Aromatic compounds, mixtures, molecular probes for hyperpolarization, metabolites, diagnostic agents, derivatizing agents, naphthalene derivatives, catechol derivatives, and compounds

Abstract

To provide an aromatic compound having longer relaxation time of 13C nucleus excited by a DNP apparatus than conventional ones.SOLUTION: An aromatic compound is composed of a stable isotope. Two adjacent carbon atoms are 13C, a spin quantum number of an atomic nucleus of other atom to which the two adjacent carbon atoms are coupled is zero, and a hydrogen atom having a spin coupling constant coupled through a carbon atom to 13C nucleus is substituted by a deuterium atom.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to aromatic compounds, mixtures, molecular probes for hyperpolarization, metabolites, diagnostic agents, derivatizing agents, naphthalene derivatives, catechol derivatives, and compounds. [Background technology]

[0002] In NMR (Nuclear Magnetic Resonance) spectroscopy and MRI (Magnetic Resonance Imaging), atomic nuclear spins (hereafter simply referred to as nuclear spins) in materials are precisely controlled under a strong static magnetic field. The electromagnetic signals (NMR signals) modulated by interactions between nuclear spins are used to extract a wealth of molecular-level information. The sensitivity of NMR signals is proportional to the polarization ratio. However, even under the strong magnetic fields of several teslas to several tens of teslas applied by superconducting magnets, the Zeeman energy of nuclear spins is extremely low. Dynamic nuclear polarization (DNP) is used to improve measurement sensitivity by increasing the polarization ratio by several orders of magnitude. However, even highly polarized nuclear spins obtained by DNP lose their polarization within a few to several tens of seconds due to modulation of the magnetic field caused by molecular motion and interactions between nuclear spins inside and outside the molecule.

[0003] Therefore, in order to perform NMR spectroscopy and MRI using DNP, which require long time periods, it is important to use nuclear spins with long relaxation times. One method to suppress the nuclear spin relaxation mechanism is to use a nuclear spin state (hereinafter also referred to as a long-lived state) that is commutative with the interaction that causes the relaxation mechanism. One relaxation mechanism that strongly induces nuclear spin relaxation is the dipolar interaction between nearest-neighbor nuclear spins, and it is known that the singlet state of the nearest-neighbor nuclear spin pair becomes a long-lived state for this interaction.

[0004] The singlet state can be generated by using radio frequency irradiation. 15 in N2O 1526 minutes for N pairs (Non-patent document 1), 13 C2-naphthalene derivatives 13 A relaxation time of over one hour has been reported for C pairs (Non-Patent Document 2). This technique not only maintains the high polarization obtained by DNP for a long time, but is also used as a probe for observing long-term dynamics and as a method for detecting weak chemical bonds. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Giuseppe Pileio, The Long-Lived Nuclear Singlet State of 15N-Nitrous Oxide in Solution, J. Am. Chem. Soc., 2008, 130, 38, 12582-12583 [Non-patent document 2] Gabriele Stevanato, et al., A Nuclear Singlet Lifetime of More than One Hour in Room-Temperature Solution, Angew. Chem. Int. Ed. 2015, 54, 3740-3743. Summary of the Invention [Problem to be solved by the invention]

[0006] MRI devices are widely used in hospitals as an essential imaging diagnostic technique. However, their sensitivity is very low compared to other analytical methods, and they are difficult to measure the amount of water molecules present in the body. 1 The DNP method has been attracting attention as a way to solve this problem. By using this technology, the development of a technique for assessing the effectiveness of cancer treatment by observing the metabolism of administered drugs is underway. In this method, a substance is hyperpolarized by a DNP device, dissolved, and administered into the body, and the drug, etc. 13However, the C nucleus excited by this DNP technique 13 Since the relaxation time of the C nucleus is at most several tens of seconds, it is not suitable for long-term observations, and its range of application has been limited.

[0007] The present invention has been made in view of the above circumstances, and provides a method for producing a photocatalyst excited by a DNP device. 13 The present invention addresses the problem of providing an aromatic compound having a longer relaxation time of C nucleus than conventional compounds. [Means for solving the problem]

[0008] [1] Aromatic compounds composed of stable isotopes, Two adjacent carbon atoms 13 C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are bonded is 0, and 13 An aromatic compound in which a hydrogen atom with a spin coupling constant bonded to a C nucleus via a carbon atom is replaced with a deuterium atom. [2] A mixture containing aromatic compounds composed of stable isotopes, Two adjacent carbon atoms 13 C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are bonded is 0, and 13 a first aromatic compound in which a hydrogen atom having a spin coupling constant bonded to a C nucleus via a carbon atom is replaced with a deuterium atom; One of the two adjacent carbon atoms 13 C, and the other of the two adjacent carbon atoms is 12 C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are bonded is 0, and 13 a second aromatic compound in which a hydrogen atom having a spin coupling constant bonded to the C nucleus via a carbon atom is replaced with a deuterium atom; A mixture comprising: [3] A molecular probe for hyperpolarization comprising the aromatic compound according to [1]. [4] A metabolite containing the aromatic compound described in [1]. [5] A diagnostic agent comprising the aromatic compound according to [1]. [6] A derivatizing agent containing the aromatic compound according to [1]. [7] A compound produced by binding the derivatizing agent according to [6] with a diagnostic agent or a metabolite. [8] A naphthalene derivative represented by formula (1). [ka] In formula (1), R 1 are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide. [9] A compound produced by binding the naphthalene derivative according to [8] with a diagnostic agent or a metabolite.

[10] A catechol derivative represented by formula (2). [ka] In formula (2), R 2 and R 3 R is independently any one group selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide. 4 are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide, provided that R 4 At least one of the atoms is a deuterium atom.

[11] A compound produced by binding the catechol derivative according to

[10] with a diagnostic agent or a metabolite. [Effects of the Invention]

[0009] The present invention is excited by a DNP device.13 To provide an aromatic compound having a longer relaxation time of C nucleus than conventional compounds. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the results of measuring the 13C NMR spectrum of 2-naphthoic acid-4a,8a-13C2 (13C2-NA-h7). [Figure 2] Figure 2 shows the pulse sequence used to generate, maintain, and observe the long-lived state. [Figure 3] FIG. 3 is a graph showing the results of measuring the longitudinal relaxation times of 2-naphthoic acid-4a,8a-13C2 (13C2-NA-h7) and 13C2-2-naphthoic acid-d7 (13C2-NA-d7). [Figure 4] FIG. 4 is a graph showing the results of measuring the relaxation times of the singlet states of 2-naphthoic acid-4a,8a-13C2 (13C2-NA-h7) and 2-naphthoic acid-4a,8a-13C2-d7 (13C2-NA-d7). DETAILED DESCRIPTION OF THE INVENTION

[0011] Although the embodiments of the present invention will be described in detail below, the present invention is not limited to the embodiments described below, and various modifications are possible without departing from the gist of the present invention. The meanings and definitions of terms used in this specification are as follows: A numerical range indicated by "to" means that the numerical values ​​before and after "to" are the lower and upper limits of the numerical range. The "D" used in the chemical formula represents a deuterium atom.

[0012] Two carbon atoms at the ring condensation site of the naphthoic acid skeleton 13By utilizing the long-lived state of the C nuclear spin pair, we were able to obtain a polarization lifetime approximately five times longer than the longitudinal relaxation time, and by substituting hydrogen atoms in the aromatic ring with deuterium, we were able to obtain a polarization lifetime approximately 13 times longer. We also performed relaxation time simulations using molecular dynamics and quantum chemical calculations to predict the relaxation time of molecules with other substituents added to the naphthoic acid skeleton, and confirmed that the relaxation time predictions could be made on the same order as the experimental results. Based on these results, we propose a long-lived nuclear polarization probe that is functionalized by adding various substituents to the naphthoic acid skeleton.

[0013] [Aromatic compounds] The aromatic compound of the present invention is an aromatic compound composed of stable isotopes, and two adjacent carbon atoms are 13 C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are bonded is 0, and 13 It is an aromatic compound in which a hydrogen atom with a spin coupling constant is replaced by a deuterium atom and bonded to a C nucleus via a carbon atom. Aromatic compounds that satisfy the above conditions are specifically: 13 In addition to the C pair being part of an aromatic ring, 13 An atom other than a hydrogen atom must be bonded to the C nucleus. For example, the bridgehead positions of the ring condensation positions of polycyclic aromatic compounds such as naphthalene, anthracene, phenanthrene, anthraquinone, and their derivatives are 13 These include compounds substituted with 13C, and aromatic compounds in which the carbon atom to which a substituent such as o-xylene, o-cresol, catechol, polyphenols, phthalic acid, and its derivatives is bonded is substituted with 13C.

[0014] In order to achieve a long polarization lifetime, the following is required to suppress relaxation due to dipolar interactions: 13 It is desirable that the hydrogen atoms in the vicinity of the C nucleus are replaced by atomic nuclei having a spin quantum number of 0. 13 The present inventors have found through theoretical calculations and experiments that even hydrogen atoms present in close proximity to the C nucleus to form spin coupling can have a sufficiently long relaxation time by deuterizing them, which led to the present invention.

[0015] Specific examples of the aromatic compound of the present invention include a naphthalene derivative represented by formula (1) and a catechol derivative represented by formula (2).

[0016] [ka]

[0017] In formula (1), R 1 are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide.

[0018] The alkyl group is, for example, an alkyl group having 1 to 10 carbon atoms. The smaller the molecular weight of the compound represented by formula (1), the more preferable it is, and the alkyl group is preferably an alkyl group having 2 or less carbon atoms, i.e., a methylene group or an ethylene group, and more preferably a methylene group.

[0019] The aryl group is, for example, an aryl group having 6 to 13 carbon atoms. The smaller the molecular weight of the compound represented by formula (1), the more preferable it is, and the aryl group is preferably an aryl group having 10 or less carbon atoms, more preferably a naphthyl group or a phenyl group.

[0020] The alkene is not particularly limited as long as it is a compound having an alkene in the molecule. The alkyne is not particularly limited as long as it is a compound having an alkyne in the molecule. The amine is not particularly limited as long as it is a compound having an amine in the molecule. The silyl group is not particularly limited as long as it is a compound having a silyl group in the molecule. The carbonyl compound is not particularly limited as long as it is a compound having a carbonyl group in the molecule. The ether is not particularly limited as long as it is a compound having an ether bond in the molecule. The thiol is not particularly limited as long as it is a compound having a thiol group in the molecule. The ester is not particularly limited as long as it is a compound having an ester bond in the molecule, and specific examples thereof include compounds obtained by dehydration condensation of carbonic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, or sulfonic acid with an alcohol. The sulfoxide is not particularly limited as long as it is a compound in which two carbon atoms in the molecule are bonded to a sulfinyl group (-S(=O)-).

[0021] [ka]

[0022] In formula (2), R 2 and R 3 are each independently any one group selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide.

[0023] The alkyl group is, for example, an alkyl group having 1 to 10 carbon atoms. Since the smaller the molecular weight of the compound represented by formula (2), the longer the relaxation time, the alkyl group is preferably an alkyl group having 2 or less carbon atoms, i.e., a methyl group or an ethyl group, and more preferably a methyl group.

[0024] The aryl group is, for example, an aryl group having 6 to 13 carbon atoms. Since the smaller the molecular weight of the compound represented by formula (2), the longer the relaxation time, the aryl group is preferably an aryl group having 10 or less carbon atoms, and more preferably a naphthyl group or a phenyl group.

[0025] The alkene is not particularly limited as long as it is a compound having an alkene in the molecule. The alkyne is not particularly limited as long as it is a compound having an alkyne in the molecule. The amine is not particularly limited as long as it is a compound having an amine in the molecule. The silyl group is not particularly limited as long as it is a compound having a silyl group in the molecule. The carbonyl compound is not particularly limited as long as it is a compound having a carbonyl group in the molecule. The ether is not particularly limited as long as it is a compound having an ether bond in the molecule. The thiol is not particularly limited as long as it is a compound having a thiol group in the molecule. The ester is not particularly limited as long as it is a compound having an ester bond in the molecule, and specific examples thereof include compounds obtained by dehydration condensation of carbonic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, or sulfonic acid with an alcohol. The sulfoxide is not particularly limited as long as it is a compound in which two carbon atoms in the molecule are bonded to a sulfinyl group (-S(=O)-).

[0026] In formula (2), R 4 are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide, provided that R 4 At least one of the atoms is a deuterium atom.

[0027] The alkyl group is, for example, an alkyl group having 1 to 10 carbon atoms. Since the smaller the molecular weight of the compound represented by formula (2), the longer the relaxation time, the alkyl group is preferably an alkyl group having 2 or less carbon atoms, i.e., a methyl group or an ethyl group, and more preferably a methyl group.

[0028] The aryl group is, for example, an aryl group having 6 to 13 carbon atoms. Since the smaller the molecular weight of the compound represented by formula (2), the longer the relaxation time, the aryl group is preferably an aryl group having 10 or less carbon atoms, and more preferably a naphthyl group or a phenyl group.

[0029] The alkene is not particularly limited as long as it is a compound having an alkene in the molecule. The alkyne is not particularly limited as long as it is a compound having an alkyne in the molecule. The amine is not particularly limited as long as it is a compound having an amine in the molecule. The silyl group is not particularly limited as long as it is a compound having a silyl group in the molecule. The carbonyl compound is not particularly limited as long as it is a compound having a carbonyl group in the molecule. The ether is not particularly limited as long as it is a compound having an ether bond in the molecule. The thiol is not particularly limited as long as it is a compound having a thiol group in the molecule. The ester is not particularly limited as long as it is a compound having an ester bond in the molecule, and specific examples thereof include compounds obtained by dehydration condensation of carbonic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, or sulfonic acid with an alcohol. The sulfoxide is not particularly limited as long as it is a compound in which two carbon atoms in the molecule are bonded to a sulfinyl group (-S(=O)-).

[0030] In the compound represented by formula (2), each oxygen atom is independently 16 O. 17 O and 18 O. 16 O. 17 O, and 18 The natural abundances of O are 99.757 atm%, 0.038 atm%, and 0.205 atm%, respectively.

[0031] Specific examples of the compound represented by formula (2) include compounds represented by the following formulas:

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] [ka]

[0036] [Mixture] The mixture of the present invention is a mixture containing aromatic compounds composed of stable isotopes, Two adjacent carbon atoms 13 C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are bonded is 0, and one or more hydrogen atoms present in the molecule are substituted with deuterium atoms; and 13 C, and the other of the two adjacent carbon atoms is 12 and a second aromatic compound having a structure in which the first aromatic compound is C, the second aromatic compound being C, the second aromatic compound having a spin quantum number of 0, and one or more hydrogen atoms present in the molecule being substituted with deuterium atoms, and the second aromatic compound being C, ... The first aromatic compound is the compound of the present invention described above. The second aromatic compound is 12 C and 13 Since the natural abundance ratios of C are 98.93 atm% and 1.07 atm%, it is synthesized as a by-product when synthesizing the first aromatic compound.

[0037] [Hyperpolarized molecular probes] The hyperpolarized molecular probe of the present invention includes the aromatic compound of the present invention described above. The hyperpolarized molecular probe of the present invention is hyperpolarized using a DNP device, administered to a living body, and then measured by nuclear magnetic resonance spectroscopy, allowing the accumulation state of the hyperpolarized molecular probe and the metabolic conversion of its metabolites to be detected in real time.

[0038] [Metabolite] The metabolites of the present invention are metabolites containing the aromatic compounds of the present invention described above. Hyperpolarization technology enables overwhelmingly high sensitivity for specific isotope-labeled probes. However, nuclear-polarized molecules rapidly relax and lose their polarization due to interactions between their molecular structure and the surrounding environment. Because this technology can suppress this relaxation phenomenon, by hyperpolarizing the aromatic compounds of the present invention using a DNP device, dissolving them, and administering them to a living body, it becomes possible to measure the metabolic conversion of aromatic compounds and their metabolites in real time.

[0039] As a specific example of the metabolite of the present invention, a compound represented by the following formula is particularly preferred.

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] [Diagnostic drugs] The diagnostic agent of the present invention is a diagnostic agent containing the aromatic compound of the present invention described above. The diagnostic agent of the present invention is hyperpolarized using a DNP device, dissolved, and administered to a living body. By accumulating the agent in a polarized state at specific sites, such as cancer lesions, in the human body, its metabolic process can be tracked with high sensitivity. This enables not only differentiation between normal tissue and tumors, but also prognosis prediction, evaluation of drug response, and detection even before the onset of disease, which is earlier than conventional methods. DOPA is already used in the treatment of Parkinson's disease. For example, if the labeling pattern demonstrated in this invention could be used to image DOPA accumulation in the brain and its metabolic transformation in real time, it could be used in research aimed at elucidating the pathology of this disease. Furthermore, by conjugating the aromatic compound of the present invention to therapeutic or diagnostic agents that are difficult to label with stable isotopes for extended lifespan, it becomes possible to use the aromatic compound-conjugated molecules in medical technologies that integrate treatment and diagnosis.

[0046] As a specific example of the diagnostic agent of the present invention, a compound represented by the following formula is particularly preferred.

[0047] [ka]

[0048] [Derivatizing agent] The derivatizing agent of the present invention is a derivatizing agent containing the aromatic compound of the present invention described above. The derivatizing agent of the present invention may further contain at least one compound selected from the group consisting of carbamate compounds, isothiocyanate compounds, N-hydroxysuccinimide esters, N-hydroxyphthalimide esters, pyrylium compounds, acid chlorides, acyl halides, and sulfonyl halides. The derivatizing agent of the present invention binds the aromatic compound of the present invention to metabolites, diagnostic agents, etc. that are difficult to label with stable isotopes to extend their lifespan, making it possible to observe the dynamics and interactions of molecules bound to the aromatic compound. [Example]

[0049] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the examples described below.

[0050] [Example 1] Of the carbon atoms in 2-naphthoic acid, the two at the fused carbon ring 13 C (the part indicated by the black circle in formula (3)) is an isotope 13 C-substituted molecules were synthesized.

[0051] [ka]

[0052] 2-Naphthoic acid-4a,8a- 13 C2( 13 C2-NA-h7) was dissolved at 0.1M in heavy water containing 0.3M potassium carbonate, and the solution was degassed with nitrogen for 30 minutes. 13 The results of the C NMR spectrum measurement are shown in Figure 1. From the results shown in Figure 1, two 13 The J coupling strength between C nuclear spins was estimated to be about 43 Hz, and the chemical shift difference was estimated to be about 245 Hz.

[0053] Figure 2 shows the pulse sequence used to generate, maintain, and observe the long-lived state. From the J coupling and chemical shift difference, t1 = 4.8 ms, t2 = 7 ms, and t3 = 1.1 ms were calculated. The spin-lock pulse intensity was set to 1.5 kHz, which is sufficiently large compared to the chemical shift difference. Using this pulse sequence, the relaxation time (T SThe longitudinal relaxation time (T1) obtained using the inversion recovery method was 7.2 seconds, and the relaxation time was approximately five times longer by using the singlet state.

[0054] To further suppress the intramolecular dipolar interactions, we have deuterated the hydrogen atoms in the aromatic ring of 2-naphthoic acid-4a,8a- 13 C2-d7( 13 C2-NA-d7) (formula (4)) was synthesized.

[0055] [ka]

[0056] 13 The longitudinal relaxation time of C2-NA-d7 was measured using a similar pulse sequence (Figure 1), and the relaxation time in the singlet state was 8.1 seconds and 104 seconds, respectively, which is approximately 13 times longer than the longitudinal relaxation time. The measurement was performed under an external magnetic field of 11.7 T at 27°C.

[0057] 13 C2-NA-h7 (dotted line) and 13 The longitudinal relaxation time measurement results for C2-NA-d7 (solid line) are shown in Figure 3. 13 C2-NA-h7 (dotted line) and 13 The results of measuring the relaxation time of the singlet state of C2-NA-d7 (solid line) are shown in FIG.

[0058] In parallel with the above experiments, relaxation time simulations were also performed using quantum chemical calculations and molecular dynamics. The results of the longitudinal relaxation time are shown in Table 1, and the results for the singlet state in Table 2. The calculation conditions were an external magnetic field of 11.7 T and 27°C.

[0059] [Table 1]

[0060] [Table 2]

[0061] R in the table i is the relaxation rate (R i,DDjk ), and the relaxation rate due to dipolar interactions originating from the nuclear spins present in other solute molecules (R i,inDD ), relaxation rate due to chemical shift anisotropy interaction (R i,CSA ) are shown for the longitudinal relaxation time (i=1) and the singlet state (i=S). In addition to these, the relaxation rate due to the dipole interaction with the nuclear spins of the solvent molecules and the spin-rotation interaction was also calculated, but since the contribution was only several orders of magnitude smaller, it is not included in the table. Comparing the numerical calculation results with the experimental results, it can be seen that the relaxation times for both the longitudinal relaxation time and the singlet state relaxation time can be predicted on the same order of magnitude.

[0062] It was found that almost 90% of the longitudinal relaxation occurs due to chemical shift anisotropy interactions. It is thought that the accuracy of the relaxation time calculations will improve by improving the accuracy of chemical shift tensor calculations, such as performing quantum chemical calculations for each state obtained by molecular dynamics calculations. In addition, when calculating the difference in the relaxation rate of the singlet state with or without deuteration, it is found that (1 / T S,H )-(1 / T S,H ) = 0.019. The difference in the relaxation rate due to intramolecular interactions predicted by the calculation was 0.020, which indicates that the dipole interaction relaxation rate due to hydrogen atoms in the aromatic ring can be estimated with high accuracy. Possible methods to extend the relaxation time of the long-lived state include using freeze-degassing instead of nitrogen degassing, and increasing the intensity of the spin-lock pulse.

[0063] [Example 2] <Relaxation time prediction for other molecules with naphthalene skeleton> As a candidate for a polarized probe with a naphthalene skeleton, 13 C2-2-naphthylamine-d7( 13C2-NAmin-d7) and Eq. (6) 13 C2-2-Naphthalenephthalimide ester-d 11 ( 13 C2-NX-d 11 ) in the aromatic ring 13 The relaxation time was predicted for the C spin pair. The calculation conditions were an external magnetic field of 11.7 T and 27°C. 13 C2-NX-d 11 Since is not expected to dissolve in water, the relaxation time in acetone was calculated. The calculated results of the longitudinal relaxation time are shown in Table 3, and the calculated results of the relaxation time in the singlet state are shown in Table 4. The results obtained indicate that the singlet state relaxation time is sufficiently larger than T1.

[0064] [ka]

[0065] [ka]

[0066] Table 3 shows: 13 C2-2-naphthylamine-d7( 13 C2-NAmin-d7) and 13 C2-2-Naphthalenephthalimide ester-d 11 ( 13 C2-NX-d 11 The longitudinal relaxation time calculation results are shown in Table 4. 13 C2-2-naphthylamine-d7( 13 C2-NAmin-d7) and 13 C2-2-Naphthalenephthalimide ester-d 11 ( 13 C2-NX-d 11 ) relaxation time calculation results for the singlet state of 10 -4 Components smaller than are shown as -.

[0067] [Table 3]

[0068] [Table 4]

[0069] [Example 3] <Relaxation time prediction for other molecules with catechol skeleton> As a candidate for a polarized probe with a catechol skeleton, the aromatic ring of DOPA-13C2-d6 represented by formula (7) 13 The relaxation time was predicted for the C spin pair, and the aromatic ring and exchangeable hydrogen atoms were replaced with deuterium atoms.

[0070] [ka]

[0071] Calculation results of longitudinal relaxation time (T1) and singlet state relaxation time (T S ) are shown in Table 5. In an external magnetic field of 11.7 T, T s The calculated relaxation time was 28.7 seconds, but when the external magnetic field was increased to 1 T, it became 298 seconds, which is expected to have a long relaxation time for the singlet state.

[0072] [Table 5]

[0073] [Example 4] <Adiponitrile-1,6- 13 Synthesis of C2> Potassium cyanide in a 200 mL eggplant flask 13C (5.820 g, 88.1 mol), ethanol (40 mL), water (20 mL), and 1,4-diiodobutane (6.07 mL, 14.3 g, 46.2 mmol, 0.525 eq) were added, and the mixture was heated to reflux for 18 hours. After cooling to room temperature, 10 mL of 2 M aqueous sodium hydroxide solution was added, and the pH of the reaction solution was confirmed to be 12 or higher. The ethanol was then removed by vacuum concentration, and the mixture was extracted with dichloromethane (200 mL × 3). The organic layer was washed with water, and after confirming that no cyanide was present in the aqueous layer, the organic layer was dried over sodium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain adiponitrile-1,6- 13 C2 was obtained (yield: 3.986 g (36.2 mmol), 82%).

[0074] Adipaldehyde-1,6- 13 Synthesis of C2> Under a nitrogen atmosphere, a 500 mL three-neck flask was charged with the adiponitrile-1,6- 13 C2 (5.436 g, 49.4 mol) and dehydrated dichloromethane (180 mL) were added and cooled to -80 °C. 1 M DIBAL-H in hexane (105 mL, 105 mol) was added dropwise using a dropping funnel over 50 minutes. After stirring for 2 hours, additional 1 M DIBAL-H in hexane (35 mL, 35 mol) was added and stirred for an additional hour. 2 M HCl (150 mL) was slowly added dropwise, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. Subsequently, 6 M HCl was added dropwise using a Pasteur pipette to dissolve the aluminum salts, followed by extraction with dichloromethane (400 mL × 3). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated at atmospheric pressure to obtain crude product 2.

[0075] <1,1,8,8-tetrabromooctane-2,7- 13 Synthesis of C2> Under a nitrogen atmosphere, carbon tetrabromide (53.06 g, 160 mmol), triphenylphosphine (83.93 g, 320 mmol), and dehydrated dichloromethane (700 mL) were placed in a 2 L eggplant flask and stirred at 0°C for 1 hour.13 A dichloromethane solution of C2 (38.4 mmol) was added and stirred for 30 minutes, followed by another 30 minutes of stirring at room temperature. Water (400 mL) was added, and the mixture was extracted with dichloromethane (300 mL × 3). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain a pale yellow solid. This pale yellow solid was dissolved in methanol (approximately 300 mL) and extracted with hexane (200 mL × 10). After confirming the absence of the target product in the methanol layer by TLC, the hexane layer was concentrated under reduced pressure to obtain a white solid. This white solid was completely dissolved in dichloromethane (30-40 mL) and reprecipitated using a large amount of hexane. The obtained white solid was separated by suction filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1,1,8,8-tetrabromooctane-2,7- 13 C2 was obtained (oil, yield 13.172 g (30.6 mmol), 62% yield).

[0076] <1,7-octadiyne-2,7- 13 Synthesis of C2> In a 1 L three-neck flask equipped with a 300 mL dropping funnel and a minus thermometer, add dehydrated THF (100 mL), 1,1,8,8-tetrabromooctane-2,7-diol obtained in the previous reaction, and 13 C2 (13.172 g, 30.6 mmol) was added and cooled to -80°C. LDA (0.8 M, 200 mL, 159 mmol) was added dropwise to a 300 mL dropping funnel over 90 minutes. After stirring at the same temperature for 1 hour, the mixture was warmed to 0°C and stirred for an additional hour. 1 M HCl (400 mL) was slowly added to terminate the reaction, followed by extraction with diethyl ether (300 mL x 3). The organic layer was washed with 10 wt% aqueous sodium thiosulfate solution (200 mL x 2), dried over anhydrous sodium sulfate, concentrated at atmospheric pressure, and purified by silica gel column chromatography.

[0077] <6-(1-hydroxyethyl)-1,2,3,4-tetrahydronaphthalene-4a,8a- 13 Synthesis of C2> Under a nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (115 mg, 0.282 mmol)4), dry dichloromethane (10 mL), and (S)-H8-BINAP (178 mg, 0.282 mmol) were placed in a 300 mL recovery flask and stirred for 10 minutes. After stirring, the nitrogen atmosphere was replaced with a hydrogen atmosphere and the mixture was stirred for 1 hour. After distilling off the dichloromethane under reduced pressure, the atmosphere was replaced with nitrogen again and dry dichloroethane (90 mL) was added. 1,7-octadiene-2,7- 13 A mixed reagent of C2 (9.4 mmol) and 3-butyn-2-ol (1.317 g, 18.8 mmol) dissolved in dehydrated dichloroethane (4 mL) was prepared and added dropwise over 10 minutes. The mixture was then stirred at room temperature for 18 hours. The reaction solvent was concentrated under reduced pressure and purified by silica gel column chromatography to give 6-(1-hydroxyethyl)-1,2,3,4-tetrahydronaphthalene-4a,8a- 13 C2 was obtained (oil, yield 1.001 g (5.61 mmol), 60% yield).

[0078] <2-Naphthoic acid-4a,8a- 13 Synthesis of C2> Under a nitrogen atmosphere, t-butanol (150 mL), potassium t-butoxide (5.139 g, 45.8 mmol), and iodine (4.362 g, 17.2 mmol) were placed in a 300 mL two-necked flask at room temperature and stirred for 10 minutes. 13 C2 (5.72 mmol) was added and stirred for 1.5 hours. After concentrating the solvent under reduced pressure, water (300 mL) was added and the aqueous layer was washed with dichloromethane (200 mL × 3). An appropriate amount of crushed ice was added to this aqueous layer, and 6 M HCl was slowly added until the pH reached 1. Extraction was performed with dichloromethane (200 mL × 3), and the organic layer was washed with 10 wt% aqueous sodium thiosulfate solution (200 mL × 2) and saturated brine (200 mL × 1). After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 2-naphthoic acid-4a,8a- 13 The crude product 7 of C2 was obtained (light yellow solid, yield 0.750 g (4.31 mmol), 75% yield).

[0079] Pulse sequence references Sarkar R., Vasos PR and Bodenhausen G. “Singlet-state exchange nmr spectroscopy for the study of very slow dynamic processes” J. Am. Chem. Soc. 129 328-334 (2007) Numerical calculation references Miyanishi K., Mizukami W., Motoyama M., Ichijo N., Kagawa A., Negoro M. and Kitagawa M. “Prediction of 1 H singlet relaxation via intermolecular dipolar couplings using the molecular dynamics method” J. Phys. Chem. B 126, 19, 3530-3538 (2022) [Industrial Applicability]

[0080] In this invention, the relaxation time of excited molecules is much longer than conventional methods, making it possible to observe molecular probes such as drugs administered to the human body for long periods of time. As a result, it is expected that various information that is difficult to obtain using PET diagnostic methods, such as the progression of tumors, will be obtained. In addition, this method, which allows the observation of long-term molecular behavior and metabolic processes, is expected to be applied in basic research and drug discovery research using DNP.

Claims

1. An aromatic compound composed of stable isotopes, Two adjacent carbon atoms that form part of the aromatic ring of the aromatic compound are １３ C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are directly bonded is 0, and １３ An aromatic compound in which a hydrogen atom with a spin coupling constant that is bonded to the C nucleus only through a carbon atom is replaced with a deuterium atom.

2. A mixture containing aromatic compounds composed of stable isotopes, Two adjacent carbon atoms that form part of the aromatic ring of the aromatic compound are １３ C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are directly bonded is 0, and １３ a first aromatic compound having a hydrogen atom having a spin coupling constant that is bonded to a C nucleus only via a carbon atom, and the hydrogen atom is substituted with a deuterium atom; One of the two adjacent carbon atoms constituting a part of the aromatic ring of the aromatic compound is １３ C, and the other of the two adjacent carbon atoms is １２ C, the spin quantum number of the nucleus of another atom to which the two adjacent carbon atoms are directly bonded is 0, and １３ a second aromatic compound having a hydrogen atom with a spin coupling constant that is bonded to the C nucleus only via a carbon atom, and the hydrogen atom is replaced with a deuterium atom.

3. A molecular probe for hyperpolarization comprising the aromatic compound of claim 1.

4. A metabolite comprising the aromatic compound of claim 1.

5. A diagnostic agent comprising the aromatic compound of claim 1.

6. A derivatizing agent comprising the aromatic compound of claim 1.

7. A compound produced by binding the derivatizing agent according to claim 6 with a diagnostic agent or a metabolite.

8. A naphthalene derivative represented by formula (1): 【Chemistry 1】 In formula (1), R １ are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide.

9. A compound produced by binding the naphthalene derivative according to claim 8 with a diagnostic agent or a metabolite.

10. A catechol derivative represented by formula (2): 【Chemistry 2】 In formula (2), R ２ and R ３ R are each independently any one group selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide. ４ are each independently any one group selected from the group consisting of a deuterium atom, an alkyl group, an aryl group, and a monovalent group derived from an alkene, an alkyne, an amine, a silyl, a carbonyl compound, an ether, a thiol, an ester, a phosphate ester, or a sulfoxide. ４ At least one of the atoms is a deuterium atom.

11. A compound produced by binding the catechol derivative according to claim 10 with a diagnostic agent or a metabolite.

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