjected to a dynamic nuclear polarization, as compared to the sample which was not subjected to the dynamic nuclear polarization, high 1 H spin signal is obtained It has been confirmed that
特開２０１７－１５４４３号公報Japanese Unexamined Patent Publication No. 2017-15443
　上記のように、動的核偏極の偏極源として光励起三重項分子が知られている。ここで、光励起三重項分子は有機化合物であることから、一般に疎水性である。そのため、実際に動的核偏極処理に使用する際には、偏極源となる光励起三重項分子を疎水性基剤と混合して偏極対象物に適用することが行われる。一方、ＮＭＲ測定法は、水素原子や炭素原子の結合状態について有用な情報を与えることから、特に生体の検査方法や生体関連物質の分析方法として期待されているが、生体組織、生体関連物質の多くは親水性である。そのため、偏極源を疎水性基剤と混合した偏極材では、生体適合性や生体関連物質との親和性が低く、医療や生命科学の分野で行う動的核偏極への活用が難しいという課題があった。 As described above, a photoexcited triplet molecule is known as a polarization source of dynamic nuclear polarization. Here, since the photoexcited triplet molecule is an organic compound, it is generally hydrophobic. Therefore, when actually used for dynamic nuclear polarization treatment, a photoexcited triplet molecule serving as a polarization source is mixed with a hydrophobic base and applied to a polarization object. On the other hand, the NMR measurement method is expected as a method for inspecting a living body and a method for analyzing a living body-related substance because it provides useful information on the bonding state of a hydrogen atom and a carbon atom. Many are hydrophilic. Therefore, the polarization material in which the polarization source is mixed with a hydrophobic base has low biocompatibility and affinity with bio-related substances, and it is difficult to utilize it for dynamic nuclear polarization in the fields of medicine and life science. There was a problem.
　そこで本発明者らは、従来よりも生体適合性が高い偏極材を提供し、生体関連物質への動的核偏極に道を開く技術を開発することを目的として検討を進めた。 Therefore, the present inventors have proceeded with studies for the purpose of providing a polarization material having higher biocompatibility than before and developing a technology that paves the way for dynamic nuclear polarization to bio-related substances.
　上記の課題を解決するために鋭意検討を行った結果、本発明者らは、スピン－格子緩和時間Ｔ１が一定以上の水溶性マトリクス材料中に偏極源を分散させて偏極材を構成することにより、生体適合性や生体関連物質との親和性が高い偏極材が実現することを見出した。本発明は、こうした知見に基づいて提案されたものであり、具体的に以下の構成を有する。 As a result of diligent studies to solve the above problems, the present inventors construct a polarization material by dispersing the polarization source in a water-soluble matrix material having a spin-lattice relaxation time T 1 of a certain value or more. By doing so, it was found that a polarization material having high biocompatibility and affinity with bio-related substances can be realized. The present invention has been proposed based on these findings, and specifically has the following configuration.
［１］　スピン－格子緩和時間Ｔ１が２．５秒以上である水溶性のマトリクス材料と、該水溶性マトリクス中に分散した偏極源を含む組成物。
［２］　前記マトリクス材料の融点が３０℃以上である、［１］に記載の組成物。
［３］　前記マトリクス材料の分子量が３００以下である、［１］または［２］に記載の組成物。
［４］　前記マトリクス材料が水素結合を形成しうる基を有している、［１］～［３］のいずれか１項に記載の組成物。
［５］　前記マトリクス材料が分子内に２つ以上のヒドロキシ基を有する、［１］～［４］のいずれか１項に記載の組成物。
［６］　前記マトリクス材料が分子内にアミノ基と該アミノ基と水素結合を形成する基を有する、［１］～［５］いずれか１項に記載の組成物。
［７］　前記マトリクス材料が分子内にアミノカルボニル基を有する、［６］に記載の組成物。
［８］　前記マトリクス材料が、水素原子、炭素原子および酸素原子のみで構成される、［１］～［５］のいずれか１項に記載の組成物。
［９］　前記マトリクス材料が、水素原子、炭素原子、酸素原子および窒素原子からなる群より選択される原子のみで構成される、［１］～［７］のいずれか１項に記載の組成物。
［１０］　前記マトリクス材料が繰り返し単位を有さない、［１］～［９］のいずれか１項に記載の組成物。
［１１］　前記マトリクス材料がアルキル基を有さない、［１］～［１０］のいずれか１項に記載の組成物。
［１２］　前記マトリクス材料が水素原子を含み、その少なくとも一部が重水素である、［８］～［１１］のいずれか１項に記載の組成物。
［１３］　前記マトリクス材料が糖アルコールである、［１］に記載の組成物。
［１４］　前記偏極源が水溶性である、［１］～［１３］のいずれか１項に記載の組成物。
［１５］　前記偏極源がイオン対を有する、［１］～［１４］のいずれか１項に記載の組成物。
［１６］　前記偏極源がカチオン性基を有する、［１］～［１５］のいずれか１項に記載の組成物。
［１７］　前記偏極源がアニオン性基を有する、［１］～［１５］のいずれか１項に記載の組成物。
［１８］　前記偏極源がポルフィリン誘導体である、［１］～［１７］のいずれか１項に記載の組成物。
［１９］　前記ポルフィリン誘導体が下記一般式（３）で表される化合物である、［１８］に記載の組成物。
Figure JPOXMLDOC01-appb-C000003
 ［一般式（３）において、Ａｒ１～Ａｒ４は各々独立に置換もしくは無置換のアリール基を表す。］
［２０］　前記ポルフィリン誘導体が下記一般式（４）で表される金属錯体である、［１８］に記載の組成物。
Figure JPOXMLDOC01-appb-C000004
 ［一般式（４）において、Ａｒ１１～Ａｒ１４は各々独立に置換もしくは無置換のアリール基を表す。］
［２１］　前記一般式（４）のＡｒ１１～Ａｒ１４の少なくとも１つが電子求引性基で置換されたアリール基である、［２０］に記載の組成物。
［２２］　前記電子求引性基がハロゲン原子である、［２１］に記載の組成物。
［２３］　前記偏極源の含有量が３ｍｏｌ％以下である、［１］～［２２］のいずれか１項に記載の組成物。
［２４］　［１］～［２３］のいずれか１項に記載の組成物からなる動的核偏極用組成物。
［２５］　［１］～［２３］のいずれか１項に記載の組成物を高偏極化したものである、高偏極化組成物。
［２６］　［２５］に記載の高偏極化組成物に物質を接触させる工程、または、［１］～［２３］のいずれか１項に記載の組成物に物質を接触させた後、前記組成物を高偏極化させて高偏極化組成物とする工程を含む、物質の高偏極化方法。
［２７］　［２５］に記載の高偏極化組成物に物質を接触させる工程を含む、１９に記載の高偏極化方法。
［２８］　［１］～［２３］のいずれか１項に記載の組成物に物質を接触させた後、前記組成物を高偏極化させて高偏極化組成物とする工程を含む、［２６］に記載の高偏極化方法。
［２９］　前記接触を、前記マトリクス材料と前記偏極源と前記物質とを混合して均一化することにより行う、［２８］に記載の高偏極化方法。
［３０］　［９］～［２９］のいずれか１項に記載の方法により高偏極化した物質。
［３１］　［１］～［２３］のいずれか１項に記載の組成物を用いて物質のＮＭＲを測定する工程を含む、ＮＭＲ測定法。 [1] A composition containing a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more and a polarization source dispersed in the water-soluble matrix.
[2] The composition according to [1], wherein the matrix material has a melting point of 30 ° C. or higher.
[3] The composition according to [1] or [2], wherein the matrix material has a molecular weight of 300 or less.
[4] The composition according to any one of [1] to [3], wherein the matrix material has a group capable of forming a hydrogen bond.
[5] The composition according to any one of [1] to [4], wherein the matrix material has two or more hydroxy groups in the molecule.
[6] The composition according to any one of [1] to [5], wherein the matrix material has an amino group and a group forming a hydrogen bond with the amino group in the molecule.
[7] The composition according to [6], wherein the matrix material has an aminocarbonyl group in the molecule.
[8] The composition according to any one of [1] to [5], wherein the matrix material is composed of only hydrogen atoms, carbon atoms and oxygen atoms.
[9] The composition according to any one of [1] to [7], wherein the matrix material is composed of only atoms selected from the group consisting of hydrogen atoms, carbon atoms, oxygen atoms and nitrogen atoms. ..
[10] The composition according to any one of [1] to [9], wherein the matrix material does not have a repeating unit.
[11] The composition according to any one of [1] to [10], wherein the matrix material does not have an alkyl group.
[12] The composition according to any one of [8] to [11], wherein the matrix material contains a hydrogen atom and at least a part thereof is deuterium.
[13] The composition according to [1], wherein the matrix material is a sugar alcohol.
[14] The composition according to any one of [1] to [13], wherein the polarization source is water-soluble.
[15] The composition according to any one of [1] to [14], wherein the polarization source has an ion pair.
[16] The composition according to any one of [1] to [15], wherein the polarization source has a cationic group.
[17] The composition according to any one of [1] to [15], wherein the polarization source has an anionic group.
[18] The composition according to any one of [1] to [17], wherein the polarization source is a porphyrin derivative.
[19] The composition according to [18], wherein the porphyrin derivative is a compound represented by the following general formula (3).
Figure JPOXMLDOC01-appb-C000003
 [In the general formula (3), Ar 1 to Ar 4 each independently represent a substituted or unsubstituted aryl group. ]
[20] The composition according to [18], wherein the porphyrin derivative is a metal complex represented by the following general formula (4).
Figure JPOXMLDOC01-appb-C000004
 [In the general formula (4), Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group. ]
[21] The composition according to [20], wherein at least one of Ar 11 to Ar 14 of the general formula (4) is an aryl group substituted with an electron-attracting group.
[22] The composition according to [21], wherein the electron-attracting group is a halogen atom.
[23] The composition according to any one of [1] to [22], wherein the content of the polarization source is 3 mol% or less.
[24] A composition for dynamic nuclear polarization comprising the composition according to any one of [1] to [23].
[25] A highly polarized composition obtained by highly polarized the composition according to any one of [1] to [23].
[26] The step of bringing the substance into contact with the highly polarized composition according to [25], or after bringing the substance into contact with the composition according to any one of [1] to [23]. A method for highly polarization a substance, which comprises a step of highly polarization the composition to obtain a highly polarized composition.
[27] The highly polarized method according to 19, which comprises a step of bringing a substance into contact with the highly polarized composition according to [25].
[28] A step of bringing a substance into contact with the composition according to any one of [1] to [23] and then highly polarized the composition to obtain a highly polarized composition is included. The highly polarized method according to [26].
[29] The highly polarized method according to [28], wherein the contact is performed by mixing and homogenizing the matrix material, the polarized source, and the substance.
[30] A substance highly polarized by the method according to any one of [9] to [29].
[31] An NMR measurement method comprising a step of measuring NMR of a substance using the composition according to any one of [1] to [23].
　本発明の組成物は、生体関連物質に対して高い親和性を示し、生体適合性が高い。また、そのマトリクス材料の核スピンを容易に高偏極化することができる。そのため、この組成物によれば、その核スピン偏極を生体関連物質の核スピンに効率よく移行させて該物質を高偏極化することができる。よって、本発明の組成物は、生体関連物質等の物質を高偏極化する偏極材として有用性が高い。 The composition of the present invention shows high affinity for bio-related substances and has high biocompatibility. In addition, the nuclear spin of the matrix material can be easily highly polarized. Therefore, according to this composition, the nuclear spin polarization can be efficiently transferred to the nuclear spin of a biologically related substance, and the substance can be highly polarized. Therefore, the composition of the present invention is highly useful as a depolarizing material for highly depolarizing substances such as bio-related substances.
マトリクス材料のスピン－格子緩和時間Ｔ１を示すグラフである。It is a graph which shows the spin-lattice relaxation time T 1 of a matrix material. 本発明の組成物による動的核偏極メカニズムを説明するための模式図である。It is a schematic diagram for demonstrating the dynamic nuclear polarization mechanism by the composition of this invention. 組成物１およびエリトリトール単独固体の粉末Ｘ線回折パターンである。It is a powder X-ray diffraction pattern of composition 1 and erythritol alone solid. 組成物１５～２０の光吸収スペクトルである。It is a light absorption spectrum of the composition 15-20. 組成物１５～２０の発光スペクトルである。It is an emission spectrum of the composition 15-20. 組成物２２、２３の光吸収スペクトルである。It is a light absorption spectrum of compositions 22 and 23. 組成物２２、２３の発光スペクトルである。It is an emission spectrum of compositions 22 and 23. 時間分解ＥＳＲ測定で起こるゼーマン副準位間での遷移を示す模式図である。It is a schematic diagram which shows the transition between Zeeman sublevels which occurs in the time-resolved ESR measurement. 組成物１５～２０、２２、２３の時間分解ＥＳＲスペクトルである。9 is a time-resolved ESR spectrum of compositions 15-20, 22, 23. 組成物１５～２０、２２、２３のＥＳＲシグナルの減衰曲線である。It is the attenuation curve of the ESR signal of the composition 15-20, 22, 23. 動的核偏極処理のプロセスを示す模式図である。It is a schematic diagram which shows the process of dynamic nuclear polarization processing. 偏極源の三重項電子スピンからマトリクス材料の核スピンへの偏極移行メカニズムを示す模式図である。It is a schematic diagram which shows the polarization transfer mechanism from the triplet electron spin of a polarization source to the nuclear spin of a matrix material. 組成物２１の動的核偏極処理を行った後の１Ｈ ＮＭＲシグナルと熱平衡状態での１Ｈ ＮＭＲシグナルを示すグラフである。It is a graph which shows the 1 1 H NMR signal after performing the dynamic nuclear polarization treatment of composition 21 and 1 1 1 H NMR signal in a thermal equilibrium state. 組成物２１に動的核偏極処理を行ったときのＮＭＲ信号強度の変化を示すグラフである。It is a graph which shows the change of the NMR signal intensity when the composition 21 is subjected to the dynamic nuclear polarization treatment. 組成物２４～２６の時間分解ＥＳＲスペクトルである。9 is a time-resolved ESR spectrum of compositions 24-26. 組成物２４～２６のＥＳＲシグナルの減衰曲線である。It is the attenuation curve of the ESR signal of compositions 24-26. 組成物２７～２９の時間分解ＥＳＲスペクトルである。9 is a time-resolved ESR spectrum of compositions 27-29. 組成物２７～２９のＥＳＲシグナルの減衰曲線である。9 is an attenuation curve of the ESR signal of the compositions 27 to 29.
　以下において、本発明の内容について詳細に説明する。以下に記載する構成要件の説明は、本発明の代表的な実施態様や具体例に基づいてなされることがあるが、本発明はそのような実施態様や具体例に限定されるものではない。なお、本明細書において「～」を用いて表される数値範囲は、「～」の前後に記載される数値を下限値および上限値として含む範囲を意味する。また、本発明に用いられる化合物の分子内に存在する水素原子の同位体種は特に限定されず、例えば分子内の水素原子がすべて１Ｈであってもよいし、一部または全部が２Ｈ（デューテリウムＤ）であってもよい。また、本明細書における「励起光」とは、対象物に励起を引き起こして発光を生じさせる光であり、その対象物の吸収波長に一致する波長の光を用いることができる。 Hereinafter, the contents of the present invention will be described in detail. The description of the constituent elements described below may be based on typical embodiments and specific examples of the present invention, but the present invention is not limited to such embodiments and specific examples. The numerical range represented by using "-" in the present specification means a range including the numerical values before and after "-" as the lower limit value and the upper limit value. Further, the isotope species of the hydrogen atom existing in the molecule of the compound used in the present invention is not particularly limited, and for example, all the hydrogen atoms in the molecule may be 1 H, or part or all of them may be 2 H. (Duterium D) may be used. Further, the “excitation light” in the present specification is light that causes excitation of an object to cause light emission, and light having a wavelength that matches the absorption wavelength of the object can be used.
＜組成物＞
　本発明の組成物は、スピン－格子緩和時間Ｔ１が２．５秒以上である水溶性のマトリクス材料と、該水溶性マトリクス中に分散した偏極源とを含むものである。 <Composition>
The composition of the present invention comprises a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more, and a polarization source dispersed in the water-soluble matrix.
　本発明における「マトリクス材料」とは、偏極源を分散状態で保持する母材のことを意味する。具体的には、マトリクス材料は、偏極源を構成する化合物のモル数に対して５倍以上のモル数で配合された化合物からなる材料のことをいう。モル数は、例えば１０倍以上の範囲内にあってもよく、５０倍以上の範囲内にあってもよく、１００倍以上の範囲内にあってもよい。マトリクス材料は１種類の化合物から構成されていても２種類以上の化合物から構成されていてもよい。マトリクス材料が２種類以上の化合物で構成されている場合には、その合計モル数が、偏極源のモル数に対して５倍以上であればよい。偏極源がマトリクス材料中に分散していることは、例えば粉末Ｘ線回折法で観測される組成物の回折パターンにおいて、マトリクス材料単独の回折パターンと同様のパターンが観測されること、すなわちマトリクス材料の結晶性が組成物に保持されていることを観測することをもって確認することができる。このとき、偏極源は他の材料に混合・吸着されることなく偏極源単独で分散しており、分散している偏極源の径はできるだけ小さいことが好ましい。最も好ましいのは単分子で分散している場合である。
　「スピン－格子緩和時間Ｔ１」とは、熱的平衡状態における核スピンの全磁化ベクトルの向きをＺ軸方向としたとき、９０°パルス励起によりＺ軸方向からずれた磁化ベクトルがＺ軸方向に回復するまでの時間のことをいう。このスピン－格子緩和時間Ｔ１が長いもの程、偏極源から移行したスピン偏極を保持し易く、そのスピン偏極を蓄積して高偏極化することができる。
　本発明では、飽和回復法により、室温下、３０ＭＨｚの９０°パルスを用いて「スピン－格子緩和時間Ｔ１」を測定することとする。
　本発明における「水溶性」とは、水中に１mmol/L以上溶解する性質を意味する。 The "matrix material" in the present invention means a base material that holds a polarization source in a dispersed state. Specifically, the matrix material refers to a material composed of a compound compounded in a molar number of 5 times or more the number of moles of the compound constituting the polarization source. The number of moles may be, for example, in the range of 10 times or more, in the range of 50 times or more, or in the range of 100 times or more. The matrix material may be composed of one kind of compound or two or more kinds of compounds. When the matrix material is composed of two or more kinds of compounds, the total number of moles thereof may be 5 times or more the number of moles of the polarization source. The fact that the polarization source is dispersed in the matrix material means that, for example, in the diffraction pattern of the composition observed by the powder X-ray diffraction method, a pattern similar to the diffraction pattern of the matrix material alone is observed, that is, the matrix. It can be confirmed by observing that the crystallinity of the material is retained in the composition. At this time, the polarization source is dispersed by itself without being mixed or adsorbed by other materials, and it is preferable that the diameter of the dispersed polarization source is as small as possible. The most preferable case is that it is dispersed in a single molecule.
"Spin-lattice relaxation time T 1 " means that the magnetization vector deviated from the Z-axis direction due to 90 ° pulse excitation is in the Z-axis direction when the direction of the total magnetization vector of the nuclear spin in the thermal equilibrium state is the Z-axis direction. It refers to the time it takes to recover. The longer the spin-lattice relaxation time T 1 , the easier it is to retain the spin polarization transferred from the polarization source, and the spin polarization can be accumulated to achieve high polarization.
In the present invention, the "spin-lattice relaxation time T 1 " is measured by the saturation recovery method using a 90 ° pulse of 30 MHz at room temperature.
The term "water-soluble" in the present invention means a property of dissolving 1 mmol / L or more in water.
　本発明における「偏極源」とは、スピン偏極を電子から核へ移行させて核スピンを高偏極化する動的核偏極において、スピン偏極した電子を生成するスピン偏極の供給源となるものである。ここで、「偏極」または「スピン偏極」とは、スピンの集合体に静磁場を印加してゼーマン***を起こさせた際、***したエネルギー準位同士で、そのエネルギー準位にあるスピンの占有数が異なっていることをいう。また、***したエネルギー準位のうち、いずれか２つからなる組み合わせを見たとき、一方のエネルギー準位におけるスピンの占有数Ｎ１と他方のエネルギー準位におけるスピンの占有数Ｎ２の差の総スピン数に対する比、すなわち、（Ｎ１－Ｎ２）／（Ｎ１＋Ｎ２）を偏極率という。ここで、ゼーマン***したエネルギー準位の全ての組み合わせで、偏極率が０であるものはスピン偏極しておらず、少なくとも１つの組み合わせで、偏極率の絶対値が０超であるもの（正または負であるもの）はスピン偏極したものと言うことができる。この偏極率が大きいもの程、いずれか一方のエネルギー準位にスピンが過剰に存在しており、スピン偏極が大きいことを意味する。 The "polarization source" in the present invention is the supply of spin polarization that generates spin-polarized electrons in the dynamic nuclear polarization that transfers the spin polarization from electrons to the nucleus to make the nuclear spin highly polarized. It is the source. Here, "polarization" or "spin polarization" refers to spins at an energy level between split energy levels when a static magnetic field is applied to an aggregate of spins to cause Zeeman splitting. It means that the occupancy number of is different. Also, when looking at a combination consisting of any two of the split energy levels, the difference between the spin occupancy N 1 in one energy level and the spin occupancy N 2 in the other energy level. The ratio to the total number of spins, that is, (N 1- N 2 ) / (N 1 + N 2 ) is called the polarization ratio. Here, in all the combinations of Zeeman-divided energy levels, those having a polarization rate of 0 are not spin-polarized, and at least one combination has an absolute value of the polarization rate of more than 0. (Positive or negative) can be said to be spin-polarized. The larger the polarization ratio, the more spin is present in one of the energy levels, and the larger the spin polarization is.
　本発明の組成物は、マトリクス材料のスピン－格子緩和時間Ｔ１が２．５秒以上であることにより、偏極源の電子スピンからマトリクス材料の核スピンに移行してきた偏極を保持して蓄積し、容易に高偏極状態とすることができる。また、マトリクス材料が水溶性であることにより、生体関連物質に対して高い親和性を示し、生体適合性が高い。そのため、この組成物は、その核スピン偏極を生体関連物質の核スピンに効率よく移行させて該物質を高偏極化することができる。よって、本発明の組成物は、生体関連物質を高偏極化する偏極材として好適に用いることができ、医療分野や生命科学分野での動的核偏極の活用に大いに貢献することができる。
　以下において、本発明の組成物を構成するマトリクス材料、偏極源およびその他の材料について説明する。 The composition of the present invention retains the polarization that has been transferred from the electron spin of the polarization source to the nuclear spin of the matrix material because the spin-lattice relaxation time T 1 of the matrix material is 2.5 seconds or more. It can be accumulated and easily put into a highly polarized state. In addition, since the matrix material is water-soluble, it exhibits high affinity for bio-related substances and has high biocompatibility. Therefore, this composition can efficiently transfer its nuclear spin polarization to the nuclear spin of a biologically related substance to highly polarize the substance. Therefore, the composition of the present invention can be suitably used as a polarization material for highly polarized bio-related substances, and can greatly contribute to the utilization of dynamic nuclear polarization in the medical field and the life science field. can.
Hereinafter, the matrix material, the polarization source, and other materials constituting the composition of the present invention will be described.
［水溶性のマトリクス材料］
　本発明で用いる水溶性のマトリクス材料は、スピン－格子緩和時間Ｔ１が２．５秒以上のものである。上記のように、スピン－格子緩和時間Ｔ１が長いマトリクス材料は、偏極源の電子スピンからその核スピンに移行してきた偏極を保持し易いことにより、その核スピン偏極を蓄積して容易に高偏極化することができる。マトリクス材料のスピン－格子緩和時間Ｔ１は、１０秒以上であることが好ましく、１４秒以上であることがより好ましく、３０秒以上であることがさらに好ましく、６０秒以上であることがさらにより好ましく、９０秒以上であることが特に好ましい。なお、以下の説明では、核スピン偏極を保持しうる性質を「偏極保持能」という。
　スピン－格子緩和時間Ｔ１が比較的長い（偏極保持能が高い）化合物の条件として、（１）使用温度で固体であること、（２）分子量が比較的小さいこと、（３）アルキル基のような結合手を軸にして回転運動する基が存在しないこと、（４）水素結合のように分子の運動や振動を妨げる要因があることが挙げられる。このような点から、マトリクス材料は、以下の物性および構造の特徴を有する化合物を含むことが好ましい。 [Water-soluble matrix material]
The water-soluble matrix material used in the present invention has a spin-lattice relaxation time T 1 of 2.5 seconds or more. As described above, the spin - Long matrix material lattice relaxation time T 1, by easily hold the polarized which has moved to the nuclear spins from electron spin Henkyokugen accumulates the nuclear spin polarization It can be easily highly polarized. The spin-lattice relaxation time T 1 of the matrix material is preferably 10 seconds or longer, more preferably 14 seconds or longer, further preferably 30 seconds or longer, and even more preferably 60 seconds or longer. It is preferably 90 seconds or more, and particularly preferably 90 seconds or more. In the following description, the property of being able to retain nuclear spin polarization is referred to as "polarization holding ability".
The conditions for a compound having a relatively long spin-lattice relaxation time T 1 (high polarization retention ability) are (1) solid at the operating temperature, (2) relatively small molecular weight, and (3) alkyl group. There is no group that rotates around the bond hand as in (4), and there are factors that hinder the movement and vibration of the molecule, such as hydrogen bonds. From this point of view, the matrix material preferably contains a compound having the following physical characteristics and structural characteristics.
　マトリクス材料を構成する化合物の融点は３０℃以上であることが好ましく、５０℃以上であることがより好ましく、７５℃以上であることがさらに好ましく、１００℃以上であることがさらにより好ましい。マトリクス材料を構成する化合物の融点が高いことにより、動的核偏極を行う際、組成物が固体状態を維持して高い偏極保持能を示す。融点（分解温度）の上限は特に制限されないが、例えば３５０℃以下の範囲内であってもよい。 The melting point of the compound constituting the matrix material is preferably 30 ° C. or higher, more preferably 50 ° C. or higher, further preferably 75 ° C. or higher, and even more preferably 100 ° C. or higher. Due to the high melting point of the compounds constituting the matrix material, the composition maintains a solid state and exhibits high polarization holding ability when performing dynamic nuclear polarization. The upper limit of the melting point (decomposition temperature) is not particularly limited, but may be in the range of, for example, 350 ° C. or lower.
　マトリクス材料を構成する化合物の分子量は、１０００以下であることが好ましく、７００以下であることがより好ましく、５００以下であることがさらに好ましく、３００以下であることがさらにより好ましい。分子量が比較的小さい分子は、プロトン核が少ないことにより分子内の相互作用が小さく、そのプロトンスピンの偏極を保持し易い傾向がある。また、分子量の下限は特に制限されないが、例えば５０以上の範囲から選択したり、１００以上の範囲から選択したりすることができる。 The molecular weight of the compound constituting the matrix material is preferably 1000 or less, more preferably 700 or less, further preferably 500 or less, and even more preferably 300 or less. Molecules with a relatively small molecular weight tend to have small intramolecular interactions due to the small number of proton nuclei, and tend to maintain the polarization of their proton spins. The lower limit of the molecular weight is not particularly limited, but for example, it can be selected from a range of 50 or more, or can be selected from a range of 100 or more.
　マトリクス材料を構成する化合物は水素結合を形成しうる基を有していることが好ましい。水素結合を形成しうる基を有する化合物分子は、水素結合を形成して分子の運動や振動が妨げられることにより、スピン－格子緩和時間Ｔ１が長く、高い偏極保持能を示す。水素結合を形成しうる基として、水素原子よりも電気陰性度が高い原子と、該原子に共有結合した水素原子を含む基を挙げることができる。水素原子よりも電気陰性度が高い原子として、炭素原子、窒素原子、酸素原子、硫黄原子、ハロゲン原子を挙げることができ、中でも、酸素原子、硫黄原子であることが好ましく、酸素原子であることがより好ましい。すなわち、水素結合を形成しうる基は、ヒドロキシ基（－ＯＨ）、チオール基（－ＳＨ）であることが好ましく、ヒドロキシ基であることがより好ましい。また、マトリクス材料を構成する化合物は、その分子内に２つ以上のヒドロキシ基を有することが好ましく、その分子内にアミノ基と該アミノ基と水素結合を形成しうる基を有することも好ましい。アミノ基と該アミノ基と水素結合を形成しうる基を有する構造の好ましい例として、アミノカルボニル基を挙げることができる。 The compounds constituting the matrix material preferably have a group capable of forming a hydrogen bond. Compound molecules having a group capable of forming a hydrogen bond, by the molecular motion or vibration to form a hydrogen bond is hindered, spin - lattice relaxation time T 1 is long, showing a high polarization holding capability. Examples of the group capable of forming a hydrogen bond include an atom having a higher electronegativity than the hydrogen atom and a group containing a hydrogen atom covalently bonded to the atom. Examples of atoms having a higher degree of electrical negativeness than hydrogen atoms include carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms, and halogen atoms. Among them, oxygen atoms and sulfur atoms are preferable, and oxygen atoms are used. Is more preferable. That is, the group capable of forming a hydrogen bond is preferably a hydroxy group (-OH) or a thiol group (-SH), and more preferably a hydroxy group. Further, the compound constituting the matrix material preferably has two or more hydroxy groups in the molecule, and preferably has an amino group and a group capable of forming a hydrogen bond with the amino group in the molecule. An aminocarbonyl group can be mentioned as a preferable example of a structure having an amino group and a group capable of forming a hydrogen bond with the amino group.
　また、マトリクス材料は、水素原子、炭素原子および酸素原子のみで構成されることが好ましく、水素原子、炭素原子、酸素原子および窒素原子からなる群より選択される原子のみで構成されることも好ましい。マトリクス材料が水素原子を含む場合、その少なくとも１つは重水素原子であってもよい。
　さらに、マトリクス材料は繰り返し単位を有さないことが好ましい。ここで、繰り返し単位とは、例えば重合体におけるモノマー由来の構成単位であって、その分子内に２つ以上存在する構成単位のことをいう。
　さらにまた、マトリクス材料を構成する化合物はアルキル基を有さないことが好ましい。アルキル基を有する化合物は、そのアルキル基が結合手（単結合）を軸にして回転運動することにより、スピン偏極状態から平衡状態へ緩和し易い傾向がある。 Further, the matrix material is preferably composed of only hydrogen atoms, carbon atoms and oxygen atoms, and is also preferably composed of only atoms selected from the group consisting of hydrogen atoms, carbon atoms, oxygen atoms and nitrogen atoms. .. If the matrix material contains hydrogen atoms, at least one of them may be deuterium atoms.
Further, the matrix material preferably has no repeating units. Here, the repeating unit means, for example, a structural unit derived from a monomer in a polymer, and is a structural unit existing in two or more in the molecule.
Furthermore, it is preferable that the compounds constituting the matrix material do not have an alkyl group. A compound having an alkyl group tends to be easily relaxed from a spin-polarized state to an equilibrium state by rotating the alkyl group around a bond (single bond).
　マトリクス材料の具体例として、エリトリトール、キシリトール、ソルビトール等の糖アルコール、フルクトース、グルコース、マルトース等の糖類、β－エストラジオール、安息香酸、カルバマゼピン等の芳香環を含む化合物、ウレア、トリアゾールを挙げることができ、スピン－格子緩和時間Ｔ１が比較的長いことから、エリトリトール、ウレア、キシリトールが好ましく、エリトリトールがより好ましい。また、糖アルコールをマトリクス材料に用いる場合、その炭素数は３～８であることが好ましい。これらのスピン－格子緩和時間Ｔ１を図１に示す。 Specific examples of the matrix material include sugar alcohols such as erythritol, xylitol and sorbitol, sugars such as fructose, glucose and maltose, compounds containing an aromatic ring such as β-estradiol, benzoic acid and carbamatepine, urea and triazole. Since the spin-lattice relaxation time T 1 is relatively long, erythritol, urea, and xylitol are preferable, and erythritol is more preferable. When sugar alcohol is used as a matrix material, it preferably has 3 to 8 carbon atoms. These spin-lattice relaxation times T 1 are shown in FIG.
　マトリクス材料には、１種類の化合物を単独で使用してもよいし、２種類以上の化合物を組み合わせて使用してもよい。 For the matrix material, one kind of compound may be used alone, or two or more kinds of compounds may be used in combination.
［偏極源］
　組成物の偏極源は特に制限されないが、下記の一般式（１）で表される分子やポルフィリン誘導体を好ましく用いることができる。 [Polarity source]
The polarization source of the composition is not particularly limited, but a molecule represented by the following general formula (1) or a porphyrin derivative can be preferably used.
（一般式（１）で表される分子）
　本発明で用いる偏極源は、下記一般式（１）で表される分子からなるものであることが好ましい。
　偏極源として用いる一般式（１）で表される分子は、１種類であってもよいし、２種類以上の組み合わせであってもよい。
　一般式（１）で表される分子は、光励起によりスピン偏極した三重項電子を生成しうる、光励起三重項分子であり、その三重項電子のスピン偏極を核へ供給する偏極源として用いることができる。また、一般式（１）で表される分子は、アセン構造を構成する１つのベンゼン環に２つの窒素原子を導入したアザアセン骨格を有することにより、酸素耐性が高いという特徴を有する。そのため、医療現場や研究施設など、空気と光が存在する環境下においても酸化されにくく、偏極源としての機能を確実に発現させることができる。このように一般式（１）で表される分子が高い酸素耐性を示すのは、アセン構造に電子求引性が高い窒素原子が導入されていることにより、ＬＵＭＯ（Lowest Unoccupied Molecular Orbital）のエネルギー準位が低くなり、当該分子から酸素分子への電子伝達が抑制されるためであると推測される。 (Molecule represented by the general formula (1))
The polarization source used in the present invention is preferably composed of a molecule represented by the following general formula (1).
The molecule represented by the general formula (1) used as the polarization source may be one kind or a combination of two or more kinds.
The molecule represented by the general formula (1) is a photoexcited triplet molecule capable of generating spin-polarized triplet electrons by photoexcitation, and serves as a polarization source for supplying the spin polarization of the triplet electrons to the nucleus. Can be used. Further, the molecule represented by the general formula (1) has a feature of having high oxygen resistance because it has an azaacene skeleton in which two nitrogen atoms are introduced into one benzene ring constituting the acene structure. Therefore, it is difficult to be oxidized even in an environment where air and light exist, such as a medical site or a research facility, and the function as a polarization source can be surely exhibited. The reason why the molecule represented by the general formula (1) exhibits high oxygen tolerance is that the energy of LUMO (Lowest Unoccupied Molecular Orbital) is due to the introduction of a nitrogen atom with high electron attraction into the acene structure. It is presumed that this is because the level becomes low and the electron transfer from the molecule to the oxygen molecule is suppressed.
　以下において、一般式（１）で表される分子の化学構造について説明する。なお、以下の説明では、一般式（１）における多環縮合構造からなる骨格を「多環縮合骨格」と言うことがある。 The chemical structure of the molecule represented by the general formula (1) will be described below. In the following description, the skeleton composed of the polycyclic condensed structure in the general formula (1) may be referred to as a "polycyclic condensed skeleton".
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　一般式（１）において、ｎは１～４の整数を表す。ｎは２～４であることが好ましく、２または３であることがより好ましい。
　一般式（１）中に存在するＺ１～Ｚ１０のうちの０～６個はＮを表し、その他はＣ－Ｒを表す。このため、Ｚ１～Ｚ１０のすべてがＣ－Ｒであってもよい。ｎが１であるときは、Ｚ１～Ｚ１０のうちの０～６個がＮを表し、その他の４～１０個がＣ－Ｒを表す。ｎが２であるときは、Ｚ１～Ｚ１０のうちの０～６個がＮを表し、その他の６～１２個がＣ－Ｒを表す。ｎが３であるときは、Ｚ１～Ｚ１０のうちの０～６個がＮを表し、その他の８～１４個がＣ－Ｒを表す。ｎが４であるときは、Ｚ１～Ｚ１０のうちの０～６個がＮを表し、その他の１０～１６個がＣ－Ｒを表す。ここでＮは窒素原子を表し、Ｃは炭素原子を表し、Ｒは水素原子または置換基を表す。ｎが２以上であるとき、複数のＺ９は同一であっても異なっていてもよく、また、複数のＺ１０は同一であっても異なっていてもよい。
　一般式（１）中に存在するＺ１～Ｚ１０のうちの２個以上がＮであるとき、例えば、以下の３つの条件の少なくとも１つを満たすものを好ましい群の一例として挙げることができる。
　＜１＞　Ｚ１とＺ４がともにＮである。
　＜２＞　Ｚ５とＺ８がともにＮである。
　＜３＞　Ｚ９とＺ１０がともにＮである。
　一般式（１）中に存在するＺ１～Ｚ１０のうちＮであるものの個数は、２～２ｎ個であることが好ましい。すなわち、ｎが１であるときは、Ｎであるものの個数は２個であることが好ましく、ｎが２であるときはＮであるものの個数は２～４個であることが好ましく、ｎが３であるときはＮであるものの個数は２～６個であることが好ましく、ｎが４であるときはＮであるものの個数は２～８個であることが好ましい。 In the general formula (1), n represents an integer of 1 to 4. n is preferably 2 to 4, more preferably 2 or 3.
Of Z 1 to Z 10 existing in the general formula (1), 0 to 6 represent N, and the others represent CR. Therefore, all of Z 1 to Z 10 may be CR. When n is 1, 0 to 6 of Z 1 to Z 10 represent N, and the other 4 to 10 represent CR. When n is 2, 0 to 6 of Z 1 to Z 10 represent N, and the other 6 to 12 represent CR. When n is 3, 0 to 6 of Z 1 to Z 10 represent N, and the other 8 to 14 represent CR. When n is 4, 0 to 6 of Z 1 to Z 10 represent N, and the other 10 to 16 represent CR. Here, N represents a nitrogen atom, C represents a carbon atom, and R represents a hydrogen atom or a substituent. When n is 2 or more, the plurality of Z 9s may be the same or different, and the plurality of Z 10s may be the same or different.
When two or more of Z 1 to Z 10 existing in the general formula (1) are N, for example, those satisfying at least one of the following three conditions can be mentioned as an example of a preferable group. ..
<1> Both Z 1 and Z 4 are N.
<2> Both Z 5 and Z 8 are N.
<3> Both Z 9 and Z 10 are N.
Of Z 1 to Z 10 existing in the general formula (1), the number of N is preferably 2 to 2 n. That is, when n is 1, the number of N is preferably 2, and when n is 2, the number of N is preferably 2 to 4, and n is 3. When is, the number of N is preferably 2 to 6, and when n is 4, the number of N is preferably 2 to 8.
　一般式（１）中に存在する複数のＲは、互いに同じであっても異なっていてもよい。このため、複数のＲのすべてが水素原子であってもよいし、一部が水素原子で一部が置換基であってもよい。置換基としては、水素原子、炭素原子、窒素原子、酸素原子、硫黄原子、ホウ素原子、リン原子、ケイ素原子、およびハロゲン原子からなる群より選択される１つ以上の原子を含む置換基であることが好ましく、これらの原子からなる群より選択される１つ以上の原子からなる置換基であることがより好ましい。置換基を構成する原子の数は、１～５０であることが好ましく、１～３５であることがより好ましく、１～２０であることがさらに好ましい。例えば、ハロゲン原子、シアノ基、カルボニル基、エステル基、カルボキシル基、スルホ基、ホウ素原子、ケイ素原子、リン原子、ヒドロキシ基、チオール基、ベンゼン環、ピリジン環、ピリダジン環、ピリミジン環、ピラジン環およびアミノ基を含む置換基を挙げることができる。ハロゲン原子、シアノ基、カルボキシル基、ヒドロキシ基、チオール基、ベンゼン環、ピリジン環、ピリダジン環、ピリミジン環、ピラジン環およびアミノ基については、これらの基のみからなる置換基であってもよい。
　水素原子は１Ｈであっても２Ｈ（重水素）であってもよい。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子を挙げることができ、アミノ基は置換されていてもいなくてもよい。カルボキシル基などの酸性基は、その酸性基のプロトンが電離してアニオン基が形成されていてもよいし、そのアニオン基と金属陽イオン（例えばナトリウムイオン、カリウムイオン）の塩が形成されていてもよい。エステル基としては、アルキルオキシカルボニル基やアリールオキシカルボニル基を例示することができる。置換アミノ基としては、ジアルキルアミノ基、ジアリールアミノ基、モノアルキルアミノ基、モノアリールアミノ基を例示することができる。ここでいうアルキル基は炭素数１～２０であるものが好ましく、１～１０であるものがより好ましい。アリール基は炭素数６～２０であるものが好ましく、６～１０であるものがより好ましい。アルキル基とアリール基は、置換されていてもよく、置換基としては例えばＲの置換基として例示したものを参照することができる。 The plurality of Rs existing in the general formula (1) may be the same as or different from each other. Therefore, all of the plurality of Rs may be hydrogen atoms, or some of them may be hydrogen atoms and some of them may be substituents. The substituent is a substituent containing one or more atoms selected from the group consisting of hydrogen atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom, boron atom, phosphorus atom, silicon atom, and halogen atom. It is preferable, and it is more preferable that it is a substituent composed of one or more atoms selected from the group consisting of these atoms. The number of atoms constituting the substituent is preferably 1 to 50, more preferably 1 to 35, and even more preferably 1 to 20. For example, halogen atom, cyano group, carbonyl group, ester group, carboxyl group, sulfo group, boron atom, silicon atom, phosphorus atom, hydroxy group, thiol group, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring and Substituents containing an amino group can be mentioned. The halogen atom, cyano group, carboxyl group, hydroxy group, thiol group, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring and amino group may be a substituent consisting of only these groups.
The hydrogen atom may be 1 H or 2 H (deuterium). Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the amino group may or may not be substituted. An acidic group such as a carboxyl group may have an anion group formed by ionizing the proton of the acidic group, or a salt of the anion group and a metal cation (for example, sodium ion or potassium ion) is formed. May be good. Examples of the ester group include an alkyloxycarbonyl group and an aryloxycarbonyl group. Examples of the substituted amino group include a dialkylamino group, a diarylamino group, a monoalkylamino group, and a monoarylamino group. The alkyl group referred to here preferably has 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms. The aryl group preferably has 6 to 20 carbon atoms, and more preferably 6 to 10 carbon atoms. The alkyl group and the aryl group may be substituted, and as the substituent, for example, those exemplified as the substituent of R can be referred to.
　一般式（１）の複数のＲのうちの少なくとも１つは、オリゴアルキレンオキシ構造を含む基であることが好ましい。オリゴアルキレンオキシ構造を含むことにより、一般式（１）で表される分子の水系媒体に対する分散性が極めて良好になる。水分散性が高い偏極源は、その三重項電子スピンの偏極を水分子のプロトンスピンに効率よく移行させることができるため、生体や生体物質のＮＭＲ分析のための偏極源として効果的に用いることができる。オリゴアルキレンオキシ構造を含む基は、好ましくはオリゴアルキレンオキシ構造を有するアンモニウムイオンを含むイオン対を有する基であり、より好ましくは一般式（１）のＣ－ＲのＣ（環骨格を構成する炭素原子）に連結するアニオン基と、オリゴアルキレンオキシ構造を有するアンモニウムイオンとのイオン対を有する基である。言い換えれば、一般式（１）で表される分子は、一般式（１）における多環縮合骨格を有するアニオンと、オリゴアルキレンオキシ構造を有するアンモニウムイオンとのイオン対であることが好ましい。 It is preferable that at least one of the plurality of Rs in the general formula (1) is a group containing an oligoalkylene oxy structure. By including the oligoalkylene oxy structure, the dispersibility of the molecule represented by the general formula (1) in an aqueous medium becomes extremely good. A highly water-dispersible polarization source can efficiently transfer the polarization of its triplet electron spin to the proton spin of water molecules, and is therefore effective as a polarization source for NMR analysis of living organisms and biological materials. Can be used for. The group containing an oligoalkylene oxy structure is preferably a group having an ion pair containing an ammonium ion having an oligoalkylene oxy structure, and more preferably C (carbon constituting a ring skeleton) of CR of the general formula (1). It is a group having an ion pair linked to an anion group (atom) and an ammonium ion having an oligoalkylene oxy structure. In other words, the molecule represented by the general formula (1) is preferably an ion pair of an anion having a polycyclic condensed skeleton in the general formula (1) and an ammonium ion having an oligoalkylene oxy structure.
　Ｒにおいて、イオン対を構成するオリゴアルキレンオキシ構造を有するアンモニウムイオンは、好ましくはＲ１１－（Ｏ－Ｒ１２）ｎ－基を有するアンモニウムイオンである。ここで、Ｒ１１は置換もしくは無置換のアルキル基、Ｒ１２は置換もしくは無置換のアルキレン基を表し、ｎは２～２０の整数である。ｎ個のＲ１２は互いに同一であっても異なっていてもよい。また、イオン対を構成するオリゴアルキレンオキシ構造を有するアンモニウムイオンは、より好ましくは［Ｒ１１－（Ｏ－Ｒ１２）ｎ］３－ＮＨ＋で表されるアンモニウムイオンある。［Ｒ１１－（Ｏ－Ｒ１２）ｎ］３－ＮＨ＋で表されるアンモニウムイオンは、その嵩高さにより、一般式（１）で表される分子の水系媒体に対する分散性を一層改善することができる。ここで、３個のＲ１１は互いに同一であっても異なっていてもよい。３ｎ個のＲ１２は互いに同一であっても異なっていてもよい。３個のｎは互いに同一であっても異なっていてもよい。イオン対を構成するアンモニウムイオンとして特に好ましいのは、［Ｒ１１－（Ｏ－Ｒ１２）ｎ］３－ＮＨ＋で表され、３個の［Ｒ１１－（Ｏ－Ｒ１２）ｎ］が同一であるアンモニウムイオンである。
　各式において、Ｒ１１におけるアルキル基は直鎖状、分枝状、環状のいずれであってもよい。アルキル基の炭素数は１～８であることが好ましく、１～４であることがより好ましく、１または２であることがさらに好ましい。例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基などを例示することができ、メチル基であることが最も好ましい。
　Ｒ１２におけるアルキレン基は直鎖状、分枝状、環状のいずれであってもよい。アルキレン基の炭素数は１～８であることが好ましく、１～４であることがより好ましく、１または２であることがさらに好ましい。例えば、メチレン基、エチレン基、プロピレン基などを例示することができ、エチレン基であることが最も好ましい。アルキル基およびアルキレン基に導入しうる置換基としては、例えばＲの置換基として例示したものを参照することができる。
　ｎは、１～８の整数であることが好ましく、１～４の整数であることがより好ましく、例えば１または２にしてもよいし、２～４の範囲内で選択してもよい。
　また、オリゴアルキレンオキシ構造を有するアンモニウムイオンは、Ｒ１１－（Ｏ－Ｒ１２）ｎ－基を有する複数のアンモニウムイオン、または、Ｒ１１－（Ｏ－Ｒ１２）ｎ－基を有するアンモニウムイオンと他のアンモニウムイオンが、Ｒ１１同士、または、Ｒ１１と他のアンモニウムイオンの置換基の末端とが互いに結合した構造を有する、多量体としてのアンモニウムイオンであってもよい。 In R, the ammonium ion having an oligoalkylene oxy structure constituting the ion pair is preferably an ammonium ion having an R 11- (OR 12 ) n- group. Here, R 11 represents a substituted or unsubstituted alkyl group, R 12 represents a substituted or unsubstituted alkylene group, and n is an integer of 2 to 20. n pieces of R 12 may be the same or different from each other. Further, the ammonium ion having an oligoalkylene oxy structure constituting the ion pair is more preferably an ammonium ion represented by [R 11 − (OR 12 ) n] 3- NH + . [R 11 - (O-R 12) n] ammonium ion represented by 3 -NH + is that the by bulkiness, to further improve the dispersibility in the aqueous medium of the molecule represented by the general formula (1) Can be done. Here, the three R 11s may be the same or different from each other. The 3n R 12 may be the same or different from each other. The three ns may be the same or different from each other. Particularly preferred as the ammonium ions constituting an ion pair, [R 11 - (O- R 12) n] is represented by 3 -NH +, 3 pieces of [R 11 - (O-R 12) n] are the same Is an ammonium ion.
In each formula, the alkyl group in R 11 may be linear, branched or cyclic. The alkyl group preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and even more preferably 1 or 2 carbon atoms. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like can be exemplified, and a methyl group is most preferable.
The alkylene group in R 12 may be linear, branched or cyclic. The alkylene group preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, and even more preferably 1 or 2 carbon atoms. For example, a methylene group, an ethylene group, a propylene group and the like can be exemplified, and an ethylene group is most preferable. As the substituent that can be introduced into the alkyl group and the alkylene group, for example, those exemplified as the substituent of R can be referred to.
n is preferably an integer of 1 to 8, more preferably an integer of 1 to 4, and may be, for example, 1 or 2, or may be selected within the range of 2 to 4.
Furthermore, ammonium ions having oligoalkyleneoxy structure, R 11 - (O-R 12) a plurality of ammonium ions having a n- group or,, R 11 - and ammonium has a (O-R 12) n- group ions other ammonium ion, R 11 s or, has a structure in which ends are bonded to each other of the substituents R 11 and other ammonium ions may be ammonium ions as multimers.
　イオン対を構成するオリゴアルキレンオキシ構造を有するアンモニウムイオンは、オリゴアルキレンオキシ構造を有するアミンと、アンモニウムイオンと塩を形成する前の、一般式（１）で表される分子の前駆体(イオン対に対応する位置にプロトン供与基を有する分子)との酸塩基反応により得ることができる。以下において、このアンモニウムイオンの生成に用いうるオリゴアルキレンオキシ構造を有するアミンの具体例を例示する。ただし、本発明で用いることができるオリゴアルキレンオキシ構造を有するアミンはこれらの具体例によって限定的に解釈されるべきものではない。下記式において、ａは１～４の整数を表し、ｍ、ｍ１～ｍ３は１～４の整数を表す。ｍ１～ｍ３は互いに同一であっても異なっていてもよい。例えば、ａ、ｍ、ｍ１～ｍ３がすべて１である場合を例示することができる。他の例として、ａ、ｍ、ｍ１～ｍ３がすべて２である場合も例示することができる。 Ammonium ion having an oligoalkylene oxy structure constituting an ion pair is a precursor (ion pair) of a molecule represented by the general formula (1) before forming a salt with an amine having an oligoalkylene oxy structure and ammonium ion. It can be obtained by an acid-base reaction with a molecule having a proton donor group at the position corresponding to. In the following, specific examples of amines having an oligoalkylene oxy structure that can be used to generate this ammonium ion will be illustrated. However, amines having an oligoalkylene oxy structure that can be used in the present invention should not be construed as being limited by these specific examples. In the following equation, a represents an integer of 1 to 4, m and m1 to m3 represent an integer of 1 to 4. m1 to m3 may be the same as or different from each other. For example, a case where a, m, and m1 to m3 are all 1 can be exemplified. As another example, the case where a, m, and m1 to m3 are all 2 can be exemplified.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　以上で説明したアンモニウムイオンの中で最も好ましいものは、トリス[2-(2-メトキシエトキシ)エチル]アミン（ＭＥＥＡ）のプロトン化により生成する、下記式で表されるアンモニウムイオンである。 The most preferable ammonium ion described above is an ammonium ion represented by the following formula, which is produced by protonation of tris [2- (2-methoxyethoxy) ethyl] amine (MEEA).
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　一方、オリゴアルキレンオキシ構造を有するアンモニウムイオンとイオン対を構成するアニオン基、すなわちＣ－ＲのＣ（環骨格を構成する炭素原子）に連結するアニオン基は、１～４価のアニオン基であることが好ましく、１価のアニオン基であることがより好ましい。アニオン基の例として、カルボキシ基（－ＣＯＯＨ）、ホスホノ基（－ＰＯ３Ｈ２）、ホスホノキシ基（－ＯＰＯ３Ｈ２）、スルホ基（－ＳＯ３Ｈ）、スルホオキシ基（－ＯＳＯ３Ｈ）等の酸性基からプロトンが電離したアニオン基、ヒドロキシ基（－ＯＨ）からプロトンが電離したアニオン基を挙げることができ、中でも－ＣＯＯ－基、－ＳＯ３ －基、－ＰＯ３Ｈ－基、－Ｏ－基であることが好ましく、－ＣＯＯ－基であることがより好ましい。
　これらのアニオン基は、Ｚ１～Ｚ１０のうちのいずれに導入されていてもよい。すなわち、Ｃ－Ｒであって、Ｃにアニオン基が連結しているものは、Ｚ１～Ｚ１０のいずれであってもよい。 On the other hand, the anion group forming an ion pair with the ammonium ion having an oligoalkylene oxy structure, that is, the anion group linked to C (carbon atom constituting the ring skeleton) of CR is a 1- to tetravalent anion group. It is preferably a monovalent anion group, and more preferably a monovalent anion group. Examples of anionic groups are carboxy group (-COOH), phosphono group (-PO 3 H 2 ), phosphonoxy group (-OPO 3 H 2 ), sulfo group (-SO 3 H), sulfooxy group (-OSO 3 H). anionic group proton from the acidic group is ionized etc., proton from the hydroxy group (-OH) may be able to include ionized anionic groups, among others -COO - group, -SO 3 - group, -PO 3 H - group, It is preferably an —O − group, and more preferably an —COO − group.
These anionic groups may be introduced into any of Z 1 to Z 10. That is, CR which has an anion group linked to C may be any of Z 1 to Z 10.
　また、アニオン基はＣ－ＲのＣに単結合で結合していてもよいし、連結基を介して結合していてもよい。連結基として、例えば置換もしくは無置換のアルキレン基、置換もしくは無置換のアリーレン基を挙げることができる。アルキレン基の説明と具体例については、上記のＲ１２におけるアルキレン基についての記載を参照することができる。アリーレン基を構成する芳香環は、単環であっても、２以上の芳香環が縮合した縮合環であっても、２以上の芳香環が連結した連結環であってもよい。２以上の芳香環が連結している場合は、直鎖状に連結したものであってもよいし、分枝状に連結したものであってもよい。芳香環の炭素数は、６～２２であることが好ましく、６～１８であることがより好ましく、６～１４であることがさらに好ましく、６～１０であることがさらにより好ましい。アリーレン基の具体例として、フェニレン基、ナフタレニレン基、ビフェニレン基を挙げることができる。アルキレン基およびアリーレン基に導入しうる置換基として、例えばＲの置換基として例示したものを参照することができる。
　連結基に結合するアニオン基の数は、１個であっても２個以上であってもよい。連結基に２個以上のアニオン基が結合するとき、複数のアニオン基は互いに同一であっても異なっていてもよい。例えば連結基がフェニレン基であるとき、該フェニレン基に結合するアニオン基は１～５個であり、２～４個であることがより好ましい。フェニレン基におけるアニオン基の結合位置は特に限定されないが、アニオン基の少なくとも１つは、多環縮合骨格への結合位置に対するメタ位またはパラ位に結合していることが好ましく、メタ位に結合していることがより好ましい。また、フェニレン基に２個以上のアニオン基が結合するとき、その少なくとも２つは互いにメタ位となる位置に結合していることが好ましい。 Further, the anion group may be bonded to C of CR with a single bond, or may be bonded via a linking group. Examples of the linking group include a substituted or unsubstituted alkylene group and a substituted or unsubstituted arylene group. The description and specific examples of the alkylene group, can be referred to for the alkylene group in the above R 12. The aromatic ring constituting the arylene group may be a monocyclic ring, a condensed ring in which two or more aromatic rings are condensed, or a linked ring in which two or more aromatic rings are linked. When two or more aromatic rings are connected, they may be linearly connected or may be branched. The number of carbon atoms in the aromatic ring is preferably 6 to 22, more preferably 6 to 18, further preferably 6 to 14, and even more preferably 6 to 10. Specific examples of the arylene group include a phenylene group, a naphthaleneylene group, and a biphenylene group. As the substituents that can be introduced into the alkylene group and the arylene group, for example, those exemplified as the substituent of R can be referred to.
The number of anion groups bonded to the linking group may be one or two or more. When two or more anion groups are attached to the linking group, the plurality of anion groups may be the same or different from each other. For example, when the linking group is a phenylene group, the number of anion groups bonded to the phenylene group is 1 to 5, more preferably 2 to 4. The bonding position of the anion group in the phenylene group is not particularly limited, but at least one of the anion groups is preferably bonded to the meta position or the para position with respect to the bonding position to the polycyclic condensed skeleton, and is bonded to the meta position. Is more preferable. Further, when two or more anion groups are bonded to the phenylene group, it is preferable that at least two of them are bonded to each other at a meta position.
　一般式（１）で表される分子において、その分子内に存在するアニオン基とアンモニウムイオンとのイオン対の個数は、好ましくは１以上、より好ましくは２以上、さらに好ましくは３以上、さらにより好ましくは４以上である。 In the molecule represented by the general formula (1), the number of ion pairs of anion groups and ammonium ions existing in the molecule is preferably 1 or more, more preferably 2 or more, still more preferably 3 or more, and even more. It is preferably 4 or more.
　また、Ｒにおけるオリゴアルキレンオキシ構造を含む基は、オリゴアルキレンオキシ構造を含む原子団が、Ｃ－ＲのＣ（環骨格を構成する炭素原子）に共有結合で結合した基（置換基）であってもよい。ここで、「オリゴアルキレンオキシ構造を含む原子団」とは、オリゴアルキレンオキシ構造を含む基であって、原子同士の結合が全て共有結合である基（イオン対を含まない基）であるものを意味する。オリゴアルキレンオキシ構造を含む原子団は、好ましくはＲ１１－（Ｏ－Ｒ１２）ｎ－基を有する原子団である。Ｒ１１およびＲ１２は、上記のＲ１１－（Ｏ－Ｒ１２）ｎ－基を有するアンモニウムイオンのＲ１１およびＲ１２と同義であり、その好ましい範囲と具体例については、上記のＲ１１およびＲ１２についての記載を参照することができる。Ｒ１１－（Ｏ－Ｒ１２）ｎ－基は、Ｃ－ＲのＣに単結合で結合していてもよいし、Ｃ－ＲのＣに共有結合で結合した連結基に単結合で結合していてもよい。 The group containing the oligoalkylene oxy structure in R is a group (substituent) in which the atomic group containing the oligoalkylene oxy structure is covalently bonded to C (carbon atom constituting the ring skeleton) of CR. You may. Here, the "atomic group containing an oligoalkylene oxy structure" is a group containing an oligoalkylene oxy structure and in which all the bonds between atoms are covalent bonds (groups not containing an ion pair). means. Atomic group containing oligoalkyleneoxy structure preferably R 11 - an atomic group having a (O-R 12) n- group. R 11 and R 12, the above R 11 - has the same meaning as R 11 and R 12 of ammonium ions having a (O-R 12) n-group, for the preferred range and specific examples, the above R 11 and The description for R 12 can be referred to. The R 11- (OR 12 ) n- group may be single-bonded to C of CR or to a covalently bonded linking group to C of CR. May be.
　以下において、Ｒがとりうる、原子団としてのオリゴアルキレンオキシ構造を含む基の具体例を例示する。ただし、本発明において用いることができるオリゴアルキレンオキシ構造を含む基はこれらの具体例によって限定的に解釈されるべきものではない。下記式において、ａは１～４の整数を表し、ｍ、ｍ１～ｍ３は１～４の整数を表す。ｍ１～ｍ３は互いに同一であっても異なっていてもよい。例えば、ａ、ｍ、ｍ１～ｍ３がすべて１である場合を例示することができる。他の例として、ａ、ｍ、ｍ１～ｍ３がすべて２である場合も例示することができる。＊はＣ－ＲのＣへの結合位置を表す。 In the following, specific examples of groups containing an oligoalkylene oxy structure as an atomic group that can be taken by R will be illustrated. However, the groups containing an oligoalkylene oxy structure that can be used in the present invention should not be construed as being limited by these specific examples. In the following equation, a represents an integer of 1 to 4, m and m1 to m3 represent an integer of 1 to 4. m1 to m3 may be the same as or different from each other. For example, a case where a, m, and m1 to m3 are all 1 can be exemplified. As another example, the case where a, m, and m1 to m3 are all 2 can be exemplified. * Represents the bond position of CR to C.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　一般式（１）で表される分子において、その分子内に存在するオリゴアルキレンオキシ構造の個数は好ましくは１以上、より好ましくは３以上、さらに好ましくは６以上、さらにより好ましくは９以上、特に好ましくは１２以上である。 In the molecule represented by the general formula (1), the number of oligoalkylene oxy structures present in the molecule is preferably 1 or more, more preferably 3 or more, still more preferably 6 or more, still more preferably 9 or more, particularly. It is preferably 12 or more.
　また、オリゴアルキレンオキシ構造を含む基、並びに、アニオン基と、オリゴアルキレンオキシ構造を有するアンモニウムイオンとのイオン対は、Ｚ１～Ｚ１０のいずれに導入されていてもよい。すなわち、Ｃ－Ｒであって、Ｒがオリゴアルキレンオキシ構造を含む基であるもの、好ましくはＣ－Ｒであって、Ｒが、アニオン基と、オリゴアルキレンオキシ構造を有するアンモニウムイオンとのイオン対を有する基であるものは、Ｚ１～Ｚ１０のいずれであってもよい。 Further, the group containing the oligoalkylene oxy structure and the ion pair of the anion group and the ammonium ion having the oligoalkylene oxy structure may be introduced into any of Z 1 to Z 10. That is, CR, in which R is a group containing an oligoalkylene oxy structure, preferably CR, and R is an ion pair of an anion group and an ammonium ion having an oligoalkylene oxy structure. The group having the above may be any of Z 1 to Z 10.
　また、一般式（１）の複数のＲのうちの少なくとも１つは、アニオン基と、オリゴアルキレンオキシ構造を有しないアンモニウムイオンとのイオン対を有する基であることも好ましく、オリゴアルキレンオキシ構造を有しない原子団（置換基）であることも好ましい。上記のように、オリゴアルキレンオキシ構造を有する基をＲに含むことにより、一般式（１）で表される分子の水分散性を改善できるが、このオリゴアルキレンオキシ構造を有する基の代わりに他の基を導入した分子も、水系媒体に対して優れた分散性を示す場合がある。そのような他の基として、アニオン基と、官能基で置換されたアルキル基を有するアンモニウムイオンとのイオン対を有する基や、官能基で置換されたアルキル基を含む置換アミノ基を有する基を挙げることができる。ここで、アルキル基の説明と具体例については、上記のＲ１１におけるアルキル基についての記載を参照することができる。官能基としては、例えばカルボキシ基やヒドロキシ基、カルボニル基などを挙げることができる。また、アニオン基の説明と好ましい範囲、具体例については、上記のＲにおけるアニオン基についての記載を参照することができる。 Further, at least one of the plurality of Rs in the general formula (1) is preferably a group having an ion pair of an anion group and an ammonium ion having no oligoalkylene oxy structure, and the oligoalkylene oxy structure is formed. It is also preferable that the atomic group (substituent) does not have. As described above, by including a group having an oligoalkylene oxy structure in R, the water dispersibility of the molecule represented by the general formula (1) can be improved, but instead of the group having this oligoalkylene oxy structure, another Molecules into which the group has been introduced may also exhibit excellent dispersibility in aqueous media. As such other groups, a group having an ion pair of an anion group and an ammonium ion having an alkyl group substituted with a functional group, or a group having a substituted amino group containing an alkyl group substituted with a functional group can be used. Can be mentioned. Here, descriptions and specific examples of the alkyl group, can be referred to for the alkyl group in the above R 11. Examples of the functional group include a carboxy group, a hydroxy group, and a carbonyl group. Further, for the description of the anion group, the preferable range, and specific examples, the description of the anion group in R can be referred to.
　以下において、オリゴアルキレンオキシ構造を有しないアンモニウムイオンの生成に用いうるアミンの具体例、および、Ｒに導入しうる、原子団としての置換アミノ基を有する基の具体例を例示する。下記式において、＊はＣ－ＲのＣへの結合位置を表す。 In the following, specific examples of amines that can be used to generate ammonium ions that do not have an oligoalkylene oxy structure and specific examples of groups that can be introduced into R and have a substituted amino group as an atomic group will be exemplified. In the following equation, * represents the bonding position of CR to C.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　本発明では、偏極源とマトリクス材料を組み合わせて組成物を構成するため、一般式（１）における多環縮合骨格は、マトリクス材料を構成する原子や原子団、さらには、マトリクス材料がイオンを含む場合には、そのイオンと相互作用する基で置換されていてもよい。これにより、偏極源の分子同士が凝集して凝集体を形成することが抑えられ、その分子をマトリクス材料中に容易に分散できるようになる。
　例えば、一般式（１）の置換基（Ｒ）が、ハロゲン原子、窒素原子、酸素原子、硫黄原子、ホウ素原子、リン原子、およびケイ素原子からなる群より選択される１つ以上の原子を含む置換基であることが好ましい。具体例として、ハロゲン原子、シアノ基、カルボニル基、エステル基、カルボキシル基、スルホ基、ホスホノ基、ホスホノキシ基、ホウ素原子、リン原子、ケイ素原子、ヒドロキシ基、チオール基、ピリジン環、ピリダジン環、ピリミジン環、ピラジン環およびアミノ基からなる群より選択される１つ以上を含む置換基を例示することができる。カルボキシ基（－ＣＯＯＨ）、スルホ基（－ＳＯ３Ｈ）、ホスホノ基（－Ｐ（Ｏ）（ＯＨ）２）、ホスホノキシ基（－ＯＰ（Ｏ）（ＯＨ）２）等の酸性基は、プロトンが電離したアニオン基であってもよく、例えばカルボキシラートアニオン基を挙げることができる。これらの基は、多環縮合骨格に直接結合していてもよいし、連結基を介して連結していてもよい。好ましい態様の一例として、一般式（１）のＺ１、Ｚ２、Ｚ７、Ｚ８、Ｚ９のうちの少なくとも１つがＣ－Ｒ１１であり、Ｚ３、Ｚ４、Ｚ５、Ｚ６、Ｚ１０のうちの少なくとも１つがＣ－Ｒ１２であり、Ｒ１１およびＲ１２が各々独立にハロゲン原子、窒素原子、酸素原子、硫黄原子、ホウ素原子、リン原子、およびケイ素原子からなる群より選択される１つ以上の原子であるものを挙げることができる。 In the present invention, since the composition is composed by combining the polarization source and the matrix material, the polycyclic condensed skeleton in the general formula (1) has atoms and atomic groups constituting the matrix material, and the matrix material contains ions. If included, it may be substituted with a group that interacts with the ion. As a result, it is possible to prevent the molecules of the polarization source from agglutinating to form an agglomerate, and the molecules can be easily dispersed in the matrix material.
For example, the substituent (R) of the general formula (1) contains one or more atoms selected from the group consisting of halogen atoms, nitrogen atoms, oxygen atoms, sulfur atoms, boron atoms, phosphorus atoms, and silicon atoms. It is preferably a substituent. Specific examples include halogen atom, cyano group, carbonyl group, ester group, carboxyl group, sulfo group, phosphono group, phosphonoxy group, boron atom, phosphorus atom, silicon atom, hydroxy group, thiol group, pyridine ring, pyridazine ring and pyrimidine. A substituent containing one or more selected from the group consisting of a ring, a pyrazine ring and an amino group can be exemplified. Acidic group such as a carboxy group (-COOH), a sulfo group (-SO 3 H), a phosphono group (-P (O) (OH) 2), phosphonoxy group (-OP (O) (OH) 2) is a proton May be an ionized anion group, and examples thereof include a carboxylate anion group. These groups may be directly bonded to the polycyclic condensed skeleton or may be linked via a linking group. As an example of a preferred embodiment, at least one of Z 1 , Z 2 , Z 7 , Z 8 , Z 9 of the general formula (1) is CR 11 , and Z 3 , Z 4 , Z 5 , Z 6 , Z 10 is CR 12 , and R 11 and R 12 are independently composed of a halogen atom, a nitrogen atom, an oxygen atom, a sulfur atom, a boron atom, a phosphorus atom, and a silicon atom. It can be mentioned that it is one or more atoms to be selected.
　一般式（１）で表される化合物に含まれる化合物群として、下記の一般式（２）で表される化合物群を例示することができる。
Figure JPOXMLDOC01-appb-C000012
 As the compound group contained in the compound represented by the general formula (1), the compound group represented by the following general formula (2) can be exemplified.
Figure JPOXMLDOC01-appb-C000012
　一般式（２）において、Ｒ１～Ｒ８は各々独立に水素原子または置換基を表す。ｎ１およびｎ２は各々独立に０～４の整数を表し、ｎ１＋ｎ２は２～５の整数である。ｎ１が２以上であるとき、複数のＲ５は同一であっても異なっていてもよく、また、複数のＲ６は同一であっても異なっていてもよい。ｎ２が２以上であるとき、複数のＲ７は同一であっても異なっていてもよく、また、複数のＲ８は同一であっても異なっていてもよい。
　一般式（２）における置換基については、一般式（１）におけるＲが表す置換基の説明を参照することができる。 In the general formula (2), R 1 to R 8 independently represent a hydrogen atom or a substituent. n1 and n2 each independently represent an integer of 0 to 4, and n1 + n2 is an integer of 2 to 5. When n1 is 2 or more, the plurality of R 5s may be the same or different, and the plurality of R 6s may be the same or different. When n2 is 2 or more, the plurality of R 7s may be the same or different, and the plurality of R 8s may be the same or different.
For the substituent in the general formula (2), the description of the substituent represented by R in the general formula (1) can be referred to.
　一般式（１）や一般式（２）で表される分子は、その少なくとも一部の水素原子が重水素原子で置換されていてもよく、重水素原子で置換されている場合は分子に存在する水素原子の３０～７０％が重水素原子で置換されていることがより好ましい。これにより、偏極源のスピン－格子緩和時間を長くして、核スピンを効果的に高偏極化することができる。ここで、分子の重水素原子で置換される箇所は、比較的動きやすい箇所であることが好ましい。例えば、多環縮合骨格に、単結合で結合した原子団（置換基）が存在する場合には、その置換基が有する水素原子の少なくとも一部が重水素原子で置換されていることが好ましく、その全部の水素原子が重水素原子で置換されていることが好ましい。重水素原子で置換するのに好ましい置換基の例として、炭素数１～２０のアルキル基を挙げることができる。 The molecule represented by the general formula (1) or the general formula (2) may have at least a part of its hydrogen atom substituted with a deuterium atom, and if it is substituted with a deuterium atom, it exists in the molecule. It is more preferable that 30 to 70% of the hydrogen atoms to be used are replaced with deuterium atoms. As a result, the spin-lattice relaxation time of the polarization source can be lengthened, and the nuclear spin can be effectively highly polarized. Here, it is preferable that the portion of the molecule substituted with the deuterium atom is a portion that is relatively easy to move. For example, when an atomic group (substituent) bonded by a single bond is present in the polycyclic condensed skeleton, it is preferable that at least a part of the hydrogen atom of the substituent is substituted with a deuterium atom. It is preferable that all the hydrogen atoms are replaced with heavy hydrogen atoms. As an example of a substituent preferable for substitution with a deuterium atom, an alkyl group having 1 to 20 carbon atoms can be mentioned.
　以下において、一般式（１）で表される分子の具体例を例示する。ただし、本発明において偏極源に用いることができる一般式（１）で表される分子はこれらの具体例によって限定的に解釈されるべきものではない。なお、以下の構造において「Ｍｅ」はメチル基を表し、「Ｒ」は置換基を表し、具体的には、フッ素原子、塩素原子、臭素原子、ヨウ素原子、シアノ基、チオール基、フェニル基、４－ピリジル基、４－メトキシカルボニルフェニル基、４－カルボキシルフェニル基、３，５－ジメトキシカルボニルフェニル基、３，５－ジカルボキシルフェニル基、ホルミル基、アミノ基、ジヒドロキシ基、－Ｂ（ＯＨ）２または
Figure JPOXMLDOC01-appb-C000013
 を表す。「Ｚ」は下記式で表されるアンモニウムイオンまたはＮａ＋を表す。
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
 In the following, specific examples of the molecule represented by the general formula (1) will be illustrated. However, the molecule represented by the general formula (1) that can be used as a polarization source in the present invention should not be construed as being limited by these specific examples. In the following structure, "Me" represents a methyl group and "R" represents a substituent, specifically, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a thiol group, a phenyl group, and the like. 4-Pyridyl group, 4-methoxycarbonylphenyl group, 4-carboxyphenyl group, 3,5-dimethoxycarbonylphenyl group, 3,5-dicarboxyphenyl group, formyl group, amino group, dihydroxy group, -B (OH) 2 or
Figure JPOXMLDOC01-appb-C000013
 Represents. "Z" represents ammonium ion or Na + represented by the following formula.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
（ポルフィリン誘導体）
　本発明で用いる偏極源は、ポルフィリン誘導体であってもよい。すなわち、本発明の組成物は、スピン－格子緩和時間Ｔ１が２．５秒以上である水溶性のマトリクス材料と、該水溶性マトリクス中に分散した偏極源であるポルフィリン誘導体とを含む組成物であってもよい。偏極源として用いるポルフィリン誘導体は、１種類であってもよいし、２種類以上の組み合わせであってもよい。
　ポルフィリン誘導体は、偏極した三重項電子を生成しうる光励起三重項分子であって、生体適合性が高い。そのため、ポルフィリン誘導体からなる動的核偏極源は、生体関連物質を含めた様々な物質を対象とする動的核偏極材に効果的に用いることができる。
　ポルフィリン誘導体の例として、下記一般式（３）で表されるポルフィリン誘導体やそのポルフィリン誘導体を配位子とする錯体を挙げることができる。 (Porphyrin derivative)
The polarization source used in the present invention may be a porphyrin derivative. That is, the composition of the present invention contains a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more, and a porphyrin derivative which is a polarization source dispersed in the water-soluble matrix. It may be a thing. The porphyrin derivative used as the polarization source may be one kind or a combination of two or more kinds.
Porphyrin derivatives are photoexcited triplet molecules capable of generating polarized triplet electrons and are highly biocompatible. Therefore, the dynamic nuclear polarization source composed of a porphyrin derivative can be effectively used as a dynamic nuclear polarization material for various substances including bio-related substances.
Examples of the porphyrin derivative include a porphyrin derivative represented by the following general formula (3) and a complex having the porphyrin derivative as a ligand.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　一般式（３）において、Ａｒ１～Ａｒ４は各々独立に置換もしくは無置換のアリール基を表す。
　Ａｒ１～Ａｒ４におけるアリール基を構成する芳香環は、単環であっても、２以上の芳香環が縮合した縮合環であっても、２以上の芳香環が連結した連結環であってもよい。２以上の芳香環が連結している場合は、直鎖状に連結したものであってもよいし、分枝状に連結したものであってもよい。芳香環の炭素数は、６～２２であることが好ましく、６～１８であることがより好ましく、６～１４であることがさらに好ましく、６～１０であることがさらにより好ましい。アリール基の具体例として、フェニル基、ナフタレニル基、ビフェニルイル基を挙げることができる。
　アリール基の置換基としては、カチオン性基、アニオン性基、イオン対の他、ハロゲン原子を挙げることができる。カチオン性基は、カチオン基であってもよいし、プロトンを受け取ってカチオン基になる基であってもよい。カチオン性基の具体例として、置換もしくは無置換のアミノ基、アンモニウム基を挙げることができる。アニオン性基は、アニオン基であってもよいし、プロトンが電離してアニオン基になる基であってもよい。アニオン性基の具体例として、カルボキシ基（－ＣＯＯＨ）、ホスホノ基（－ＰＯ３Ｈ２）、ホスホノキシ基（－ＯＰＯ３Ｈ２）、スルホ基（－ＳＯ３Ｈ）、スルホオキシ基（－ＯＳＯ３Ｈ）、ヒドロキシ基（－ＯＨ）、およびこれらの基からプロトンが電離したアニオン基を挙げることができる。カチオン基およびアニオン基は、それぞれ、アニオン、カチオンとイオン対を形成してもよい。アニオンとしては、上記のアニオン基を有する化合物を挙げることができ、カチオンとしては、アンモニウムイオン、Ｎａ＋、Ｋ＋などのアルカリ金属イオンを挙げることができる。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子を挙げることができ、フッ素原子であることが好ましい。
　ここで、金属錯体を形成していないポルフィリン誘導体において、ハロゲン原子（例えばフッ素原子）のような電子求引性基でアリール基を置換した場合、その電子求引性基の置換数が大きくなる程、電子間の双極子相互作用強度（Ｄ値）が大きくなって、スピン－格子緩和時間Ｔ１が短くなる傾向がある。そのため、Ａｒ１～Ａｒ４におけるアリール基を電子求引性基で置換する場合、その置換数は、４以下とすることが好ましく、３以下とすることがより好ましく、２以下とすることがさらに好ましい。本明細書における「電子求引性基」とは、ハメットのσｐ値が正である置換基を意味する。ハメットのσｐ値の説明と数値については、Hansch,C.et.al.,Chem.Rev.,91,165-195(1991)の記載を参照することができる。 In the general formula (3), Ar 1 to Ar 4 each independently represent a substituted or unsubstituted aryl group.
The aromatic ring constituting the aryl group in Ar 1 to Ar 4 is a connecting ring in which two or more aromatic rings are linked, whether it is a monocyclic ring or a condensed ring in which two or more aromatic rings are condensed. May be good. When two or more aromatic rings are connected, they may be linearly connected or may be branched. The number of carbon atoms in the aromatic ring is preferably 6 to 22, more preferably 6 to 18, further preferably 6 to 14, and even more preferably 6 to 10. Specific examples of the aryl group include a phenyl group, a naphthalenyl group, and a biphenylyl group.
Examples of the substituent of the aryl group include a cationic group, an anionic group, an ion pair, and a halogen atom. The cationic group may be a cationic group or a group that receives a proton and becomes a cationic group. Specific examples of the cationic group include a substituted or unsubstituted amino group and an ammonium group. The anionic group may be an anionic group or a group in which protons are ionized to become an anionic group. Specific examples of the anionic group include a carboxy group (-COOH), a phosphono group (-PO 3 H 2 ), a phosphonoxy group (-OPO 3 H 2 ), a sulfo group (-SO 3 H), and a sulfooxy group (-OSO 3). H), a hydroxy group (-OH), and an anionic group in which a proton is ionized from these groups can be mentioned. The cation group and the anion group may form an ion pair with the anion and the cation, respectively. Examples of the anion include the above-mentioned compounds having an anion group, and examples of the cation include alkali metal ions such as ammonium ion, Na + , and K +. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is preferable.
Here, in a porphyrin derivative that does not form a metal complex, when an aryl group is substituted with an electron-attracting group such as a halogen atom (for example, a fluorine atom), the larger the number of substitutions of the electron-attracting group, the larger the number of substitutions. , The dipole interaction intensity (D value) between electrons tends to increase, and the spin-lattice relaxation time T 1 tends to become shorter. Therefore, when the aryl group in Ar 1 to Ar 4 is replaced with an electron-attracting group, the number of substitutions is preferably 4 or less, more preferably 3 or less, and further preferably 2 or less. preferable. As used herein, the term "electron-attracting group" means a substituent having a positive Hammett σp value. For a description and numerical value of Hammett's σp value, refer to the description in Hansch, C.et.al., Chem.Rev., 91,165-195 (1991).
　ポルフィリン誘導体は、その少なくとも一部の水素原子が重水素原子で置換されていてもよく、重水素原子で置換されている場合は分子に存在する水素原子の３０～７０％が重水素原子で置換されていることがより好ましい。これにより、偏極源のスピン－格子緩和時間を長くして、核スピンを効果的に高偏極化することができる。ここで、分子の重水素原子で置換される箇所は、比較的動きやすい箇所であることが好ましい。例えば、ポルフィリン骨格に、単結合で結合した原子団（置換基）が存在する場合には、その置換基が有する水素原子の少なくとも一部が重水素原子で置換されていることが好ましく、その全部の水素原子が重水素原子で置換されていることが好ましい。重水素原子で置換するのに好ましい置換基の例として、炭素数１～２０のアルキル基を挙げることができる。 A porphyrin derivative may have at least a part of its hydrogen atoms substituted with deuterium atoms, and when it is substituted with deuterium atoms, 30 to 70% of the hydrogen atoms present in the molecule are substituted with deuterium atoms. It is more preferable that it is. As a result, the spin-lattice relaxation time of the polarization source can be lengthened, and the nuclear spin can be effectively highly polarized. Here, it is preferable that the portion of the molecule substituted with the deuterium atom is a portion that is relatively easy to move. For example, when an atomic group (substituent) bonded by a single bond is present in the porphyrin skeleton, it is preferable that at least a part of the hydrogen atom of the substituent is substituted with a heavy hydrogen atom, and all of them are substituted. It is preferable that the hydrogen atom of the above is replaced with a heavy hydrogen atom. As an example of a substituent preferable for substitution with a deuterium atom, an alkyl group having 1 to 20 carbon atoms can be mentioned.
　また、一般式（３）で表されるポルフィリン誘導体を配位子とする錯体として、下記一般式（４）で表されるポルフィリン金属錯体を挙げることができる。 Further, as a complex having a porphyrin derivative represented by the general formula (3) as a ligand, a porphyrin metal complex represented by the following general formula (4) can be mentioned.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　一般式（４）において、Ａｒ１１～Ａｒ１４は各々独立に置換もしくは無置換のアリール基を表す。アリール基およびその置換基の説明と好ましい範囲、具体例については、一般式（１）のＡｒ１～Ａｒ４におけるアリール基および置換基についての説明と好ましい範囲、具体例を参照することができる。Ｍは中心金属を表す。中心金属として、Ｚｎ、Ｍｇ、Ｆｅ、Ｎｉ、Ｐ、Ｓｂ、Ａｓ、Ｓｉ、Ｇｅ、Ｓｎ等を挙げることができる。
　ここで、このポルフィリン金属錯体のアリール基をハロゲン原子（例えばフッ素原子）のような電子求引性基で置換すると、無置換の場合に比べて電子スピンにおけるスピン－格子緩和時間に相当する、偏極寿命τが長くなり、さらに、電子求引性基の置換数が大きくなる程、τが長くなる傾向が見られる。これは、金属錯体では中心金属と電子の間に強い相互作用が働いているところ、その電子が電子求引性基に引っ張られてアリール基側に局在化することにより、その相互作用が弱くなるためであると考えられる。したがって、Ａｒ１１～Ａｒ１４におけるアリール基は、フッ素原子のような電子求引性基で置換されていることが好ましく、その置換数が２以上であることが好ましい。 In the general formula (4), Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group. For the description and preferable range of the aryl group and its substituent and specific examples, the description and preferable range and specific example of the aryl group and the substituent in Ar 1 to Ar 4 of the general formula (1) can be referred to. M represents the central metal. Examples of the central metal include Zn, Mg, Fe, Ni, P, Sb, As, Si, Ge, Sn and the like.
Here, when the aryl group of this porphyrin metal complex is replaced with an electron-attracting group such as a halogen atom (for example, a fluorine atom), the bias corresponds to the spin-lattice relaxation time in the electron spin as compared with the case of no substitution. The longer the polar lifetime τ and the larger the number of substitutions of the electron attracting group, the longer the τ tends to be. This is because in a metal complex, a strong interaction acts between the central metal and an electron, but the electron is pulled by an electron-attracting group and localized to the aryl group side, so that the interaction is weak. It is thought that this is because. Therefore, the aryl group in Ar 11 to Ar 14 is preferably substituted with an electron-attracting group such as a fluorine atom, and the number of substitutions is preferably 2 or more.
　以下において、偏極源に用いうるポルフィリン誘導体の具体例を例示する。ただし、本発明において偏極源に用いることができるポルフィリン誘導体はこれらの具体例によって限定的に解釈されるべきものではない。
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
 Hereinafter, specific examples of porphyrin derivatives that can be used as a polarization source will be illustrated. However, the porphyrin derivative that can be used as a polarization source in the present invention should not be construed as being limited by these specific examples.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
　ポルフィリン誘導体は、下記に示すような軸配位型のポルフィリン誘導体であってもよい。これらのポルフィリン誘導体は、I N. Meshkov, et al. Chem. Commun., 2017, 53, 9918に記載の合成法にしたがって合成することができる。下記３つのポルフィリン誘導体は、溶解性が高く、三重項電子スピンの偏極が観測されている。 The porphyrin derivative may be an axially coordinated porphyrin derivative as shown below. These porphyrin derivatives can be synthesized according to the synthetic method described in IN. Meshkov, et al. Chem. Communi., 2017, 53, 9918. The following three porphyrin derivatives have high solubility, and triplet electron spin polarization has been observed.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　以上で説明した偏極源のうち、本発明の組成物には水溶性の偏極源を用いることが好ましい。水溶性の偏極源は、水溶性のマトリクス材料と高い親和性を示すため、マトリクス材料中に容易に分散させることができる。また、水溶性マトリクスとの親和性の点から、偏極源は、イオン対を有するものであることが好ましく、カチオン性基やアニオン性基を有するものであることも好ましい。
　「水溶性」の定義については、上記のマトリクス材料における「水溶性」の定義を参照することができる。 Among the polarization sources described above, it is preferable to use a water-soluble polarization source for the composition of the present invention. Since the water-soluble polarization source has a high affinity with the water-soluble matrix material, it can be easily dispersed in the matrix material. Further, from the viewpoint of affinity with the water-soluble matrix, the polarization source preferably has an ion pair, and preferably has a cationic group or an anionic group.
For the definition of "water-soluble", the definition of "water-soluble" in the above matrix material can be referred to.
［その他の成分］
　本発明の組成物は、マトリクス材料と偏極源のみから構成されていてもよいし、その他の成分を含んでいてもよい。例えば、偏極源を構成する分子が酸性基を有する場合には、水酸化ナトリウム、水酸化カリウム等の塩基性物質を組成物に添加することが好ましい。これにより、偏極源の酸性基からプロトンが電離して共役塩基が形成され、マトリクス材料との親和性が向上する場合がある。
　また、本発明の組成物は、タンパク質、ペプチド、ＤＮＡ等の偏極対象物や、溶媒分子、テンプレート分子等をその他の成分として含んでいてもよい。ここで、偏極対象物は、組成物で生成した核スピン偏極を移行させうる物質である。偏極対象物の説明と好ましい範囲、具体例については、＜高偏極化方法＞の欄の対応する記載を参照することができる。 [Other ingredients]
The composition of the present invention may be composed of only a matrix material and a polarization source, or may contain other components. For example, when the molecule constituting the polarization source has an acidic group, it is preferable to add a basic substance such as sodium hydroxide or potassium hydroxide to the composition. As a result, protons are ionized from the acidic group of the polarization source to form a conjugate base, which may improve the affinity with the matrix material.
Further, the composition of the present invention may contain a polarized object such as a protein, a peptide or DNA, a solvent molecule, a template molecule or the like as other components. Here, the polarization target is a substance capable of transferring the nuclear spin polarization generated in the composition. For the description of the polarized object, the preferable range, and specific examples, the corresponding description in the column of <Highly polarized method> can be referred to.
［偏極源の含有量］
　組成物における偏極源の含有量は、マトリクス材料を構成する化合物のモル数に対して１０ｍｏｌ％以下であることが好ましく、３ｍｏｌ％以下であることがより好ましく、例えば１ｍｏｌ％以下の範囲内にしてもよい。また、偏極源の含有量は、マトリクス材料を構成する化合物の全モル数に対して０．０１ｍｏｌ％以上であることが好ましく、０．１ｍｏｌ％以上の範囲内にしてもよく、０．５ｍｏｌ％以上の範囲内にしてもよい。 [Content of polarized source]
The content of the polarization source in the composition is preferably 10 mol% or less, more preferably 3 mol% or less, and for example, in the range of 1 mol% or less with respect to the number of moles of the compound constituting the matrix material. You may. The content of the polarization source is preferably 0.01 mol% or more, preferably in the range of 0.1 mol% or more, and 0.5 mol, based on the total number of moles of the compounds constituting the matrix material. It may be within the range of% or more.
［組成物の製造方法］
　本発明の組成物の製造方法として、下記の（１）～（３）の製造方法を挙げることができる。これらの製造方法の中から、使用する材料によって適宜最適な製造方法を選択することができる。
（１）マトリクス材料および偏極源を水に溶解して調製した水溶液を、加熱乾燥して粉末を作製し、さらに、この粉末をデシケーター内で静置して固体の組成物を製造する方法。
（２）（１）と同様にして作製した粉末を加熱融解した後、液体窒素で急冷することにより固体の組成物を製造する方法。
（３）マトリクス材料の粉末と偏極源の粉末を混合して調製した混合粉末を、加熱融解した後、液体窒素で急冷することにより固化した組成物を製造する方法。 [Method for producing composition]
Examples of the method for producing the composition of the present invention include the following production methods (1) to (3). From these manufacturing methods, the optimum manufacturing method can be appropriately selected depending on the material used.
(1) A method for producing a solid composition by heating and drying an aqueous solution prepared by dissolving a matrix material and an polarization source in water to prepare a powder, and further allowing the powder to stand in a desiccator.
(2) A method for producing a solid composition by heating and melting a powder prepared in the same manner as in (1) and then quenching with liquid nitrogen.
(3) A method for producing a solidified composition by heating and melting a mixed powder prepared by mixing a powder of a matrix material and a powder of an polarization source, and then quenching with liquid nitrogen.
［動的核偏極のメカニズム］
　本発明の組成物は動的核偏極処理を行うことにより高偏極化することができる。以下において、その動的核偏極処理とメカニズムを、図２を参照しながら説明する。ただし、本発明の組成物に行う動的核偏極処理は、以下で説明するものによって限定的に解釈されるべきものではない。動的核偏極処理は、具体的には下記工程［１］および工程［２］により行うことができる。 [Mechanism of dynamic nuclear polarization]
The composition of the present invention can be highly polarized by performing dynamic nuclear polarization treatment. In the following, the dynamic nuclear polarization treatment and the mechanism will be described with reference to FIG. However, the dynamic nuclear polarization treatment performed on the composition of the present invention should not be construed as being limited by what is described below. Specifically, the dynamic nuclear polarization treatment can be performed by the following steps [1] and [2].
［１］偏極源の励起工程
　この工程では、組成物に励起光を照射して、組成物が含む偏極源を励起三重項状態へ遷移させる。
　組成物に励起光を照射すると、図２に示すように、偏極源の分子が基底一重項状態Ｓ０から励起一重項状態Ｓ１へと遷移し、さらに、励起一重項状態Ｓ１からの項間交差が起こって励起三重項状態Ｔｎになる。続いて、励起三重項状態Ｔｎが、それよりも低次の励起三重項状態へと段階的に内部転換し、終には最低エネルギー準位の励起三重項状態Ｔ１になる。この励起三重項状態Ｔ１での電子スピン（三重項電子スピン）のゼーマン準位の数は、磁気量子数ｍ＝－１、０、＋１のそれぞれに相当する３つであり、これらのうち、ｍ＝０のゼーマン準位に電子スピンが大きく偏って分布した電子スピン高偏極状態になっている。一方、核のゼーマン準位の数は、例えばプロトン１Ｈでは、磁気量子数ｍ＝＋１／２、－１／２のそれぞれに相当する２つである。これらのうちｍ＝＋１／２のゼーマン準位の方が、僅かに核スピンの占有数が多いものの、偏極率は１０－６程度であり、極めて低い核スピン偏極状態にある。 [1] Excitation Step of Polarized Polar Source In this step, the composition is irradiated with excitation light to transition the polarized light source contained in the composition to the excited triplet state.
When the composition is irradiated with excitation light, as shown in FIG. 2, the polarization source molecule transitions from the basal singlet state S 0 to the excited singlet state S 1 , and further from the excited singlet state S 1 . intersystem crossing is excited triplet state T n is happening. Subsequently, the excited triplet state T n is gradually internally converted to a lower-order excited triplet state, and finally becomes the excited triplet state T 1 at the lowest energy level. The number of Zeeman levels of electron spin (triplet electron spin) in the excited triplet state T 1 is three corresponding to each of the magnetic quantum numbers m = -1, 0, and +1. The electron spins are highly biased and distributed at the Zeeman level of m = 0. On the other hand, the number of Zeeman levels of the nucleus, for example, the proton 1 H, magnetic quantum number m = + 1/2, are two corresponding to each of the -1 / 2. Of these, the Zeeman level with m = + 1/2 has a slightly larger number of nuclear spins, but has a polarization ratio of about 10-6, which is an extremely low nuclear spin polarization state.
［２］高偏極化工程
　この工程では、偏極源で生成した三重項電子スピンの偏極を、マトリクス材料の核スピンに移行して、核スピンを高偏極化する。
　具体的には、偏極源の三重項電子スピンが生じた組成物に、例えば電子スピンが共鳴する電磁波を照射して磁場掃引を行う。すると、積分型固体効果により、電子のスピン偏極がマトリクス材料の核に移行して核スピンが高偏極化される。高偏極化の条件は特に制限されないが、例えば外部磁場の強度は、０．１～１Ｔ、電磁波の周波数は２～２０ＧＨｚ、電磁場の強度は０．１～１００Ｗの各範囲から適宜選択することができる。
　こうして核スピンが高偏極化された組成物からは、強度が高いＮＭＲ信号を得ることができ、ＮＭＲ分光法やＭＲＩにおいて高い測定感度を実現することができる。
　ここで、本発明の組成物は、マトリクス材料が水溶性であることにより、生体関連物質に対して高い親和性を示す。そのため、組成物に予め生体関連物質を混合していた場合には、この高偏極化工程で、マトリクス材料の核スピンを介して生体関連物質の核スピンにも容易に偏極が移行して、該生体関連物質を高偏極化することができる。また、この工程で高偏極化した組成物に生体関連物質を接触させた場合には、組成物と生体関連物質の親和性が高いことにより、この組成物で生じた核スピン偏極を生体関連物質の核スピンへ容易に移行させて、該生体関連物質を高偏極化することができる。マトリクス材料から生体関連物質への核スピン偏極移行の例として、例えばマトリクス材料の１Ｈ核から生体関連物質の１３Ｃ核へのスピン偏極移行が挙げられる。
　なお、上記の工程［１］、［２］は、工程［１］を行った後に、工程［２］を行うようにしてもよいし、工程［１］と工程［２］を同時に行ってもよい。後者の場合には、組成物に外部磁場を印加しつつ、励起光と電子スピンが共鳴する電磁波を同時に照射する。 [2] Highly polarized step In this step, the polarization of the triplet electron spin generated by the polarization source is transferred to the nuclear spin of the matrix material, and the nuclear spin is highly polarized.
Specifically, the composition in which the triplet electron spin of the polarization source is generated is irradiated with an electromagnetic wave in which the electron spin resonates, for example, to perform magnetic field sweeping. Then, due to the integral solid effect, the spin polarization of the electron is transferred to the nucleus of the matrix material, and the nuclear spin is highly polarized. The conditions for high polarization are not particularly limited, but for example, the intensity of the external magnetic field should be appropriately selected from the range of 0.1 to 1 T, the frequency of the electromagnetic wave should be 2 to 20 GHz, and the intensity of the electromagnetic field should be appropriately selected from the range of 0.1 to 100 W. Can be done.
From the composition in which the nuclear spin is highly polarized in this way, an NMR signal having high intensity can be obtained, and high measurement sensitivity in NMR spectroscopy and MRI can be realized.
Here, the composition of the present invention exhibits a high affinity for biological substances because the matrix material is water-soluble. Therefore, when a bio-related substance is mixed in the composition in advance, the polarization is easily transferred to the nuclear spin of the bio-related substance via the nuclear spin of the matrix material in this high polarization step. , The bio-related substance can be highly polarized. In addition, when a bio-related substance is brought into contact with the highly polarized composition in this step, the nuclear spin polarization generated by this composition becomes a living body due to the high affinity between the composition and the bio-related substance. The bio-related material can be highly polarized by easily transferring to the nuclear spin of the related material. Examples of nuclear spin polarization transfer from the matrix material into a biological substance, include, for example, spin-polarized transfer of the 1 H nucleus matrix material to 13 C nuclei biological substance.
In the above steps [1] and [2], the step [2] may be performed after the step [1] is performed, or the step [1] and the step [2] may be performed at the same time. good. In the latter case, while applying an external magnetic field to the composition, an electromagnetic wave in which excitation light and electron spin resonate are simultaneously irradiated.
＜動的核偏極用組成物＞
　次に、本発明の動的核偏極用組成物について説明する。
　本発明の動的核偏極用組成物は、本発明の組成物からなることを特徴とする。
　本発明の組成物の説明と好ましい範囲、具体例については、上記の＜組成物＞の項の記載を参照することができる。
　上記のように、本発明の組成物は生体関連物質に対する親和性が高く、また、マトリクス材料の核スピンを容易に高偏極化することができるため、その核スピン偏極を生体関連物質の核スピンに容易に移行させて、該生体関連物質を効果的に高偏極化することができる。 <Composition for dynamic nuclear polarization>
Next, the composition for dynamic nuclear polarization of the present invention will be described.
The composition for dynamic nuclear polarization of the present invention is characterized by comprising the composition of the present invention.
For the description, preferable range, and specific examples of the composition of the present invention, the description in the above section <Composition> can be referred to.
As described above, the composition of the present invention has a high affinity for a bio-related substance, and the nuclear spin of the matrix material can be easily highly polarized. The biorelated material can be effectively highly polarized by easily translocating to nuclear spin.
＜高偏極化組成物＞
　次に、本発明の高偏極化組成物について説明する。
　本発明の高偏極化組成物は、本発明の組成物を高偏極化したものである。
　本発明の組成物の説明と好ましい範囲、具体例、高偏極化の方法（高偏極化処理）とメカニズムについては、上記の＜組成物＞の項の記載を参照することができる。
　上記のように、本発明の組成物では、マトリクス材料のスピン－格子緩和時間Ｔ１が２．５秒以上に規定されているため、動的核偏極過程において、偏極源の電子スピンからマトリクス材料の核スピンに移行してきた偏極が核スピンに保持されて蓄積し、組成物全体を高偏極化することができる。また、この高偏極化組成物は、マトリクス材料の水溶性を反映して生体関連物質に対して高い親和性を示す。そのため、この高偏極化組成物に生体関連物質を接触させると、高偏極化組成物の核スピン偏極が生体関連物質の核スピンに容易に移行して該生体関連物質を高偏極化することができる。なお、本発明には、生体関連物質そのものをマトリクス材料として用いる場合も含まれる。このため本発明には、偏極源の電子スピンから生体関連物質（例えばピルビン酸ナトリウム）の核スピンへ偏極を直接移行する態様も含まれる。
　本発明の「高偏極化組成物」であることは、そのＮＭＲスペクトルにおいて、熱平衡状態にある組成物のＮＭＲスペクトルよりも、強度が大きいピーク（増感したピーク）が観測されることをもって確認することができる。高偏極化組成物の増感したピークの強度は、熱平衡状態にある組成物の対応するピーク強度に対して、１０倍以上であることが好ましく、１００倍以上であることがより好ましく、１０００倍以上であることがさらに好ましい。 <Highly polarized composition>
Next, the highly polarized composition of the present invention will be described.
The highly polarized composition of the present invention is a highly polarized composition of the present invention.
For the description and preferable range of the composition of the present invention, specific examples, the method of high polarization (high polarization treatment) and the mechanism, the description in the above section <Composition> can be referred to.
As described above, in the composition of the present invention, since the spin-lattice relaxation time T 1 of the matrix material is defined to be 2.5 seconds or more, the electron spin of the polarization source is used in the dynamic nuclear polarization process. The polarization that has migrated to the nuclear spins of the matrix material is retained and accumulated in the nuclear spins, and the entire composition can be highly polarized. In addition, this highly polarized composition shows a high affinity for biological substances, reflecting the water solubility of the matrix material. Therefore, when a bio-related substance is brought into contact with this highly polarized composition, the nuclear spin polarization of the highly polarized composition easily shifts to the nuclear spin of the bio-related substance, and the bio-related substance is highly polarized. Can be transformed into. The present invention also includes the case where the bio-related substance itself is used as the matrix material. Therefore, the present invention also includes an embodiment in which the polarization is directly transferred from the electron spin of the polarization source to the nuclear spin of a biorelated substance (for example, sodium pyruvate).
The fact that the composition is a "highly polarized composition" of the present invention is confirmed by observing a peak (sensitized peak) having a higher intensity than the NMR spectrum of the composition in a thermal equilibrium state in the NMR spectrum. can do. The intensity of the sensitized peak of the highly polarized composition is preferably 10 times or more, more preferably 100 times or more, more preferably 1000 times or more the corresponding peak intensity of the composition in thermal equilibrium. It is more preferable that the amount is double or more.
＜高偏極化方法＞
　次に、本発明の高偏極化方法について説明する。
　本発明の高偏極化方法の第１態様は、本発明の高偏極化組成物に物質を接触させる工程を含む高偏極化方法である。また、本発明の高偏極化方法の第２態様は、本発明の組成物に物質を接触させた後、その組成物を高偏極化させて高偏極化組成物とする工程を含む高偏極化方法である。
　なお、本明細書中では、上記の動的核偏極用組成物を用いて、その核スピンを偏極化する物質（偏極化の対象）、および本発明の高偏極化組成物または本発明の組成物に接触または含有させて核スピンを偏極化する物質（偏極化の対象）を「偏極対象物」という。
　組成物の説明については、上記の＜組成物＞の項の記載を参照することができ、高偏極化組成物の説明については、上記の＜高偏極化組成物＞の項の記載を参照することができる。 <Highly polarized method>
Next, the highly polarized method of the present invention will be described.
The first aspect of the highly polarized method of the present invention is a highly polarized method including a step of bringing a substance into contact with the highly polarized composition of the present invention. In addition, the second aspect of the highly polarized method of the present invention includes a step of bringing a substance into contact with the composition of the present invention and then highly polarized the composition to obtain a highly polarized composition. This is a highly polarized method.
In the present specification, using the above-mentioned dynamic nuclear polarization composition, a substance that polarizes the nuclear spin (target of polarization), and the highly polarized composition of the present invention or A substance that polarizes nuclear spin by contacting or containing it in the composition of the present invention (object of polarization) is referred to as "object of polarization".
For the description of the composition, the description in the above <composition> section can be referred to, and for the description of the highly polarized composition, the description in the above <highly polarized composition> section can be referred to. You can refer to it.
　第１態様の高偏極化方法では、高偏極化組成物が水溶性のマトリクス材料を含むことにより、特に生体関連物質等の親水性偏極対象物を、高偏極化組成物に親和性よく接触性させることができる。そのため、高偏極化組成物で生じた核スピンの偏極を生体関連物質の核スピンへ容易に移行させて、該生体関連物質の高偏極化することができる。
　高偏極化組成物と偏極対象物を接触させる際の温度は特に制限されない。例えば－７８℃未満の低温域で行ってもよいし、－７８℃～０℃の範囲内で行ってもよいが、好ましいのは０℃超３０℃未満で行う場合であり、より好ましくは２０～３０℃の室温域で行う場合である。
　この高偏極化方法では、さらに、高偏極化組成物の核スピン偏極を、偏極対象物に移行させる工程を含んでいてもよい。
　高偏極化組成物の核スピン偏極は、別段の工程を行わなくても、高偏極化組成物に偏極対象物を接触させることにより該偏極対象物に移行、拡散するが、その際、核スピン偏極の移行を誘起するための工程を行ってもよい。そのような手法として、交差分極法（ＣＰ法）、交差分極とマジック角回転と広帯域デカップリングを併用したＣＰ／ＭＡＳ法、断熱通過交差分極（Adiabatic passage cross polarization）等が挙げられる。 In the highly polarized method of the first aspect, since the highly polarized composition contains a water-soluble matrix material, a hydrophilic polarized object such as a biological substance is particularly compatible with the highly polarized composition. It can be made into good contact. Therefore, the polarization of the nuclear spins generated in the highly polarized composition can be easily transferred to the nuclear spins of the bio-related substance, and the bio-related substance can be highly polarized.
The temperature at which the highly polarized composition and the polarized object are brought into contact with each other is not particularly limited. For example, it may be carried out in a low temperature range of less than −78 ° C. or in the range of −78 ° C. to 0 ° C., but it is preferably carried out at a temperature of more than 0 ° C. and lower than 30 ° C., more preferably 20 ° C. This is the case when the operation is performed in a room temperature range of about 30 ° C.
This highly polarized method may further include a step of transferring the nuclear spin polarization of the highly polarized composition to the polarized object.
The nuclear spin polarization of the highly polarized composition is transferred to and diffuses to the polarized object by bringing the polarized object into contact with the highly polarized composition without performing a separate step. At that time, a step for inducing the transition of the nuclear spin polarization may be performed. Examples of such a method include a cross polarization method (CP method), a CP / MAS method in which cross polarization is used in combination with magic angle spinning and wideband decoupling, and adiabatic passage cross polarization.
　高偏極化組成物に接触させる偏極対象物は、固体、ガス、液体または溶液のいずれであってもよい。これらの偏極対象物を、本発明の高偏極化組成物に接触させると、高偏極化組成物の核のスピン偏極が偏極対象物に移行し、該偏極対象物の核スピンが高偏極化される。
　ガス、液体または溶液の高偏極化組成物への接触方法は特に限定されず、例えばこれらのものを高偏極化組成物へ注入してもよいし、容器内にこれらのものを充填し、その中に容器を配置して浸透させてもよい。
　また、偏極対象物を液体中に溶解または分散させた状態で高偏極化組成物と混合してもよい。このとき、高偏極化組成物が偏極対象物を直接偏極してもよいし、液体を介して偏極してもよい。 The polarized object to be brought into contact with the highly polarized composition may be a solid, a gas, a liquid or a solution. When these polarized objects are brought into contact with the highly polarized composition of the present invention, the spin polarization of the nucleus of the highly polarized composition shifts to the polarized object, and the nucleus of the polarized object is transferred. The spin is highly polarized.
The method of contacting the gas, liquid or solution with the highly polarized composition is not particularly limited, and for example, these may be injected into the highly polarized composition, or the container may be filled with these. , A container may be placed therein and permeated.
Further, the polarized object may be mixed with the highly polarized composition in a state of being dissolved or dispersed in the liquid. At this time, the highly polarized composition may directly polarize the object to be polarized, or may polarize the object via a liquid.
　一方、第２態様の高偏極化方法では、本発明の組成物に偏極対象物を接触させた後、その組成物を高偏極化させて高偏極化組成物とする工程を含む。接触は、マトリクス材料と偏極源と偏極対象物とを混合して均一化することにより行うことが好ましい。ここでの混合は、例えば、上記の［組成物の製造方法］の欄における（１）または（２）の製造方法において、マトリクス材料および偏極源とともに偏極対象物を水に溶解して混合する方法や、（３）の製造方法において、マトリクス材料の粉末および偏極源の粉末とともに偏極対象物の粉末を混合する方法により行うことができる。
　本発明で用いるマトリクス材料は水溶性であることにより、偏極対象物としての生体関連物質を他の材料と均一に混合することができ、偏極源と偏極対象物がマトリクス中に均一に分散した組成物を作製することができる。そして、この組成物に高偏極化処理を行うことにより、偏極源で生じた電子スピンの偏極が、マトリクス材料や偏極対象物の核スピンに移行し、さらに、マトリクス材料の核スピン偏極が偏極対象物の核スピンに移行して偏極対象物を高偏極化することができる。高偏極化処理については、＜組成物＞の項の動的核偏極処理についての記載を参照することができる。
　組成物に配合する生体関連物質の量は、組成物全量に対して０．１～５０重量％であることが好ましく、ＮＭＲ信号の検出感度が高くなることから１０～４０重量％であることが好ましい。 On the other hand, the highly polarized method of the second aspect includes a step of contacting the composition of the present invention with an object to be polarized and then highly polarization the composition to obtain a highly polarized composition. .. The contact is preferably performed by mixing and homogenizing the matrix material, the polarization source, and the polarization object. The mixing here is, for example, in the production method (1) or (2) in the above-mentioned [Method for producing composition] column, the polarization target is dissolved in water together with the matrix material and the polarization source and mixed. The method can be carried out by the method of mixing the powder of the polarization target together with the powder of the matrix material and the powder of the polarization source in the production method of (3).
Since the matrix material used in the present invention is water-soluble, a bio-related substance as a polarization target can be uniformly mixed with other materials, and the polarization source and the polarization target are uniformly mixed in the matrix. A dispersed composition can be prepared. Then, by performing a high polarization treatment on this composition, the polarization of the electron spin generated at the polarization source is transferred to the nuclear spin of the matrix material or the polarization target object, and further, the nuclear spin of the matrix material is transferred. The polarization can be transferred to the nuclear spin of the polarization object to make the polarization object highly polarized. For the highly polarized treatment, the description of the dynamic nuclear polarization treatment in the <Composition> section can be referred to.
The amount of the biological substance to be blended in the composition is preferably 0.1 to 50% by weight based on the total amount of the composition, and is 10 to 40% by weight because the detection sensitivity of the NMR signal is high. preferable.
　第１態様および第２態様の高偏極化方法において、核スピン偏極の移行は、高偏極化した組成物の１Ｈから偏極対象物の１Ｈへの移行のように、同じ核種同士の間の移行であってもよいし、高偏極化した組成物の１Ｈから偏極対象物の１３Ｃと異なる核種への移行のように、異なる核種同士の間の移行であってもよいし、その両方であってもよい。核スピン偏極を移行させる偏極対象物の核種は、スピン量子数Ｉが０以外のものであれば特に制限なく用いることができる。核種の具体例として、１Ｈ、２Ｈ、３Ｈｅ、１１Ｂ、１３Ｃ、１４Ｎ、１５Ｎ、１７Ｏ、１９Ｆ、２９Ｓｉ、３１Ｐ、１２９Ｘｅ等を挙げることができ、天然存在比が高いことから１Ｈ、１４Ｎ、１９Ｆ、３１Ｐであることが好ましく、ＮＭＲ信号強度が高いことから１Ｈ、１９Ｆであることがより好ましい。
　また、偏極対象物は生体関連物質が好ましいが、これに限るものではなく、ＮＭＲ測定法で解析を行う各種物質を偏極対象とすることができる。本発明の組成物は、マトリクス材料のスピン－格子緩和時間Ｔ１が一定以上に規定されていることにより、それ自体が高偏極化し易く、その核スピン偏極を各種物質に移行させて該物質を高偏極化することができる。
　偏極対象物は、炭化水素、および、少なくとも１つの水素原子が置換基で置換された炭化水素の誘導体から選択される少なくとも１種の化合物を含有することが好ましい。
　炭化水素は、非環系化合物（脂肪族化合物）であっても環系化合物であってもよく、飽和炭化水素であっても不飽和炭化水素であってもよく、低分子化合物であっても高分子化合物であってもよい。環系化合物は、脂環系および芳香族系のいずれであってもよい。炭化水素の炭素数は特に制限されず、通常は１～１０の範囲である。また、炭化水素は、分子内の一部の炭素原子がヘテロ原子で置換されたものであってもよい。ヘテロ原子は特に限定されないが、Ｎ，Ｐ、Ｏ、Ｓ等を挙げることができる。
　炭化水素の誘導体において、置換基は特に限定されないが、置換基の少なくとも１つは、スピン量子数Ｉが０以外である原子を含む置換基であることが好ましく、１３Ｃ、１５Ｎ、１９Ｆ、２９Ｓｉ、３１Ｐ等を含む置換基であることがより好ましく、１３Ｃを含む基やフッ素原子であることがさらに好ましい。
　以下において、偏極対象物の具体例を例示する。ただし、本発明の高偏極化方法に用いうる偏極対象物は、この具体例によって、限定的に解釈されるものではない。 In high polarization poling method of the first aspect and the second aspect, as in the transition nuclear spin polarization may transition the 1 H high polarization poling the composition to 1 H of polarized object, the same nuclide may be a transition between each other, so that the 1 H high polarization poling the composition of 13 transition C into different nuclides polarized object, a transition between different nuclides with each other It may be both or both. The nuclide of the polarization object that shifts the nuclear spin polarization can be used without particular limitation as long as the spin quantum number I is other than 0. Specific examples of nuclides include 1 H, 2 H, 3 He, 11 B, 13 C, 14 N, 15 N, 17 O, 19 F, 29 Si, 31 P, 129 Xe, etc., which are naturally present. Since the ratio is high , it is preferably 1 H, 14 N, 19 F, and 31 P, and because the NMR signal intensity is high, it is more preferably 1 H, 19 F.
Further, the object to be polarized is preferably a biological substance, but the object is not limited to this, and various substances to be analyzed by the NMR measurement method can be the object to be polarized. Since the spin-lattice relaxation time T 1 of the matrix material is defined to be equal to or higher than a certain level, the composition of the present invention tends to be highly polarized by itself, and the nuclear spin polarization is transferred to various substances. The substance can be highly polarized.
The polarization target preferably contains a hydrocarbon and at least one compound selected from a derivative of a hydrocarbon in which at least one hydrogen atom is substituted with a substituent.
The hydrocarbon may be an acyclic compound (aliphatic compound) or a ring compound, may be a saturated hydrocarbon, an unsaturated hydrocarbon, or a low molecular weight compound. It may be a polymer compound. The ring-based compound may be either an alicyclic-based compound or an aromatic-based compound. The number of carbon atoms in the hydrocarbon is not particularly limited, and is usually in the range of 1 to 10. Further, the hydrocarbon may be one in which some carbon atoms in the molecule are replaced with heteroatoms. Heteroatoms are not particularly limited, and examples thereof include N, P, O, and S.
In the hydrocarbon derivative, the substituent is not particularly limited, but at least one of the substituents is preferably a substituent containing an atom having a spin quantum number I other than 0, 13 C, 15 N, 19 F. , 29 Si, 31 P and the like are more preferable, and a group containing 13 C and a fluorine atom are further preferable.
In the following, specific examples of the polarized object will be illustrated. However, the polarized object that can be used in the highly polarized method of the present invention is not limitedly interpreted by this specific example.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　また、偏極対象物として特に好ましいものは生体関連物質である。本明細書中において「生体関連物質」とは、生体を構成する物質および生体を構成する物質の誘導体を意味する。生体を構成する物質として、例えば生体高分子（核酸、タンパク質、多糖）や、これらの構成要素であるヌクレオチド、ヌクレオシド、ペプチド、アミノ酸および糖、並びに、脂質、ビタミン、ホルモン等が挙げられる。偏極対象物とする生体関連物質の具体例として、本明細書の一部としてここに引用するChem.Soc.Rev.,2014,43,1627-1659のFig.2(A)の赤丸部分を１３Ｃラベルした分子を例示することができる。このような分子をプローブとして生体内に導入して本発明を利用してMRI観測を行うことができる。 Further, a particularly preferable object to be polarized is a bio-related substance. As used herein, the term "living body-related substance" means a substance constituting a living body and a derivative of a substance constituting the living body. Examples of substances constituting a living body include biopolymers (nucleic acids, proteins, polysaccharides), nucleotides, nucleosides, peptides, amino acids and sugars, and lipids, vitamins, hormones and the like, which are components thereof. As a specific example of the biological substance to be polarized, the red circle part in Fig. 2 (A) of Chem.Soc.Rev., 2014,43,1627-1659 cited here as a part of this specification is shown. 13 C-labeled molecules can be exemplified. By introducing such a molecule into a living body as a probe and using the present invention, MRI observation can be performed.
＜高偏極化した物質＞
　次に、本発明の高偏極化した物質について説明する。
　本発明の高偏極化した物質は、本発明の高偏極化方法により高偏極化した物質である。本発明の高偏極化方法の説明については、上記の＜高偏極化方法＞の項の記載を参照することができる。高偏極化する対象物質については、上記の＜高偏極化方法＞の項に記載した偏極対象物の説明と好ましい範囲、具体例を参照することができる。
　本発明の高偏極化した物質の偏極率は、１０－４以上であることが好ましく、１０－２以上であることがより好ましく、１０－１以上であることがさらに好ましい。
　物質の偏極率は、高偏極化を実施した場合のＮＭＲ信号強度と実施しなかった場合の信号強度を比較することにより測定することができる。 <Highly polarized substance>
Next, the highly polarized substance of the present invention will be described.
The highly polarized substance of the present invention is a highly polarized substance by the highly polarized method of the present invention. For the description of the highly polarized method of the present invention, the description in the above section <Highly polarized method> can be referred to. For the target substance to be highly polarized, the description of the highly polarized object described in the above section <Highly polarized method>, a preferable range, and a specific example can be referred to.
Polarization rate of the high polarization poled substance of the present invention is preferably 10 -4 or more, more preferably 10 -2 or more, further preferably 10 -1 or more.
The polarization ratio of a substance can be measured by comparing the NMR signal intensity when the high polarization is performed and the signal intensity when the high polarization is not performed.
＜ＮＭＲ測定法＞
　次に、本発明のＮＭＲ測定法について説明する。本発明のＮＭＲ測定法は、本発明の組成物を用いて物質のＮＭＲ（核磁気共鳴）を測定する工程を含むものである。また、本発明のＮＭＲ測定法は、ＭＲＩ法も含む概念である。
　本発明の組成物の説明と好ましい範囲、具体例については、上記の＜組成物＞の項を参照することができる。
　本発明のＮＭＲ測定法は、本発明の組成物に動的核偏極を行って得た高偏極化組成物にＮＭＲの測定対象物を接触させて、該測定対象物の核スピンを高偏極化した後、公知のＮＭＲ信号の検出方法を用いて測定対象物のＮＭＲを観測することにより行うことができる。あるいは、ＮＭＲの測定対象物を本発明の組成物に導入した後、動的核偏極を行って該測定対象物の核スピンを高偏極化した後、公知のＮＭＲ信号の検出方法を用いて測定対象物のＮＭＲを観測することにより行うことができる。なお、ＮＭＲで観測したい核種が１３Ｃや１９Ｆである場合は、高偏極化した１Ｈから１３Ｃや１９Ｆへ更に偏極を移してからＮＭＲを観測する。
　ＮＭＲの測定対象物を本発明の組成物に導入する方法および高偏極化の各工程については、上記の＜高偏極化方法＞および＜組成物＞の項の記載を参照することができる。
　ＮＭＲ信号の検出は、連続波法、パルスフーリエ変換法等の公知の方法を用いて行うことができ、例えばパルスフーリエ変換法によるＮＭＲ信号の検出には、ＲＦコイル（プローブ）、増幅器等を備えた装置を用いることができる。
　本発明では、本発明の組成物を用いて、測定対象物の核スピンを高偏極化するため、測定対象物からのＮＭＲ信号を高い強度で検出することができる。そのため、このＮＭＲ測定法を応用することにより、ＮＭＲ分光法による化合物の構造や物性の解析、ＭＲＩによる生体器官の検査を感度よく行うことができる。 <NMR measurement method>
Next, the NMR measurement method of the present invention will be described. The NMR measurement method of the present invention includes a step of measuring NMR (nuclear magnetic resonance) of a substance using the composition of the present invention. Further, the NMR measurement method of the present invention is a concept including the MRI method.
For a description of the composition of the present invention, a preferable range, and specific examples, the above section <Composition> can be referred to.
In the NMR measurement method of the present invention, an object to be measured by NMR is brought into contact with a highly polarized composition obtained by performing dynamic nuclear polarization on the composition of the present invention to increase the nuclear spin of the object to be measured. After polarization, it can be performed by observing the NMR of the measurement target using a known NMR signal detection method. Alternatively, after introducing the NMR measurement object into the composition of the present invention, dynamic nuclear polarization is performed to highly polarize the nuclear spin of the measurement object, and then a known NMR signal detection method is used. This can be done by observing the NMR of the object to be measured. If the nuclide to be observed by NMR is 13 C or 19 F, the polarization is further transferred from the highly polarized 1 H to 13 C or 19 F before observing NMR.
For the method of introducing the object to be measured by NMR into the composition of the present invention and each step of high polarization, the above description of <Highly polarized method> and <Composition> can be referred to. ..
The NMR signal can be detected by using a known method such as a continuous wave method or a pulse Fourier transform method. For example, an RF coil (probe), an amplifier or the like is provided for detecting an NMR signal by the pulse Fourier transform method. Equipment can be used.
In the present invention, since the nuclear spin of the object to be measured is highly polarized by using the composition of the present invention, the NMR signal from the object to be measured can be detected with high intensity. Therefore, by applying this NMR measurement method, it is possible to analyze the structure and physical properties of a compound by NMR spectroscopy and to inspect living organs by MRI with high sensitivity.
　以下に実施例を挙げて本発明の特徴をさらに具体的に説明する。以下に示す材料、処理内容、処理手順等は、本発明の趣旨を逸脱しない限り適宜変更することができる。したがって、本発明の範囲は以下に示す具体例により限定的に解釈されるべきものではない。なお、光吸収スペクトルの測定は、分光光度計（日本分光社製：Ｖ－６７０、Ｖ－７７０）を用いて行い、発光スペクトルの測定は、分光蛍光光度計（日本分光社製：ＦＰ－８７００）、ＮＭＲ信号の測定は、ＮＭＲ装置（日本電子社製：ＪＮＭ－ＥＣＡ４００）を用いて行った。時間分解ＥＳＲスペクトルの測定および動的核偏極は、５４５ｎｍのパルスレーザー、電磁石、マイクロ波発生器（アナログデバイセズ社製：ＨＭＣ－Ｔ２２２０）、ＥＳＲ検出器を組み合わせて行った。
　本実施例で偏極源に用いた化合物は以下のようにして合成した。 The features of the present invention will be described in more detail with reference to Examples below. The materials, treatment contents, treatment procedures, etc. shown below can be appropriately changed as long as they do not deviate from the gist of the present invention. Therefore, the scope of the present invention should not be construed as limited by the specific examples shown below. The light absorption spectrum is measured using a spectrophotometer (manufactured by JASCO Corporation: V-670, V-770), and the emission spectrum is measured using a spectrofluorescent photometer (manufactured by JASCO Corporation: FP-8700). ), The NMR signal was measured using an NMR apparatus (manufactured by JASCO Corporation: JNM-ECA400). The measurement of the time-resolved ESR spectrum and the dynamic nuclear polarization were performed by combining a 545 nm pulse laser, an electromagnet, a microwave generator (manufactured by Analog Devices, Inc .: HMC-T2220), and an ESR detector.
The compound used as the polarization source in this example was synthesized as follows.
（合成例１）　化合物４の合成
Figure JPOXMLDOC01-appb-C000023
 (Synthesis Example 1) Synthesis of Compound 4
Figure JPOXMLDOC01-appb-C000023
　ピロール（３４０μＬ、４．０４ｍｍｏｌ）と２，６－ジフルオロベンズアルデヒド（５５０ｍｇ、３．８７ｍｍｏｌ）を、窒素雰囲気下でジクロロメタン（８０ｍＬ）に溶解させ、三フッ化ほう素ジエチルエーテル錯体（６０μＬ、０．４７６ｍｍｏｌ））を加えて室温で１日撹拌した。この反応液に、ｐ－クロラニル（３９０ｍｇ、１．５９ｍｍｏｌ）を加え、室温で１８時間撹拌した。生成した反応生成物をメタノールで洗浄した後、ヘキサン：クロロホルム＝２０：８０（容量比）の混合溶媒を溶離液に用いてシリカゲルカラムクロマトグラフィーにて精製することにより、目的の化合物４を収率１３％で得た。
1H NMR (400 MHz, CDCl3, TMS): δ = 7.35-7.40 (t, 8H), 7.75-7.83 (quin, 4H), 8.86 (s, 8H), -2.77 (s, 2H). 19F NMR (376 MHz, CDCl3) δ = -108.08 (s, 8F). Pyrrole (340 μL, 4.04 mmol) and 2,6-difluorobenzaldehyde (550 mg, 3.87 mmol) were dissolved in dichloromethane (80 mL) under a nitrogen atmosphere and the boron trifluoride diethyl ether complex (60 μL, 0.476 mmol) was dissolved. )) Was added, and the mixture was stirred at room temperature for 1 day. To this reaction solution, p-chloranil (390 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After washing the produced reaction product with methanol, the desired compound 4 was obtained by purification by silica gel column chromatography using a mixed solvent of hexane: chloroform = 20: 80 (volume ratio) as an eluent. Obtained at 13%.
1 H NMR (400 MHz, CDCl3, TMS): δ = 7.35-7.40 (t, 8H), 7.75-7.83 (quin, 4H), 8.86 (s, 8H), -2.77 (s, 2H). 19 F NMR (376 MHz, CDCl3) δ = -108.08 (s, 8F).
（合成例２）　化合物７の合成
Figure JPOXMLDOC01-appb-C000024
 (Synthesis Example 2) Synthesis of Compound 7
Figure JPOXMLDOC01-appb-C000024
　化合物４（５０ｍｇ）をクロロホルム（１０ｍＬ）に溶解させ、メタノールの酢酸亜鉛飽和溶液を数滴添加した後、７時間加熱還流した。生成した反応生成物を水で洗浄し、無水硫酸ナトリウムで乾燥させた。この粗生成物を、クロロホルムを溶離液に用いてシリカゲルカラムクロマトグラフィーにて精製することにより、目的の化合物７を収率５４％で得た。
1H NMR (400 MHz, CDCl3, TMS): δ = 7.36-7.41 (t, 8H), 7.76-7.84 (quin, 4H), 8.97 (s, 8H). 19F NMR (376 MHz, CDCl3) δ = -108.40 (s, 8F). Compound 4 (50 mg) was dissolved in chloroform (10 mL), a few drops of a saturated solution of methanol in zinc acetate were added, and the mixture was heated under reflux for 7 hours. The resulting reaction product was washed with water and dried over anhydrous sodium sulfate. This crude product was purified by silica gel column chromatography using chloroform as an eluent to obtain the desired compound 7 in a yield of 54%.
1 H NMR (400 MHz, CDCl 3 , TMS): δ = 7.36-7.41 (t, 8H), 7.76-7.84 (quin, 4H), 8.97 (s, 8H). 19 F NMR (376 MHz, CDCl 3 ) δ = -108.40 (s, 8F).
（合成例３）　化合物８の合成
Figure JPOXMLDOC01-appb-C000025
 (Synthesis Example 3) Synthesis of Compound 8
Figure JPOXMLDOC01-appb-C000025
　市販のテトラキス（ペンタフルオロフェニル）ポルフィリン（東京化成工業社製、化合物５）（５０ｍｇ）をクロロホルム（１０ｍＬ）に溶解させ、メタノールの酢酸亜鉛飽和溶液を数滴添加した後、１２時間加熱還流した。生成した反応生成物を水で洗浄し、無水硫酸ナトリウムで乾燥させた。この粗生成物を、クロロホルム：ヘキサン＝２：１（容量比）の混合溶媒を溶離液に用いてシリカゲルカラムクロマトグラフィーにて精製することにより、目的の化合物８を収率８４％で得た。
1H NMR (400 MHz, CDCl3, TMS): δ = 9.00 (s, 8H). 19F NMR (376 MHz, CDCl3) δ = -136.63-136.70 (d, 8F), -151.66-151.72 (d, 4F), -161.48-161.70 (t, 8F). Commercially available tetrakis (pentafluorophenyl) porphyrin (manufactured by Tokyo Chemical Industry Co., Ltd., compound 5) (50 mg) was dissolved in chloroform (10 mL), several drops of a saturated solution of methanol in zinc acetate were added, and the mixture was heated under reflux for 12 hours. The resulting reaction product was washed with water and dried over anhydrous sodium sulfate. This crude product was purified by silica gel column chromatography using a mixed solvent of chloroform: hexane = 2: 1 (volume ratio) as an eluent to obtain the desired compound 8 in a yield of 84%.
1 1 H NMR (400 MHz, CDCl 3 , TMS): δ = 9.00 (s, 8H). 19 F NMR (376 MHz, CDCl 3 ) δ = -136.63-136.70 (d, 8F), -151.66-151.72 (d) , 4F), -161.48-161.70 (t, 8F).
　各実施例で用いた偏極源およびマトリクス材料を以下に示す。マトリクス材料のスピン－格子緩和時間Ｔ１は飽和回復法により測定した。具体的には、各マトリクス材料を融解後急冷することにより固体の測定試料を作製し、ＥＣＺ４００Ｓを用い、室温下、３０ＭＨｚのパルス周波数でスピン－格子緩和時間Ｔ１を測定した。
　また、各実施例での偏極源の割合を示す「ｍｏｌ％」は、マトリクス材料のモル数に対するモル百分率である。 The polarization source and matrix material used in each example are shown below. Spin matrix material - lattice relaxation time T 1 was measured by saturation recovery method. Specifically, each matrix material to produce a solid sample to be measured by quenching after melting, using ECZ400S, spin at room temperature, 30 MHz pulse frequency - was measured lattice relaxation time T 1.
Further, "mol%" indicating the ratio of the polarization source in each example is a molar percentage with respect to the number of moles of the matrix material.
偏極源Polarization source
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
マトリクス材料
　エリトリトール、ソルビトール、フルクトース、ウレア、グルコース、マルトースのスピン－格子緩和時間Ｔ１は、図１に示す通りである。その他のマトリクス材料のスピン－格子緩和時間Ｔ１は、β－エストラジオールで３秒、安息香酸で８０秒、カルバマゼピンで１４秒である。下記構造式においてＤは重水素を表す。
Figure JPOXMLDOC01-appb-C000028
 Matrix material erythritol, sorbitol, fructose, urea, glucose, maltose spin - lattice relaxation time T 1 is as shown in FIG. Other matrix materials spin - lattice relaxation time T 1 is 3 seconds β- estradiol, 80 seconds benzoic acid, 14 seconds carbamazepine. In the following structural formula, D represents deuterium.
Figure JPOXMLDOC01-appb-C000028
(実施例１)　偏極源として化合物１を用い、マトリクス材料としてエリトリトールを用いた組成物１の作製
　エリトリトール（１ｍＭ）と化合物１（０．０５ｍｏｌ％）の水溶液を調製し、この水溶液（１ｍＬ）を７０℃で１時間加熱乾燥した。得られた粉末を油浴で１２１℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物１を得た。 (Example 1) Preparation of composition 1 using compound 1 as a polarization source and erythritol as a matrix material An aqueous solution of erythritol (1 mM) and compound 1 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was heated and dried at 70 ° C. for 1 hour. The obtained powder was heated to 121 ° C. in an oil bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 1.
（実施例２）　偏極源として化合物９を用い、マトリクス材料としてエリトリトールを用いた組成物２の作製
　化合物１の代わりに化合物９を用いること以外は、実施例１と同様にして固体の組成物２を作製した。 (Example 2) Preparation of composition 2 using compound 9 as a polarization source and erythritol as a matrix material A solid composition in the same manner as in Example 1 except that compound 9 is used instead of compound 1. 2 was prepared.
（実施例３）　偏極源として化合物１を用い、マトリクス材料としてウレアを用いた組成物３の作製
　ウレア（１ｍＭ）と化合物１（０．０５ｍｏｌ％）の水溶液を調製し、この水溶液（１ｍＬ）を７０℃で１時間加熱乾燥した。得られた粉末を油浴で１２１℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物３を得た。 (Example 3) Preparation of composition 3 using compound 1 as a polarization source and urea as a matrix material An aqueous solution of urea (1 mM) and compound 1 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was dried by heating at 70 ° C. for 1 hour. The obtained powder was heated to 121 ° C. in an oil bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 3.
（実施例４）　偏極源として化合物１を用い、マトリクス材料としてソルビトールを用いた組成物４の作製
　ソルビトール（２．５ｍｍｏｌ）と化合物１（１．２５×１０－３ｍｍｏｌ）の各粉末をそれぞれ量りとってグラインドし、混合粉末を調製した。この混合粉末を湯浴で９５℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物４を得た。 (Example 4) Preparation of composition 4 using compound 1 as a polarization source and sorbitol as a matrix material Each powder of sorbitol (2.5 mmol) and compound 1 (1.25 × 10 -3 mmol) is prepared. Weighed and ground to prepare a mixed powder. This mixed powder was heated to 95 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 4.
（実施例５、６）　偏極源として化合物９または化合物１０を用い、マトリクス材料としてソルビトールを用いた組成物５、６の作製
　化合物１の代わりに、化合物９または化合物１０を用いること以外は、実施例４と同様にして固体の組成物５、６を作製した。 (Examples 5 and 6) Preparation of compositions 5 and 6 using compound 9 or compound 10 as a polarization source and sorbitol as a matrix material, except that compound 9 or compound 10 is used instead of compound 1. Solid compositions 5 and 6 were prepared in the same manner as in Example 4.
（実施例７）　偏極源として化合物１０を用い、マトリクス材料としてソルビトールを用いた組成物７の作製
　ソルビトール（１ｍＭ）と化合物１０（０．０５ｍｏｌ％）の水溶液を調製し、この水溶液（１ｍＬ）を７０℃で１時間加熱乾燥した。得られた粉末をデシケーター内で１日静置することにより固体の組成物７を得た。 (Example 7) Preparation of composition 7 using compound 10 as a polarization source and sorbitol as a matrix material An aqueous solution of sorbitol (1 mM) and compound 10 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was heated and dried at 70 ° C. for 1 hour. The obtained powder was allowed to stand in a desiccator for 1 day to obtain a solid composition 7.
（実施例８）　偏極源として化合物１を用い、マトリクス材料としてフルクトースを用いた組成物９の作製
　フルクトース（２．５ｍｍｏｌ）と化合物１（１．２５×１０－３ｍｍｏｌ）の各粉末を量りとってグラインドし、混合粉末を得た。この混合粉末を湯浴で９５℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物８を得た。 (Example 8) Preparation of composition 9 using compound 1 as a polarization source and fructose as a matrix material Weigh each powder of fructose (2.5 mmol) and compound 1 (1.25 × 10 -3 mmol). Grinded to obtain a mixed powder. This mixed powder was heated to 95 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 8.
（実施例９）　偏極源として化合物９を用い、マトリクス材料としてフルクトースを用いた組成物９の作製
　フルクトース（２．５ｍｍｏｌ）と化合物９（１．２５×１０－３ｍｍｏｌ）の各粉末を量りとってグラインドし、混合粉末を調製した。この混合粉末を湯浴で１０３℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物９を得た。 (Example 9) Preparation of composition 9 using compound 9 as a polarization source and fructose as a matrix material Weigh each powder of fructose (2.5 mmol) and compound 9 (1.25 × 10 -3 mmol). Grinded to prepare a mixed powder. This mixed powder was heated to 103 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 9.
（実施例１０）　偏極源として化合物１を用い、マトリクス材料としてグルコースを用いた組成物１０の作製
　グルコース（２．５ｍｍｏｌ）と化合物１（１．２５×１０－３ｍｍｏｌ）の各粉末を量りとってグラインドし、混合粉末を調製した。この混合粉末を湯浴で１４６℃に加熱して融解し、液体窒素を用いて急冷することにより固体の組成物１０を得た。 (Example 10) Preparation of composition 10 using compound 1 as a polarization source and glucose as a matrix material Weigh each powder of glucose (2.5 mmol) and compound 1 (1.25 × 10 -3 mmol). It was ground and a mixed powder was prepared. This mixed powder was heated to 146 ° C. in a hot water bath to melt it, and rapidly cooled with liquid nitrogen to obtain a solid composition 10.
（実施例１１）　偏極源として化合物１０を用い、マトリクス材料としてグルコースを用いた組成物１１の作製
　グルコース（１ｍＭ）と化合物１０（０．０５ｍｏｌ％）の水溶液を調製し、この水溶液（１ｍＬ）を７０℃で１時間加熱乾燥した。得られた粉末をデシケーター内で１日静置することにより固体の組成物１１を得た。 (Example 11) Preparation of composition 11 using compound 10 as a polarization source and glucose as a matrix material An aqueous solution of glucose (1 mM) and compound 10 (0.05 mol%) was prepared, and this aqueous solution (1 mL) was prepared. Was heated and dried at 70 ° C. for 1 hour. The obtained powder was allowed to stand in a desiccator for 1 day to obtain a solid composition 11.
（実施例１２）　偏極源として化合物４を用い、マトリクス材料としてβ-エストラジオールを用いた組成物１２の作製
　化合物４（０．１ｍｏｌ％）とβ－エストラジオール（２００ｍｇ，０．７３ｍｍｏｌ）を混合し、４００℃で加熱することにより、化合物４が分散したβ－エストラジオールの融液を得た。この融液を液体窒素により急冷してβ－エストラジオールをガラス化させた後、このガラスを砕いてキャピラリー内に入れ、再度４００℃で加熱して融解させた。この融液を液体窒素により急冷してガラス化させることにより組成物１２を得た。 (Example 12) Preparation of composition 12 using compound 4 as a polarization source and β-estradiol as a matrix material Compound 4 (0.1 mol%) and β-estradiol (200 mg, 0.73 mmol) were mixed. , A melt of β-estradiol in which compound 4 was dispersed was obtained by heating at 400 ° C. The melt was rapidly cooled with liquid nitrogen to vitrify β-estradiol, and then the glass was crushed and placed in a capillary and heated again at 400 ° C. to melt it. The composition 12 was obtained by quenching the melt with liquid nitrogen and vitrifying it.
（実施例１３、１４）　偏極源として化合物７または化合物８を用い、マトリクス材料としてβ-エストラジオールを用いた組成物１３、１４の作製
　化合物４の代わりに、化合物７または化合物８を用いること以外は、実施例１２と同様にして組成物１３、１４を得た。 (Examples 13 and 14) Preparation of compositions 13 and 14 using compound 7 or compound 8 as a polarization source and β-estradiol as a matrix material Other than using compound 7 or compound 8 instead of compound 4. Obtained compositions 13 and 14 in the same manner as in Example 12.
（実施例１５～２１）　偏極源として化合物１を用い、マトリクス材料としてエリトリトール、キシリトール、ソルビトール、グルコース、フルクトース、マルトース、またはエリトリトールの重水素置換体を用いた組成物１５～２１の作製
　ここでは、組成物１５～２１をメルトクエンチ法にて作製した。
　具体的には、融点～（融点＋１０）℃の温度に加熱して融解した各マトリックス材料に、０．０１ｍｏｌ％の化合物１を溶解させた後、液体窒素で室温まで急冷することにより組成物を得た。このとき、エリトリトールまたはキシリトールをマトリクス材料に用いた組成物は室温で素早く再結晶化し、マルトースをマトリクス材料に用いた組成物は室温で非晶質固体を形成した。ソルビトール、グルコースまたはフルクトースをマトリクス材料に用いた組成物は室温では融解したままであったが、冷却することにより固体になった（１００Ｋでは固体）。 (Examples 15 to 21) Preparation of compositions 15 to 21 using compound 1 as a polarization source and deuterium substitution products of erythritol, xylitol, sorbitol, glucose, fructose, maltose, or erythritol as a matrix material. , Compositions 15 to 21 were prepared by the melt quench method.
Specifically, the composition is prepared by dissolving 0.01 mol% of Compound 1 in each matrix material melted by heating to a temperature of melting point to (melting point +10) ° C., and then rapidly cooling to room temperature with liquid nitrogen. Obtained. At this time, the composition using erythritol or xylitol as the matrix material was rapidly recrystallized at room temperature, and the composition using maltose as the matrix material formed an amorphous solid at room temperature. Compositions using sorbitol, glucose or fructose as the matrix material remained melted at room temperature but became solid upon cooling (solid at 100 K).
（実施例２２、２３）　偏極源として化合物２を用い、マトリクス材料として安息香酸またはカルバマゼピンを用いた組成物２２、２３の作製
　化合物１の代わりに化合物２を用い、エリトリトールの代わりに安息香酸またはカルバマゼピンを用いること以外は、実施例１５と同様にして組成物２２、２３を作製した。 (Examples 22 and 23) Preparation of compositions 22 and 23 using compound 2 as a polarization source and benzoic acid or carbamazepine as a matrix material Compound 2 is used instead of compound 1 and benzoic acid or benzoic acid is used instead of erythritol. The compositions 22 and 23 were prepared in the same manner as in Example 15 except that carbamazepine was used.
（実施例２４～２９）　偏極源として化合物３～８を用い、マトリクス材料としてβ－エストラジオールを用いた組成物２４～２９の作製
　化合物１の代わりに化合物３～８のいずれかを０．１ｍｏｌ％の割合で用い、エリトリトールの代わりにβ－エストラジオールを用いること以外は、実施例１５と同様にして組成物２４～２９を作製した。
　実施例１５～２９で使用した偏極源とマトリクス材料を表１にまとめて示す。 (Examples 24 to 29) Preparation of compositions 24 to 29 using compounds 3 to 8 as a polarization source and β-estradiol as a matrix material 0.1 mol of any of compounds 3 to 8 instead of compound 1. Compositions 24-29 were prepared in the same manner as in Example 15 except that β-estradiol was used instead of erythritol.
Table 1 summarizes the polarization sources and matrix materials used in Examples 15 to 29.
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
［評価１］組成物１の分散性の評価
　組成物１、およびエリトリトールを融解後急冷することにより得た固体（エリトリトール単独固体）の粉末Ｘ線回折パターンを図３に示す。図３に示すように、組成物１の回折パターンは、エリトリトールの回折パターンとよく一致していた。このことから、組成物１は、エリトリトールの結晶性をほぼ保持しており、エリトリトール結晶中に化合物１が分散して存在していることがわかった。 [Evaluation 1] Evaluation of Dispersibility of Composition 1 The powder X-ray diffraction pattern of the composition 1 and the solid (erythritol alone solid) obtained by melting and quenching erythritol is shown in FIG. As shown in FIG. 3, the diffraction pattern of composition 1 was in good agreement with the diffraction pattern of erythritol. From this, it was found that the composition 1 substantially retained the crystallinity of erythritol, and the compound 1 was dispersed and present in the erythritol crystal.
［評価２］組成物１５～２０、２２、２３の分散性の評価
　組成物１５～２０の光吸収スペクトルを図４に示し、５３２ｎｍ励起光による蛍光スペクトルを図５に示す。組成物２２、２３の光吸収スペクトルを図６に示し、５３２ｎｍ励起光による蛍光スペクトルを図７に示す。また、参考のため、図４、５には、化合物１の１０μＭ水溶液と単独固体のスペクトルを併せて示し、図６、７には、化合物２の１０μＭＤＭＳＯ（ジメチルスルホキシド）溶液と単独固体のスペクトルを併せて示す。
　まず、図４および図５において、化合物１の水溶液と固体のスペクトルを見ると、水溶液では５１７ｎｍに吸収ピークが認められ、６４７ｎｍに発光ピークが認められるが、固体のスペクトルでは、その吸収ピークおよび発光ピークが長波長側にシフトしてブロードな形状をなしていることがわかる。また、図６および図７に示すＤＭＳＯ溶液と固体のスペクトルを比較しても、同様の傾向が認められる。固体で見られるピークの長波長シフトは、偏極源の分子が凝集して分子間相互作用が大きくなることによるものと考えられる。一方、化合物１をマトリクス材料中に分散させた組成物１５～２０、および、化合物２をマトリクス材料中に分散させた組成物２２、２３では、水溶液とほぼ同一のスペクトル形状が観測されるか、固体に比べて、ピークの長波長シフトが抑えられていた。このことから、各マトリクス材料中に化合物１、２が分散して存在していることを確認することができた。 [Evaluation 2] Evaluation of Dispersibility of Compositions 15 to 20, 22 and 23 The light absorption spectrum of the compositions 15 to 20 is shown in FIG. 4, and the fluorescence spectrum by 532 nm excitation light is shown in FIG. The light absorption spectra of the compositions 22 and 23 are shown in FIG. 6, and the fluorescence spectra of the 532 nm excitation light are shown in FIG. For reference, FIGS. 4 and 5 show the spectra of the 10 μM aqueous solution of Compound 1 and the single solid, and FIGS. 6 and 7 show the spectra of the 10 μM DMSO (dimethyl sulfoxide) solution of Compound 2 and the single solid. Also shown.
First, looking at the spectra of the aqueous solution and the solid of Compound 1 in FIGS. 4 and 5, an absorption peak is observed at 517 nm and an emission peak is observed at 647 nm in the aqueous solution, but the absorption peak and emission are observed in the solid spectrum. It can be seen that the peak shifts to the long wavelength side and forms a broad shape. Further, when the spectra of the DMSO solution and the solid shown in FIGS. 6 and 7 are compared, the same tendency is observed. The long wavelength shift of the peak seen in solids is considered to be due to the aggregation of the molecules of the polarization source and the increase of intermolecular interaction. On the other hand, in the compositions 15 to 20 in which the compound 1 is dispersed in the matrix material and the compositions 22 and 23 in which the compound 2 is dispersed in the matrix material, almost the same spectral shape as that of the aqueous solution is observed. Compared with the solid, the long wavelength shift of the peak was suppressed. From this, it was confirmed that compounds 1 and 2 were dispersed and present in each matrix material.
［評価３］組成物１５～２０、２２、２３の三重項電子のスピン偏極の評価
　組成物１５～２０、２２、２３に、室温で５３２ｎｍパルス励起光（１０Ｈｚ、８ナノ秒、１２ｍＪ／パルス）を照射して偏極源を励起三重項状態とし、その直後に、時間分解ＥＳＲ（電子スピン共鳴）測定を行った。時間分解ＥＳＲ測定では、マイクロ波（９ＧＨｚ、１０μＷ）を照射しながら静磁場掃引を行い、ゼーマン副準位間での電子スピン遷移に由来するマイクロ波吸収およびマイクロ波放出を観測した。すなわち、図８に示すように、励起三重項状態に遷移した分子に静磁場を印加すると、その三重項電子スピンが磁気量子数ｍ＝－１、０、＋１のそれぞれに相当するゼーマン準位に***する。このとき、電子スピン占有数が、ｍ＝０のゼーマン準位で他のゼーマン準位よりも大きい場合には、電子スピン共鳴により、特定の磁場強度でＴ１,０→T１,－１遷移（ｍ＝０からｍ＝－１への遷移）が起きてマイクロ波が放出され、また、他の特定の磁場強度でＴ１，０→T１，＋１遷移（ｍ＝０からｍ＝＋１への遷移）が起きてマイクロ波が吸収される。したがって、このマイクロ波放出およびマイクロ波吸収を観測することにより、その三重項電子スピンの偏極状態を把握することができる。
　この時間分解ＥＳＲ測定で観測された組成物１５～２０、２２、２３のＥＳＲスペクトルを図９に示し、特定の磁場強度で観測されたＥＳＲシグナルの減衰曲線を図１０に示す。図９中、「→Ｅ」の方向に立ち下がるピークはマイクロ波吸収を表し、「→Ａ」の方向に立ち上がるピークはマイクロ波の放出を表す。図９には、Easyspin toolbox（MATLAB）（登録商標）の計算により求めたＥＳＲスペクトルのシミュレーション曲線sim（滑らかな曲線）を併せて示す。図１０に用いたＥＳＲシグナルの観測磁場強度は、組成物１５～１７で３２７ｍＴ、組成物１８で３２６ｍＴ、組成物１９で３３０ｍＴ、組成物２０で３２８ｍＴ、組成物２２で３２７ｍＴ、組成物２３で３２９ｍＴである。また、図１０には、減衰曲線の単一指数フィッティング曲線を併せて示す。
　図９に示すように、組成物１５～２０、２２、２３のＥＳＲスペクトルには、いずれも発光ピークと吸収ピークが認められ三重項電子スピンに特徴的なスペクトル形状を示した。このことから、化合物１、２は各マトリクス中で励起三重項状態に遷移し、電子スピン偏極状態をとりうることを確認することができた。 [Evaluation 3] Evaluation of Spin Polarization of Triplet Electrons of Compositions 15-20, 22, 23 To compositions 15-20, 22, 23, 532 nm pulse excitation light (10 Hz, 8 nanoseconds, 12 mJ / pulse) at room temperature. ) Was irradiated to bring the polarization source into an excited triplet state, and immediately after that, time-resolved ESR (electron spin resonance) measurement was performed. In the time-resolved ESR measurement, a static magnetic field sweep was performed while irradiating microwaves (9 GHz, 10 μW), and microwave absorption and microwave emission derived from electron spin transitions between Zeeman sublevels were observed. That is, as shown in FIG. 8, when a static magnetic field is applied to a molecule that has transitioned to an excited triplet state, the triplet electron spin becomes a Zeeman level corresponding to each of the magnetic quantum numbers m = -1, 0, and +1. Divide. At this time, when the number of electron spins occupied is larger than other Zeeman levels at the Zeeman level of m = 0, the transition from T 1 , 0 to T 1 , -1 at a specific magnetic field strength is caused by electron spin resonance. (Transition from m = 0 to m = -1) occurs and microwaves are emitted, and T 1 , 0 → T 1 , +1 transition (from m = 0 to m = + 1) at other specific magnetic field strengths. Transition) occurs and the microwave is absorbed. Therefore, by observing the microwave emission and microwave absorption, the polarization state of the triplet electron spin can be grasped.
The ESR spectra of the compositions 15 to 20, 22, and 23 observed by this time-resolved ESR measurement are shown in FIG. 9, and the decay curve of the ESR signal observed at a specific magnetic field strength is shown in FIG. In FIG. 9, a peak falling in the direction of “→ E” represents microwave absorption, and a peak rising in the direction of “→ A” represents microwave emission. FIG. 9 also shows a simulation curve sim (smooth curve) of the ESR spectrum obtained by calculation of the Easyspin toolbox (MATLAB) (registered trademark). The observed magnetic field strengths of the ESR signals used in FIG. 10 were 327 mT for compositions 15 to 17, 326 mT for composition 18, 330 mT for composition 19, 328 mT for composition 20, 327 mT for composition 22, and 329 mT for composition 23. Is. In addition, FIG. 10 also shows a single exponential fitting curve of the attenuation curve.
As shown in FIG. 9, in the ESR spectra of the compositions 15 to 20, 22 and 23, emission peaks and absorption peaks were observed, and the spectral shapes characteristic of triplet electron spins were shown. From this, it was confirmed that compounds 1 and 2 can transition to the excited triplet state in each matrix and take an electron spin polarization state.
［評価４］組成物２１の動的核偏極の評価
　組成物２１について、偏極源（化合物１）からマトリクス材料（エリトリトール重水素置換体）への動的核偏極を評価した。動的核偏極処理のプロセスを図１１に示す。具体的には、組成物２１に、１００Ｋで５４５ｎｍパルス励起光（１ｋＨｚ）を照射して偏極源を励起三重項状態とした後、外部磁場を０．６５Ｔ付近で掃引しながらマイクロ波（１７．７ＧＨｚ）を１３μｓ照射するという動的核偏極処理を繰り返し行い、この間に、一定時間毎に１Ｈ ＮＭＲ信号を測定した。図１２に示すように、外部磁場により三重項電子スピンが偏極状態になった組成物にマイクロ波を照射すると、積分型固体効果により、ｍ＝０のゼーマン準位にある電子スピンがｍ＝－１に遷移すると同時に、マトリクス（エリトリトール重水素置換体）において、ｍ＝－１／２のゼーマン準位にある１Ｈ核スピンがｍ＝＋１／２に遷移して、三重項電子スピンの偏極が１Ｈ核スピンに移行し、１Ｈ ＮＭＲ信号が強くなる。よって、この１Ｈ ＮＭＲ信号の増強度から組成物の動的核偏極能を評価することができる。
　組成物２１について動的核偏極処理を１００Ｋで１５分間繰り返した後の１Ｈ ＮＭＲ信号と、１５分間の待ち時間の後１００Ｋで１６回積算した後（熱平衡状態）の１Ｈ ＮＭＲ信号を図１３に示す。また、動的核偏極処理を繰り返す過程で測定した１Ｈ ＮＭＲ信号（信号電圧）を積算1回分の熱平衡状態で測定した１Ｈ ＮＭＲ信号で除すことでエンハンスメントファクターεを求め、処理時間を横軸にしてプロットした結果（１Ｈスピン偏極のビルドアップ曲線）を図１４に示す。
　図１３の黒線で示された１Ｈ ＮＭＲ信号は、エリトリトール重水素置換体の熱平衡状態で観測された１Ｈスピンに基づく微弱な信号である。したがって、１００Ｋの動的核偏極処理後に観測された強い１Ｈ ＮＭＲ信号は、化合物１からエリトリトール重水素置換体に移行したスピン偏極に由来するものである。
　図１４に示すように、組成物２１の１Ｈ ＮＭＲ信号強度は動的核偏極処理の繰り返しにより顕著に増強し、１５分後には１２０倍以上の信号強度を示した。このことから、組成物２１は、その化合物１の三重項電子スピンの偏極をエリトリトール核スピンへ効率よく移行させることが可能であり、高偏極化組成物や動的核偏極用組成物として有用であることがわかった。また、この結果は、天然生体分子であるエリトリトールに三重項電子スピンの偏極が移行できることを確認できた点で意義が大きい。 [Evaluation 4] Evaluation of Dynamic Nuclear Polarization of Composition 21 The dynamic nuclear polarization of the composition 21 from the polarization source (Compound 1) to the matrix material (erythritol deuterium substituent) was evaluated. The process of dynamic nuclear polarization processing is shown in FIG. Specifically, the composition 21 is irradiated with 545 nm pulse excitation light (1 kHz) at 100 K to bring the polarization source into an excited triplet state, and then a microwave (17) is swept while sweeping an external magnetic field at around 0.65 T. The dynamic nuclear polarization treatment of irradiating with .7 GHz) for 13 μs was repeated, and during this period, 1 H NMR signal was measured at regular intervals. As shown in FIG. 12, when a composition in which triplet electron spins are polarized by an external magnetic field is irradiated with microwaves, the electron spins at the Zeeman level of m = 0 are m = due to the integral solid-state effect. at the same time a transition to -1, the matrix (erythritol deuterium substitutions), m = -1 / 2 of the 1 H nuclear spins in the Zeeman levels transits the m = + 1/2, the triplet electron spin polarized pole moves to 1 H nuclear spin, 1 H NMR signal becomes stronger. Therefore, the dynamic nuclear polarization ability of the composition can be evaluated from the increased intensity of this 1 H NMR signal.
1 H NMR signals and after repeating 15 minutes at 100K dynamic nuclear polarization process for compositions 21, figure 1 H NMR signal after integration 16 times 100K after a 15 minute waiting time (thermal equilibrium) It is shown in 13. Also, determine the enhancement factor ε by dividing the 1 H NMR signal measured by integrating batch of thermal equilibrium state 1 H NMR signal measured (signal voltage) in the course of repeating the dynamic nuclear polarization process, the processing time FIG. 14 shows the results (1 H spin polarization build-up curve) plotted on the horizontal axis.
The 1 H NMR signal shown by the black line in FIG. 13 is a weak signal based on the 1 H spin observed in the thermal equilibrium state of the erythritol deuterium substituent. Therefore, the strong 1 H NMR signal observed after 100K dynamic nuclear polarization treatment is derived from the spin polarization transferred from compound 1 to the erythritol deuterium substituent.
As shown in FIG. 14, the 1 H NMR signal intensity of the composition 21 was remarkably enhanced by repeating the dynamic nuclear polarization treatment, and after 15 minutes, the signal intensity was 120 times or more. From this, the composition 21 can efficiently transfer the polarization of the triplet electron spin of the compound 1 to the erythritol nuclear spin, and is a highly polarized composition or a composition for dynamic nuclear polarization. It turned out to be useful as. In addition, this result is significant in that it was confirmed that the polarization of triplet electron spins can be transferred to erythritol, which is a natural biomolecule.
［評価５］組成物２４～２９の三重項電子のスピン偏極の評価
　パルス励起光の波長を変えたこと以外は、評価３と同様の条件で組成物２４～２９の時間分解ＥＳＲスペクトルとＥＳＲシグナルの減衰曲線を測定した。パルス励起光には、組成物２４、２５では５１５ｎｍ、組成物２６では５１０ｎｍ、組成物２７では５５０ｎｍ、組成物２８、２９では５４０ｎｍの各波長の光を使用した。また、減衰曲線に用いたＥＳＲシグナルの観測磁場強度は、組成物２４で３２８ｍＴ、組成物２５で３３２ｍＴ、組成物２６で３３８ｍＴ、組成物２７で２９０ｍＴ、組成物２８で２８７ｍＴ、組成物２９で３０９ｍＴである。
　組成物２４～２６の時間分解ＥＳＲスペクトルを図１５に示し、そのＥＳＲシグナルの減衰曲線を図１６に示す。組成物２７～２９の時間分解ＥＳＲスペクトルを図１７に示し、そのＥＳＲシグナルの減衰曲線を図１８に示す。
　図１５、１７に示すように、組成物２４～２９のＥＳＲスペクトルには、いずれも発光ピークと吸収ピークが認められ三重項電子スピンに特徴的なスペクトル形状を示した。このことから、化合物３～８もマトリクス材料中で励起三重項状態に遷移し、電子スピン偏極をとりうることを確認することができた。
　また、図１６、１８に示す減衰曲線の偏極寿命τは、各組成物のスピン－格子緩和時間に相当する。ここで、フリーのポルフィリン誘導体（金属錯体を形成していないポルフィリン誘導体）を偏極源に用いた組成物２４～２６では、そのポルフィリン誘導体のフッ素原子の置換数が大きい程（組成物２６、２５、２４の順に）、τが短くなり、ポルフィリン亜鉛錯体を偏極源に用いた組成物２７～２９では、その亜鉛錯体のフッ素原子の置換数が大きい程（組成物２９、２８、２７の順に）、τが長くなる傾向が見られた。 [Evaluation 5] Evaluation of spin polarization of triplet electrons of compositions 24-29 The time-resolved ESR spectra and ESRs of compositions 24-29 under the same conditions as in evaluation 3 except that the wavelength of the pulse excitation light was changed. The signal decay curve was measured. As the pulse excitation light, light having a wavelength of 515 nm for the compositions 24 and 25, 510 nm for the composition 26, 550 nm for the composition 27, and 540 nm for the compositions 28 and 29 was used. The observed magnetic field strength of the ESR signal used for the attenuation curve was 328 mT for the composition 24, 332 mT for the composition 25, 338 mT for the composition 26, 290 mT for the composition 27, 287 mT for the composition 28, and 309 mT for the composition 29. Is.
The time-resolved ESR spectra of the compositions 24-26 are shown in FIG. 15, and the attenuation curve of the ESR signal is shown in FIG. The time-resolved ESR spectra of the compositions 27-29 are shown in FIG. 17, and the attenuation curve of the ESR signal is shown in FIG.
As shown in FIGS. 15 and 17, the ESR spectra of the compositions 24-29 showed emission peaks and absorption peaks, and showed a spectral shape characteristic of triplet electron spins. From this, it was confirmed that compounds 3 to 8 also transition to the excited triplet state in the matrix material and can take electron spin polarization.
The polarization lifetime τ of the attenuation curve shown in FIGS. 16 and 18 corresponds to the spin-lattice relaxation time of each composition. Here, in the compositions 24 to 26 using a free porphyrin derivative (porphyrin derivative not forming a metal complex) as a polarization source, the larger the number of substitutions of fluorine atoms in the porphyrin derivative (compositions 26, 25). , In the order of 24), τ becomes shorter, and in the compositions 27 to 29 using the porphyrin zinc complex as the polarization source, the larger the number of substitutions of fluorine atoms in the zinc complex (in the order of compositions 29, 28, 27). ), τ tended to be longer.
　また、組成物２～１１についても同様の評価を行ったところ、いずれも動的核偏極処理を行うことで１Ｈ ＮＭＲ信号の増強が認められ、動的核偏極能を示すことが確認された。
　また、組成物１２～１４について、時間分解ＥＳＲ測定を行ったところ、化合物４、７、８に由来する三重項電子スピンの偏極を確認することができた。ここで、化合物４の励起には５１５ｎｍ励起光を使用し、化合物７、８の励起には５４０ｎｍ励起光を使用した。 In addition, when the same evaluations were performed on the compositions 2 to 11, it was confirmed that the 1 H NMR signal was enhanced by the dynamic nuclear polarization treatment, and that the dynamic nuclear polarization ability was exhibited. Was done.
Moreover, when the time-resolved ESR measurements were performed on the compositions 12 to 14, it was possible to confirm the polarization of the triplet electron spins derived from the compounds 4, 7 and 8. Here, 515 nm excitation light was used for excitation of compound 4, and 540 nm excitation light was used for excitation of compounds 7 and 8.
　本発明の組成物は、生体関連物質に対する親和性が高く、また、その偏極源の三重項電子スピンの偏極をマトリクス材料の核スピンに効率よく移行させることができる。そのため、本発明の組成物は、生体関連物質への動的核偏極の実現に大いに貢献するものであり、産業上の利用可能性が高い。 The composition of the present invention has a high affinity for bio-related substances, and can efficiently transfer the polarization of the triplet electron spin of the polarization source to the nuclear spin of the matrix material. Therefore, the composition of the present invention greatly contributes to the realization of dynamic nuclear polarization to bio-related substances, and has high industrial applicability.

Claims (31)

  1. 　スピン－格子緩和時間Ｔ１が２．５秒以上である水溶性のマトリクス材料と、該水溶性マトリクス中に分散した偏極源とを含む組成物。 A composition comprising a water-soluble matrix material having a spin-lattice relaxation time T 1 of 2.5 seconds or more and a polarization source dispersed in the water-soluble matrix.
  2. 　前記マトリクス材料の融点が３０℃以上である、請求項１に記載の組成物。 The composition according to claim 1, wherein the matrix material has a melting point of 30 ° C. or higher.
  3. 　前記マトリクス材料の分子量が３００以下である、請求項１または２に記載の組成物。 The composition according to claim 1 or 2, wherein the matrix material has a molecular weight of 300 or less.
  4. 　前記マトリクス材料が水素結合を形成しうる基を有している、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, wherein the matrix material has a group capable of forming a hydrogen bond.
  5. 　前記マトリクス材料が分子内に２つ以上のヒドロキシ基を有する、請求項１～４のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 4, wherein the matrix material has two or more hydroxy groups in the molecule.
  6. 　前記マトリクス材料が分子内にアミノ基と該アミノ基と水素結合を形成する基を有する、請求項１～５のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 5, wherein the matrix material has an amino group and a group forming a hydrogen bond with the amino group in the molecule.
  7. 　前記マトリクス材料が分子内にアミノカルボニル基を有する、請求項６に記載の組成物。 The composition according to claim 6, wherein the matrix material has an aminocarbonyl group in the molecule.
  8. 　前記マトリクス材料が、水素原子、炭素原子および酸素原子のみで構成される、請求項１～５のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 5, wherein the matrix material is composed of only hydrogen atoms, carbon atoms and oxygen atoms.
  9. 　前記マトリクス材料が、水素原子、炭素原子、酸素原子および窒素原子からなる群より選択される原子のみで構成される、請求項１～７のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 7, wherein the matrix material is composed of only atoms selected from the group consisting of hydrogen atoms, carbon atoms, oxygen atoms and nitrogen atoms.
  10. 　前記マトリクス材料が繰り返し単位を有さない、請求項１～９のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 9, wherein the matrix material does not have a repeating unit.
  11. 　前記マトリクス材料がアルキル基を有さない、請求項１～１０のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 10, wherein the matrix material does not have an alkyl group.
  12. 　前記マトリクス材料が水素原子を含み、その少なくとも一部が重水素原子である、請求項８～１１のいずれか１項に記載の組成物。 The composition according to any one of claims 8 to 11, wherein the matrix material contains a hydrogen atom, and at least a part thereof is a deuterium atom.
  13. 　前記マトリクス材料が糖アルコールである、請求項１に記載の組成物。 The composition according to claim 1, wherein the matrix material is a sugar alcohol.
  14. 　前記偏極源が水溶性である、請求項１～１３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 13, wherein the polarization source is water-soluble.
  15. 　前記偏極源がイオン対を有する、請求項１～１４のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 14, wherein the polarization source has an ion pair.
  16. 　前記偏極源がカチオン性基を有する、請求項１～１５のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 15, wherein the polarization source has a cationic group.
  17. 　前記偏極源がアニオン性基を有する、請求項１～１５のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 15, wherein the polarization source has an anionic group.
  18. 　前記偏極源がポルフィリン誘導体である、請求項１～１７のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 17, wherein the polarization source is a porphyrin derivative.
  19. 　前記ポルフィリン誘導体が下記一般式（３）で表される化合物である、請求項１８に記載の組成物。
    Figure JPOXMLDOC01-appb-C000001
     ［一般式（３）において、Ａｒ１～Ａｒ４は各々独立に置換もしくは無置換のアリール基を表す。］     The composition according to claim 18, wherein the porphyrin derivative is a compound represented by the following general formula (3).
    Figure JPOXMLDOC01-appb-C000001
     [In the general formula (3), Ar 1 to Ar 4 each independently represent a substituted or unsubstituted aryl group. ]
  20. 　前記ポルフィリン誘導体が下記一般式（４）で表される金属錯体である、請求項１８に記載の組成物。
    Figure JPOXMLDOC01-appb-C000002
     ［一般式（４）において、Ａｒ１１～Ａｒ１４は各々独立に置換もしくは無置換のアリール基を表す。］     The composition according to claim 18, wherein the porphyrin derivative is a metal complex represented by the following general formula (4).
    Figure JPOXMLDOC01-appb-C000002
     [In the general formula (4), Ar 11 to Ar 14 each independently represent a substituted or unsubstituted aryl group. ]
  21. 　前記一般式（４）のＡｒ１１～Ａｒ１４の少なくとも１つが電子求引性基で置換されたアリール基である、請求項２０に記載の組成物。 The composition according to claim 20, wherein at least one of Ar 11 to Ar 14 of the general formula (4) is an aryl group substituted with an electron-attracting group.
  22. 　前記電子求引性基がハロゲン原子である、請求項２１に記載の組成物。 The composition according to claim 21, wherein the electron-attracting group is a halogen atom.
  23. 　前記偏極源の含有量が３ｍｏｌ％以下である、請求項１～２２のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 22, wherein the content of the polarization source is 3 mol% or less.
  24. 　請求項１～２３のいずれか１項に記載の組成物からなる動的核偏極用組成物。 A composition for dynamic nuclear polarization comprising the composition according to any one of claims 1 to 23.
  25. 　請求項１～２３のいずれか１項に記載の組成物を高偏極化したものである、高偏極化組成物。 A highly polarized composition obtained by highly polarized the composition according to any one of claims 1 to 23.
  26. 　請求項２５に記載の高偏極化組成物に物質を接触させる工程、または、請求項１～２３のいずれか１項に記載の組成物に物質を接触させた後、前記組成物を高偏極化させて高偏極化組成物とする工程を含む、物質の高偏極化方法。 After contacting the substance with the highly polarized composition according to claim 25 or contacting the substance with the composition according to any one of claims 1 to 23, the composition is highly polarized. A method for highly polarization a substance, which comprises a step of polarizing the composition into a highly polarized composition.
  27. 　請求項２５に記載の高偏極化組成物に物質を接触させる工程を含む、請求項２６に記載の高偏極化方法。 The highly polarized method according to claim 26, which comprises a step of bringing a substance into contact with the highly polarized composition according to claim 25.
  28. 　請求項１～２３のいずれか１項に記載の組成物に物質を接触させた後、前記組成物を高偏極化させて高偏極化組成物とする工程を含む、請求項２６に記載の高偏極化方法。 26. Highly polarized method.
  29. 　前記接触を、前記マトリクス材料と前記偏極源と前記物質とを混合して均一化することにより行う、請求項２８に記載の高偏極化方法。 The highly polarized method according to claim 28, wherein the contact is performed by mixing and homogenizing the matrix material, the polarized source, and the substance.
  30. 　請求項２６～２９のいずれか１項に記載の方法により高偏極化した物質。 A substance highly polarized by the method according to any one of claims 26 to 29.
  31. 　請求項１～２３のいずれか１項に記載の組成物を用いて物質のＮＭＲを測定する工程を含む、ＮＭＲ測定法。 An NMR measurement method comprising a step of measuring NMR of a substance using the composition according to any one of claims 1 to 23.
PCT/JP2021/005096 2020-02-28 2021-02-10 Composition, composition for dynamic nuclear polarization, highly polarized composition, method for highly polarizing substance, highly polarized substance, and nmr measurement method WO2021172030A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022503252A JPWO2021172030A1 (en) 2020-02-28 2021-02-10

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020034326 2020-02-28
JP2020-034326 2020-02-28

Publications (1)

Publication Number Publication Date
WO2021172030A1 true WO2021172030A1 (en) 2021-09-02

Family

ID=77491449

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/005096 WO2021172030A1 (en) 2020-02-28 2021-02-10 Composition, composition for dynamic nuclear polarization, highly polarized composition, method for highly polarizing substance, highly polarized substance, and nmr measurement method

Country Status (2)

Country Link
JP (1) JPWO2021172030A1 (en)
WO (1) WO2021172030A1 (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04506970A (en) * 1989-07-21 1992-12-03 ニユコメド・アクシエセルカペト Granular contrast agent
JPH0667854B2 (en) * 1984-11-01 1994-08-31 ニユエガ−ド・アンド・コンパニ−・アクシエ／セルカペト Diagnostic agent
JPH07505117A (en) * 1991-02-01 1995-06-08 イマアーレクス・フアーマシユーチカル・コーポレーシヨン Phosphorylated contrast agent for MRI of the gastrointestinal tract
JPH07110815B2 (en) * 1985-11-18 1995-11-29 ボ−ド・オブ・リ−ジェンツ、ザ・ユニバ−シティ−・オブ・テキサス・システム Polychelating agent for image and spectral enhancement (and spectral shift)
US20110104075A1 (en) * 2006-08-28 2011-05-05 Ivan Dmochowski 129Xe BIOSENSORS AND THEIR USE
US20160306020A1 (en) * 2015-04-17 2016-10-20 Ecole Polytechnique Federale De Lausanne (Epfl) Transportable long-lived hyperpolarized samples
WO2019082951A1 (en) * 2017-10-26 2019-05-02 国立大学法人九州大学 Composition, composition for dynamic nuclear polarization, high polarization method, highly polarized substance, and nmr measuring method

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0667854B2 (en) * 1984-11-01 1994-08-31 ニユエガ−ド・アンド・コンパニ−・アクシエ／セルカペト Diagnostic agent
JPH07110815B2 (en) * 1985-11-18 1995-11-29 ボ−ド・オブ・リ−ジェンツ、ザ・ユニバ−シティ−・オブ・テキサス・システム Polychelating agent for image and spectral enhancement (and spectral shift)
JPH04506970A (en) * 1989-07-21 1992-12-03 ニユコメド・アクシエセルカペト Granular contrast agent
JPH07505117A (en) * 1991-02-01 1995-06-08 イマアーレクス・フアーマシユーチカル・コーポレーシヨン Phosphorylated contrast agent for MRI of the gastrointestinal tract
US20110104075A1 (en) * 2006-08-28 2011-05-05 Ivan Dmochowski 129Xe BIOSENSORS AND THEIR USE
US20160306020A1 (en) * 2015-04-17 2016-10-20 Ecole Polytechnique Federale De Lausanne (Epfl) Transportable long-lived hyperpolarized samples
WO2019082951A1 (en) * 2017-10-26 2019-05-02 国立大学法人九州大学 Composition, composition for dynamic nuclear polarization, high polarization method, highly polarized substance, and nmr measuring method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHENG, RU-JEN, CHANG SHU-HAO, HUNG KUO-CHENG: "An Anomalous Spin-Polarization Mechanism in High-Spin Manganese(III) Porphyrin Complexes", INORGANIC CHEMISTRY, vol. 46, no. 6, 1 March 2007 (2007-03-01), pages 1948 - 1950, XP055850800, DOI: 10.1021/ic0617238 *

Also Published As

Publication number Publication date
JPWO2021172030A1 (en) 2021-09-02

Similar Documents

Publication Publication Date Title
Nguyen et al. Heavy-atom-free photosensitizers: from molecular design to applications in the photodynamic therapy of cancer
Biedenbänder et al. Dynamic nuclear polarization for sensitivity enhancement in biomolecular solid-state NMR
Jiang et al. Multifunctional AIEgens: ready synthesis, tunable emission, mechanochromism, mitochondrial, and bacterial imaging
Rehmat et al. Carbazole-perylenebisimide electron donor/acceptor dyads showing efficient spin orbit charge transfer intersystem crossing (SOCT-ISC) and photo-driven intermolecular electron transfer
Schröder Xenon for NMR biosensing–inert but alert
Wu et al. Controlling the structure and photophysics of fluorophore dimers using multiple cucurbit [8] uril clampings
Han et al. To direct the self-assembly of AIEgens by three-gear switch: Morphology study, amine sensing and assessment of meat spoilage
Voinov et al. Cysteine-specific labeling of proteins with a nitroxide biradical for dynamic nuclear polarization NMR
HU229718B1 (en) Method for preparation of hyperpolarised solution of an agent with high t1 for magnetic resonance investigation of human or non-human bodies and preparation to be administered
Bari et al. Effect of axial ligation on the magnetic and electronic properties of lanthanide complexes of octadentate ligands
WO2006116021A2 (en) Mri technique based on electron spin resonance and endohedral contrast agent
Gao et al. One-step synthesis of ultrabright amphiphilic carbon dots for rapid and precise tracking lipid droplets dynamics in biosystems
WO2019082951A1 (en) Composition, composition for dynamic nuclear polarization, high polarization method, highly polarized substance, and nmr measuring method
Tanuma et al. Robust coherent spin centers from stable azafullerene radicals entrapped in cycloparaphenylene rings
Kong et al. A two-photon AIE fluorophore as a photosensitizer for highly efficient mitochondria-targeted photodynamic therapy
Cipolloni et al. Time-resolved fluorescence anisotropy of bicyclo [1.1. 1] pentane/tolane-based molecular rods included in tris (o-phenylenedioxy) cyclotriphosphazene (TPP)
WO2021172030A1 (en) Composition, composition for dynamic nuclear polarization, highly polarized composition, method for highly polarizing substance, highly polarized substance, and nmr measurement method
Kalita et al. Synthesis of meso‐Pyrrole‐Substituted 22‐Oxacorroles by a “3+ 2” Approach
Sukhanov et al. Time-Resolved Continuous-Wave and Pulse EPR Investigation of Photoinduced States of Zinc Porphyrin Linked with an Ethylenediamine Copper Complex
Yau et al. Nitroxide-based triradical dopants for efficient low-temperature dynamic nuclear polarization in aqueous solutions over a broad pH range
US20220143223A1 (en) Composition and composite
Sun et al. Highly Emissive Organic Cage in Single-Molecule and Aggregate States by Anchoring Multiple Aggregation-Caused Quenching Dyes
JP2020144123A (en) Polarization source for dynamic nuclear polarization, composition, composition for dynamic nuclear polarization, high polarization method, highly polarized substance, and nmr measurement method
Dixit et al. Synthesis and photophysical properties of near infra-red absorbing BODIPy derivatives and their nanoaggregates
Harris et al. Magnetofluorescent nanoaggregates incorporating terbium (III) complexes as potential bimodal agents for magnetic resonance and optical imaging

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21759649

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022503252

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21759649

Country of ref document: EP

Kind code of ref document: A1