A Cu-based 2+ Synthesis methods and applications of imaging dual-modal probes

Abstract

The application discloses a synthesis method and application of a bimodal probe based on Cu 2+ imaging, and a structure of the bimodal probe based on Cu 2+ imaging is as follows: the bimodal probe based on Cu 2+ has high sensitivity and selectivity, and can interact with Cu 2+ under the action of Cu 2+ , and the photoacoustic signal is enhanced by 3-5 times. After the interaction with Cu 2+ , the hydrophobicity of the bimodal probe is enhanced, the interaction between the bimodal probe and proteins is further enhanced, the rotation-related time of the bimodal probe is changed, and the magnetic resonance signal is enhanced by 1-2 times. Therefore, the probe can be used as a developing agent of magnetic resonance imaging or photoacoustic imaging, and is applied to monitoring fluctuation of Cu 2+ in a living body, so as to provide a solution for in-vivo detection of metal ions.

Description

Technical Field

[0001] This invention belongs to the field of magnetic resonance imaging technology, specifically relating to a Cu-based... 2+ Synthesis method and application of imaging dual-modal probes. Background Technology

[0002] In recent years, the biomedical field has been able to accurately detect biomarkers closely related to tumors, such as the pH of biological systems, metal ions, enzymes, and biothiols. Furthermore, the detection of these biomarkers can visualize the tumor treatment process. Of particular note is the crucial role that molecular imaging technology has played in the detection of these biomarkers. Currently, various molecular imaging techniques have been applied to biomedical research, such as magnetic resonance imaging (MRI), positron emission tomography (PET), X-ray computed tomography (CT), single-photon emission computed tomography (SPECT), optical imaging, photoacoustic imaging (PA), and ultrasound imaging (US). However, single molecular imaging techniques still present many challenges in the early diagnosis and later treatment of tumors. Therefore, integrating two or more molecular imaging techniques can provide complementary molecular imaging information, perfectly addressing multiple issues related to tumor detection sensitivity, resolution, and tissue penetration. For example, MRI, as a non-invasive imaging technique, has high spatial resolution and good tissue penetration, but its sensitivity is relatively low; SPECT and PET have high sensitivity, but involve ionizing radiation and have low spatial resolution; optical imaging has high sensitivity, but is limited by autofluorescence and tissue penetration depth; photoacoustic imaging can achieve sufficiently high resolution and image contrast at certain depths, but is affected by bone and air cavities, resulting in lower sensitivity for detecting tumors. Furthermore, scientists have developed novel multimodal probe molecules targeting tumor biomarkers, which are of great significance for advancing biomedical progress and clinical research.

[0003] Copper ions are an essential metallic element in the human body, participating in physiological processes such as energy production, neuropeptide activation, gene expression, brain development, and immune function regulation. Furthermore, the dynamic balance of copper ions is closely related to various diseases, including atherosclerosis, cardiovascular disease, liver damage, Alzheimer's disease, and Wilson's disease. Therefore, achieving efficient monitoring of copper ion levels in vivo using magnetic resonance imaging and photoacoustic imaging provides an important tool for the in vivo detection of metal ions. Summary of the Invention

[0004] Based on the above-mentioned prior art, the present invention provides a Cu-based 2+ A dual-modal probe for imaging, its synthesis method, and its applications; this dual-modal probe can selectively target Cu. 2+Magnetic resonance and photoacoustic imaging were performed, with a 1-2 fold increase in the magnetic resonance signal and a 3-5 fold increase in the photoacoustic signal, enabling in vivo Cu imaging. 2+ Monitoring of this technology has enormous potential for disease diagnosis.

[0005] The technical solution adopted to achieve the above-mentioned objectives of this invention is as follows:

[0006] A Cu-based 2+ The dual-modal imaging probe has the following structural formula:

[0007]

[0008] The above is based on Cu 2+ The method for synthesizing an imaging dual-modal probe includes the following steps:

[0009] 1. Under the catalysis of potassium iodide, 2,3,3-trimethylindole reacts with 5-chloropentyne in a substitution reaction to produce compound (1), the reaction formula of which is as follows:

[0010]

[0011] 2. Under alkaline conditions, compound (1) and 2-chloro-3-(hydroxymethylene)-cyclohex-1-encarbaldehyde undergo an addition reaction to form compound (2), as shown in the following reaction formula:

[0012]

[0013] 3. Under the action of a reducing agent, dimethylpyridinium and 2,4-dihydroxybenzaldehyde undergo a reductive amination reaction to generate compound (3), as shown in the following reaction formula:

[0014]

[0015] 4. In the presence of a base, compounds (2) and (3) undergo a substitution reaction to produce compound (a), as shown in the following reaction equation:

[0016]

[0017] 5. Tri-tert-butyl triacetate of 2,2,2-(10-(2-((2-aminoethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid and azidoacetic acid undergo an amide condensation reaction under alkaline conditions to form compound (5), as shown in the following reaction formula:

[0018]

[0019] 6. Compound (5) undergoes hydrolysis in HCl-ethyl acetate solution. Upon further addition of gadolinium chloride aqueous solution, it coordinates with the compound to form compound (b). The reaction formula is as follows:

[0020]

[0021] 7. Compounds (a) and (b) undergo a Click reaction in the presence of copper sulfate and sodium ascorbate catalysts. Further addition of terpyridine triggers a copper removal reaction, yielding the Cu-based compound. 2+ The imaging dual-modal probe has the following reaction formula:

[0022]

[0023] Preferably, the temperature of the substitution reaction in step 1 is 100–130°C, and the reaction time is 12–24 h;

[0024] Preferably, the temperature of the addition reaction in step 2 is 60-80°C, the base is sodium acetate, and the reaction time is 3-6 hours.

[0025] Preferably, the temperature of the reductive amination reaction in step 3 is 25–40°C, the reducing agent is sodium triacetoxyborohydride, and the reaction time is 3–8 h.

[0026] Preferably, the temperature of the substitution reaction in step 4 is 45-80°C, the base used is potassium carbonate or cesium carbonate, and the reaction time is 12-24 hours.

[0027] Preferably, the amide condensation reaction temperature in step 5 is 25-30°C, the activator used is 2-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate, and the base is N,N-diisopropylethylamine or triethylamine.

[0028] Preferably, the hydrolysis and coordination reactions in step 6 are carried out at a temperature of 25–35°C for 3–8 hours.

[0029] Preferably, the temperature of the Click reaction in step 7 is 25-35°C, and the reaction time is 12-24 hours.

[0030] The above Cu 2+ Application of dual-modal imaging probes in the preparation of developing agents for magnetic resonance imaging or photoacoustic imaging: Gd-FL-dpa probes and Cu 2+ After interaction, the photoacoustic signal is enhanced by 3 to 5 times; the Gd-FL-dpa probe and Cu 2+ The interaction between the probe and BSA enhances the relaxation rate by 1 to 2 times, thus allowing it to be used as a contrast agent in magnetic resonance imaging or photoacoustic imaging to monitor in vivo Cu levels.2+ Fluctuations.

[0031] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0032] 1. This compound is a novel dual-mode probe, similar to Cu. 2+ There is a strong interaction with Cu 2+ It exhibits high sensitivity and selectivity, and is compatible with Cu. 2+ After combination, it has a significant enhancement effect on magnetic resonance and photoacoustic signals, and can achieve in vivo horizontal Cu 2+ Monitoring of this substance is highly effective for disease diagnosis.

[0033] 2. This compound exhibits good biocompatibility and water dispersibility, making it suitable for use in vivo at the Cu level. 2+ Dual-modal imaging using magnetic resonance and photoacoustic techniques at the living cell level for Cu 2+ It has great application potential in monitoring. Attached Figure Description

[0034] Figure 1 The dual-mode probe prepared for Example 1 at different Cu concentrations 2+ The ultraviolet-visible absorption spectrum under the influence of the action.

[0035] Figure 2 The dual-mode probe prepared for Example 1 at different Cu concentrations 2+ Fluorescence emission spectrum under the action.

[0036] Figure 3 The dual-mode probe prepared for Example 1 at different Cu concentrations 2+ The change in photoacoustic imaging signal under the influence of the agent.

[0037] Figure 4 The photoacoustic signal changes of the dual-modal probe prepared in Example 1 to metal selectivity.

[0038] Figure 5 The graph shows the changes in magnetic resonance signals of the dual-mode probe prepared in Example 1 under different systems. Detailed Implementation

[0039] The present invention will now be described in detail with reference to specific embodiments.

[0040] Example 1 based on Cu 2+ Synthesis method of dual-modal probe for imaging

[0041] 1. Synthesis of compound (1)

[0042] 1.1 Weigh 18.74 g (120.0 mmol, 1.0 eq) of 2,3,3-trimethylindole, 29.31 g (180 mmol, 1.5 eq) of potassium iodide, and 12.0 g (120.0 mmol, 1 eq) of 5-chloropentyne into a 500 mL round-bottom flask. Then add 300 mL of toluene solution to the round-bottom flask. Reflux at 125 °C for 12 h. After the reaction is complete, cool to room temperature, remove toluene by vacuum distillation to obtain a solid. Filter and wash the obtained solid with petroleum ether, ethyl acetate, and water in small amounts several times. Finally, dry in a vacuum drying oven to obtain a brownish-red solid compound (1) (10 g, yield 37.6%). The reaction formula is as follows:

[0043]

[0044] 2. Synthesis of compound (2)

[0045] Weigh 10 g (28.3 mmol, 2.4 eq) of the brownish-red solid obtained in step 1, 2.0 g (11.8 mmol, 1 eq) of 2-chloro-3-(hydroxymethylene)-cyclohex-1-encarbaldehyde, and 3.9 g (47.2 mmol, 4 eq) of sodium acetate into a 500 mL round-bottom flask. Add 300 mL of acetic anhydride to the round-bottom flask and heat to 70 °C for 6 h. After the reaction is complete, cool to room temperature and remove the acetic anhydride by vacuum distillation to obtain a solid. Filter the solid and wash it several times with petroleum ether, ethyl acetate, and water in small amounts. Finally, dry it in a vacuum drying oven to obtain a green solid compound (2) (6.4 g, yield 76.2%). The reaction formula is as follows:

[0046]

[0047] 3. Synthesis of compound (3)

[0048] Weigh 5 g (25.0 mmol, 1.0 eq) of dimethylpyridinium chloride and 7 g (50.2 mmol, 2 eq) of 2,4-dihydroxybenzaldehyde into a 250 mL round-bottom flask, add 150 mL of chloroform, heat to 60 °C for 3 h under nitrogen protection, cool to room temperature, then add 10.6 g (50.2 mmol, 2 eq) of sodium triacetoxyborohydride in small amounts several times, and react overnight at room temperature. After the reaction is complete, extract with CH2Cl2 / H2O, separate the liquid phase and retain the aqueous phase, wash three times with CH2Cl2, remove the solvent under reduced pressure, and purify the residue by column chromatography (eluent CH3OH:CH2Cl2 = 5:95, v / v) to give a white solid compound (3) (4 g, yield 50%); the reaction formula is as follows:

[0049]

[0050] 4. Synthesis of compound (a)

[0051] Weigh 2.2 g (6.8 mmol, 2 eq) of the white solid compound (3) obtained in the above experiment and 0.9 g (6.8 mmol, 2.0 eq) of potassium carbonate into a 250 mL round-bottom flask, add 150 mL of N,N-dimethylformamide, and react under nitrogen protection for 30 min. Then, use a syringe to add 2 g (3.4 mmol, 1.0 eq) of N,N-dimethylformamide mixture of compound (2) into the round-bottom flask, and react at 70 °C for 12 h. After the reaction is completed... Cool to room temperature, remove potassium carbonate by filtration to obtain a liquid, remove the solvent from the liquid under reduced pressure, extract the residue with CH2Cl2 / H2O, separate the liquid and retain the aqueous phase, wash three more times with CH2Cl2, collect the organic phase, dry with anhydrous sodium sulfate for 30 min, then remove the solvent by reduced pressure distillation, purify the residue by column chromatography (eluent CH3OH:CH2Cl2 = 6:94, v / v) to give a blue solid compound (a) (1.0 g, yield 45.5%); the reaction formula is as follows:

[0052]

[0053] 5. Synthesis of compound (5)

[0054] Weigh 126.2 mg (1.3 mmol, 1.2 eq) of azidoacetic acid and 475.0 mg (1.3 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate into a 100 mL round-bottom flask, add 15 mL of N,N-dimethylformamide, and react at room temperature for 10 min. Then add 640.0 mg (1.0 mmol, 1 eq) of tritert-butyl 2,2',2”-(10-(2-((2-aminoethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid. A mixture of 201.8 mg (1.6 mmol, 1.5 eq) of N,N-diisopropylethylamine and N,N-dimethylformamide was reacted at room temperature for 4 h. After the reaction, N,N-dimethylformamide was removed by vacuum distillation. The residue was extracted with CH2Cl2 / H2O, and the aqueous phase was separated and retained. The residue was washed three times with CH2Cl2, and the organic phase was collected and dried over anhydrous sodium sulfate for 30 min. The solvent was then removed by vacuum distillation. The residue was purified by column chromatography (eluent CH3OH:CH2Cl2 = 4:96, v / v) to give an oily compound (5) (320.1 g, yield 47.0%). The reaction formula is as follows:

[0055]

[0056] 6. Synthesis of compound (b)

[0057] Weigh 300 mg (0.43 mmol, 1.0 eq) of compound (5) obtained in the above experiment into a 100 mL round-bottom flask, add 60 mL of 4 M HCl-ethyl acetate solution, and react overnight at room temperature. A white solid precipitates. After the reaction is complete, remove the HCl-ethyl acetate solution by rotary evaporation under reduced pressure. Dissolve the residue in 30-40 mL of ultrapure water and add an aqueous solution of 226.7 mg (0.86 mmol, 2.0 eq) of gadolinium chloride. Then adjust the pH of the solution to 5.8-6.2. After the reaction is complete, remove half of the solvent by rotary evaporation under vacuum. Filter the residue through a 0.22 μm nylon filter and then purify it by reverse column chromatography. The product is freeze-dried under vacuum at -80 °C to obtain a white solid compound (b) (215.4 mg, yield 73.1%). The reaction formula is as follows:

[0058] ;

[0059] 7. Based on Cu 2+ Synthesis of dual-modal probes for imaging

[0060] Weigh 210 mg (0.32 mmol, 1.0 eq) of compound (a) and 266.6 mg (0.39 mmol, 1.2 eq) of compound (b) obtained in the above experiments into a 100 mL round-bottom flask, add 40 mL of N,N-dimethylformamide, then weigh 96.3 mg (0.49 mmol, 1.5 eq) of sodium ascorbate and 80.9 mg (0.32 mmol, 1.0 eq) of copper sulfate, dissolve them separately in 500 μL of ultrapure water, then mix the aqueous solutions of sodium ascorbate and copper sulfate and add to the flask. The reaction was carried out overnight in the reaction solution. Then, 149.0 mg (0.64 mmol, 2.0 eq) of terpyridine was weighed and dissolved in N,N-dimethylformamide, which was then added to the reaction solution. The reaction was carried out at room temperature for 6 h. After the reaction, N,N-dimethylformamide was removed by vacuum rotary evaporation. The residue was dissolved in preparative grade acetonitrile and ultrapure water (3:7, v / v), and then purified by reversed-phase column chromatography. The product was lyophilized at -80 °C to obtain a dual-modal probe based on copper ion imaging (15 mg, yield 3%), abbreviated as Gd-FL-dpa probe; the reaction formula is as follows:

[0061]

[0062] Example 2: Gd-FL-dpa probe at different Cu concentrations 2+ Experiments on ultraviolet and fluorescence spectra under the influence of [the substance]

[0063] Experimental method: The Cu-based sample prepared in Example 1 was used... 2+The imaging dual-modal probe was dissolved in ultrapure water to prepare a 1 mM Gd-FL-dpa probe stock solution. 16.0 mg of copper sulfate was weighed and dissolved in ultrapure water to prepare a 1 mM Cu... 2+ The solution was then prepared by adding the Gd-FL-dpa probe stock solution directly into HEPES buffer (100 mM, pH 7.4, 25 °C) to a final concentration of 10 μM. Subsequently, different concentrations of Cu were added. 2+ (0, 2, 4, 6, 8, 10, 12, 16, 20 μM), the UV absorption spectrum and fluorescence spectrum of each group of solutions were tested.

[0064] Experimental results: The Gd-FL-dpa probe prepared in Example 1 and Cu 2+ The ultraviolet absorption spectra of the interaction are as follows Figure 1 As shown, the maximum absorption peak red-shifts significantly from 660 nm to 680 nm, and the absorption intensity is significantly enhanced; the Gd-FL-dpa probe and Cu 2+ Interaction fluorescence spectra such as Figure 2 As shown, the fluorescence emission of the Gd-FL-dpa probe is observed in the presence of 10 μM Cu. 2+ The binding process almost quenches. This explains why Cu... 2+ It has a strong interaction with the Gd-FL-dpa probe.

[0065] Example 3: Gd-FL-dpa probe and Cu 2+ Interactive photoacoustic imaging experiment

[0066] Experimental method: The 1 mM Gd-FL-dpa probe stock solution prepared in Experiment Example 2 was directly added to HEPES buffer (100 mM, pH 7.4, 25℃) to a final concentration of 10 μM. Subsequently, different concentrations of Cu were added. 2+ After (0, 2, 4, 6, 8, 10, 20 μM), the PA signal of each group of solutions was recorded under 680 nm laser excitation.

[0067] Experimental Results: The Gd-FL-dpa probe prepared in Example 1 reacted with different concentrations of Cu 2+ After the interaction, the photoacoustic signal follows Cu 2+ Concentration changes such as Figure 3 As shown, its photoacoustic signal changes with Cu 2+ The effect gradually increases with the addition of Gd-FL-dpa probe and 10 μM Cu. 2+ Through interaction, the photoacoustic signal has reached its maximum and has been enhanced by 3 to 5 times.

[0068] Example 4: Photoacoustic Imaging Experiment of the Interaction Between Gd-FL-dpa Probe and Different Metal Ions

[0069] Experimental method: The 1 mM Gd-FL-dpa probe stock solution prepared in Experiment Example 2 was directly added to HEPES buffer (100 mM, pH 7.4, 25℃) to a final concentration of 10 μM. Then, different metal ions (Zn) were added. 2+ Fe 3+ Mg 2+ Ca 2+ Na + K + Cu 2+ The concentration of metal ions in the solution was 10 μM, and the PA signal of each group of solutions was recorded under 680 nm laser excitation.

[0070] Experimental Results: After the Gd-FL-dpa probe prepared in Example 1 interacted with different metal ions, the changes in photoacoustic signals and the different metal ions were as follows: Figure 4 As shown, the Gd-FL-dpa probe only interacts with Cu 2+ After interaction, the photoacoustic signal is enhanced by 3 to 5 times. When the Gd-FL-dpa probe interacts with other metal ions, the photoacoustic signal of the Gd-FL-dpa probe does not change significantly.

[0071] Example 5: Gd-FL-dpa probe and Cu 2+ Experiment on changes in magnetic resonance signals under action

[0072] Experimental Methods: The Gd-FL-dpa probe prepared in Example 1, bovine serum albumin (BSA), and CuSO4 were dissolved in ultrapure water to prepare 5 mM, 2.5 mM, and 5 mM solutions, respectively, to prepare four groups of Gd-FL-dpa probe solutions (Groups A to D) with different components. Group A: 5 mM Gd-FL-dpa probe was directly added to HEPES buffer (100 mM, pH 7.4, 25℃) to make the final concentrations of Gd-FL-dpa probe 0.1 mM, 0.15 mM, 0.2 mM, and 0.25 mM; Group B: Gd-FL-dpa probe concentrations and 1 eq CuSO4 were prepared... 2+ Group A: Mixtures of Gd-FL-dpa probes with different concentrations were prepared, resulting in four Gd-FL-dpa probe concentrations of 0.1 mM, 0.15 mM, 0.2 mM, and 0.25 mM. Group D: Mixtures of Gd-FL-dpa probes with different concentrations and 0.6 M BSA were prepared, resulting in four Gd-FL-dpa probe concentrations of 0.1 mM, 0.15 mM, 0.2 mM, and 0.25 mM. Group D: Mixtures of Gd-FL-dpa probes with 1 eq Cu 2+The mixture of Gd-FL-dpa and 0.6 mM BSA was used to obtain four Gd-FL-dpa probe concentrations of 0.1 mM, 0.15 mM, 0.2 mM, and 0.25 mM. The longitudinal relaxation time T1 of each solution was measured at 25 °C using a 20 MHz magnetic spectrometer, and the relaxation rate r1 of each component was calculated.

[0073] Experimental Results: After the Gd-FL-dpa probe prepared in Example 1 interacted with the substance, the Gd-FL-dpa probe exhibited different r1 values, as shown in the following figures. Figure 5 As shown, compared with the relaxation rate of the Gd-FL-dpa probe, the Gd-FL-dpa probe and Cu 2+ The interaction between the three, BSA, and BSA, increases the relaxation rate by 1 to 2 times.

Claims

1. A Cu-based 2+ A dual-modal probe for imaging, characterized in that, Its structural formula is as follows:

2. The Cu-based [method / technology] according to claim 1 2+ A method for synthesizing a dual-modal probe for imaging, characterized in that, Includes the following steps: Compounds (a) and (b) undergo a Click reaction in the presence of copper sulfate and sodium ascorbate catalysts, followed by the addition of terpyridine to undergo a copper removal reaction, yielding Cu. 2+ The imaging dual-modal probe has the following reaction formula:

3. The Cu-based method according to claim 2 2+ A method for synthesizing a dual-modal probe for imaging, characterized in that, The synthesis steps of compound (a) are as follows: (1) 2,3,3-Trimethylindole and 5-chloropentyne undergo a substitution reaction in the presence of potassium iodide catalyst to generate compound (1), as shown in the following reaction formula: (2) Under alkaline conditions, compound (1) and 2-chloro-3-(hydroxymethylene)-cyclohex-1-encarbaldehyde undergo an addition reaction to form compound (2), as shown in the following reaction formula: ； (3) Under nitrogen protection and with the aid of a reducing agent, dimethylpyridinium and 2,4-dihydroxybenzaldehyde undergo a reductive amination reaction to produce compound (3), as shown in the following reaction formula: ； (4) Under nitrogen protection and alkaline conditions, compounds (2) and (3) undergo a substitution reaction to produce compound (a), as shown in the following reaction formula:

4. The Cu-based method according to claim 2 2+ A method for synthesizing a dual-modal probe for imaging, characterized in that, The synthesis steps of compound (b) are as follows: (1) 2,2',2”-(10-(2-((2-aminoethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tritert-butyl ester and azidoacetic acid undergo an amide condensation reaction under alkaline conditions to generate compound (5), as shown in the following reaction formula: (2) Compound (5) undergoes a hydrolysis reaction in HCl-ethyl acetate solution. Further addition of gadolinium chloride aqueous solution coordinates with it to generate compound (b), as shown in the following reaction formula: 。 5. The Cu-based method according to claim 3 2+ A method for synthesizing dual-modal probes for imaging, characterized by: The temperature of the substitution reaction in step (1) is 100-130℃ and the reaction time is 12-24h; the base in step (2) is sodium acetate, the temperature of the addition reaction is 60-80℃ and the reaction time is 3-6h; the temperature of the reductive amination reaction in step (3) is 25-40℃, the reducing agent is sodium triacetoxyborohydride and the reaction time is 3-8h; the base in step (4) is potassium carbonate or cesium carbonate, the temperature of the substitution reaction is 45-80℃ and the reaction time is 12-24h.

6. The Cu-based method according to claim 4 2+ A method for synthesizing a dual-modal probe for imaging, characterized in that, The amide condensation reaction in step (1) is carried out at a temperature of 25–30°C, the activator used is 2-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate, and the base is N,N-diisopropylethylamine or triethylamine; the hydrolysis reaction and coordination reaction in step (2) are carried out at a temperature of 25–35°C and the reaction time is 3–8 h.

7. The Cu-based [system / mechanism] according to claim 1 2+ The application of dual-modal probes for imaging is characterized by, The probe is used to prepare a developing agent for magnetic resonance imaging or photoacoustic imaging.

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