Targeted dopamine D3 receptor molecular probe as well as preparation method and application thereof

Abstract

The invention relates to a targeted dopamine D3 receptor molecular probe as well as a preparation method and application thereof, 7-methoxy-2-(N-propyl) amino tetrahydronaphthalene is taken as a raw material, acylation, deprotection, substitution and hydroxyl protection reaction are carried out, then a precursor is marked by utilizing a nucleophilic substitution reaction of < 18 > F, and a drug [< 18 > F] standard substance of a dopamine D3 receptor is obtained. The drug has good in-vitro stability, low radioactive uptake in skull, stability of more than 90% after incubation in normal saline for 5 h, good in-vivo stability, and negligible defluorination [< 18 > F] effect; the antibody has specific binding to a dopamine D3 receptor at an animal level; the logP value is 1.97, and the dopamine D3 can penetrate through a blood brain barrier to enter the brain, so that a dopamine D3 receptor in the brain is subjected to tracing imaging, and the imaging effect is good. The molecular probe targeting the dopamine D3 receptor has a great prospect in clinical application of diagnosis, treatment and curative effect monitoring of diseases related to the dopamine D3 receptor.

Description

Technical Field

[0001] This invention relates to a method for preparing a molecular probe targeting the dopamine D3 receptor and its application. A D3 receptor molecular probe with high affinity, high selectivity, appropriate lipophilicity and ideal metabolic properties in vivo was designed, belonging to the field of chemical technology. Background Technology

[0002] Dopamine is an important neurotransmitter that functions through its corresponding membrane receptors. It is an endogenous nitrogen-containing organic compound with the molecular formula C8H2O. 11 NO2, a type of catecholamine, was proposed by the late Swedish scientist Arvid Carlsson. It plays an important physiological role in the human body, functioning as both a hormone and a neurotransmitter. It is widely distributed and abundant in the brain, serving as a mediator for many functions in the central nervous system, such as exploration, perception, and reward. Dopamine is primarily produced in the basal ganglia of the brain, particularly the substantia nigra and ventral tegmentum. The substantia nigra is mainly associated with motor control, while the ventral tegmentum connects to the prefrontal cortex and participates in cognitive functions such as decision-making and motivation formation. Currently, dopamine receptors are classified into five types: DRD1, DRD2, DRD3, DRD4, and DRD5. D3 receptors are mainly distributed in the limbic regions of the brain, such as the ventral striatum complex, which consists of the nucleus accumbens, olfactory tubercle, ventral globus white, ventral tegmentum, and Calleja's island. D3 receptors play a crucial role in addiction, schizophrenia, Parkinson's disease, and related disorders.

[0003] Positron emission tomography (PET) is an advanced clinical imaging technique in the field of nuclear medicine that can... 18 F, 11 C 13 Positron emission tomography (PET) scans, using positron emission tomography (PET) to detect the accumulation of positron-emitting radionuclides in local organs and tissues, reflecting the state of the body's tissues. Modern medicine utilizes PET scans to detect these accumulations. 18 Using other radiolabeled compounds such as F, combined with images, we can analyze the lesion areas in the human body, thereby more accurately and efficiently diagnosing and treating diseases.

[0004] One of the key steps in realizing this technology is the development of highly efficient molecular probes. Currently reported molecular probes for the dopamine D3 receptor have varying structures, but for clinical application, the ligands require very high standards, including high affinity, high selectivity, appropriate lipophilicity, and ideal metabolic properties in vivo. Summary of the Invention

[0005] The technical problem solved by this invention is that the current clinical and commercially available drugs lack highly selective dopamine D3R molecular probes, which seriously hinders research on the distribution and function of dopamine D3 receptors. This invention... 18 F-labeled molecular probes targeting D3R exhibit good in vivo stability and meet clinical needs for the diagnosis, treatment, and efficacy monitoring of D3R-related diseases.

[0006] To solve the above-mentioned technical problems, the technical solution proposed by this invention is: a molecular probe targeting the dopamine D3 receptor, wherein the molecular probe is [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-valerate)aminotetrahydronaphthyl, and the structural formula of the molecular probe is as follows:

[0007]

[0008] To address the aforementioned technical problems, another technical solution proposed by this invention is: a method for preparing the dopamine D3 receptor-targeting molecular probe, the synthetic route of which is shown below:

[0009] Includes the following steps:

[0010] (1) Dissolve 7-methoxytetrahydronaphthone and n-propylamine in ethanol, then add reducing agent and acid. Under inert gas protection, stir the reaction at room temperature for 72 h. After the reaction is completed, add acid dropwise to adjust pH=2. After vacuum distillation, a light yellow solid is obtained. After separation, adjust pH≥9 with saturated sodium bicarbonate solution, extract with organic solvent, separate, dry with anhydrous sodium sulfate, and then purify by column chromatography to obtain a light yellow solid 7-methoxy-2-(N-propyl)aminotetrahydronaphthone.

[0011] (2) Dissolve the 7-methoxy-2-(N-propyl)aminotetrahydronaphthyl chloride obtained in step (1) in an organic solvent, add alkali, stir at room temperature for 4 hours, extract and separate with organic solution, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a light yellow solid 7-methoxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthyl chloride;

[0012] (3) Dissolve the 7-methoxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthalene obtained in step (2) in an organic solvent. Then, cool the reaction flask to -78°C and slowly add a demethylating agent. After slowly returning to room temperature, stir the reaction for 12 hours. Then add alcohol and react for 4 hours. After the reaction is complete, extract and separate with an organic solution. Dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a light yellow solid 7-hydroxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthalene.

[0013] (4) Dissolve the 7-hydroxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl obtained in step (3) in an organic solvent, then add DHP and PPTS, stir at room temperature for 24 h, after the reaction is completed, extract and separate with organic solution, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain colorless solid 7-tetrahydropyranyl-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl;

[0014] (5) Dissolve the 7-tetrahydropyrano-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthalene obtained in step (4) in 1 mL of ultrapure acetonitrile solution, then add... 18 F - The solution (prepared using a GE PETtrace cyclotron) was reacted at 110°C for 10 min, followed by the addition of hydrochloric acid and a further reaction at 110°C for 10 min. After the reaction was completed, the pH was adjusted to neutral using an alkali, and the product was purified and separated by high performance liquid chromatography to obtain [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene.

[0015] (6) Dissolve the 7-hydroxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl obtained in step (3) in an organic solvent, add potassium fluoride and tetrabutylammonium fluoride, stir at room temperature for 24 h, then quench with water, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a pale yellow product, namely 7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthyl.

[0016] Preferably, the organic solvent in step (1) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; the reducing agent is one of lithium aluminum hydride, sodium borohydride, sodium triacetyl borohydride and sodium cyanoborohydride; and the acid is one of acetic acid, hydrochloric acid and sulfuric acid.

[0017] Preferably, the organic solvent in step (2) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; and the base is one of potassium carbonate, sodium carbonate and sodium bicarbonate.

[0018] Preferably, the organic solvent in step (3) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; the demethylating agent is one of boron tribromide, boron trichloride and aluminum tribromide; and the alcohol is one of methanol, ethanol and propanol.

[0019] Preferably, the organic solvent in step (4) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene.

[0020] Preferably, the acid in step (5) is one of acetic acid, hydrochloric acid, and sulfuric acid; and the base is one of potassium carbonate, sodium carbonate, and sodium bicarbonate.

[0021] Preferably, the organic solvent in step (6) is one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate and toluene.

[0022] To address the aforementioned technical problems, another technical solution proposed by this invention is the application of the dopamine D3 receptor-targeting molecular probe, wherein the 18F-labeled D3R-targeting molecular probe with good in vivo stability is used to prepare reagents for clinical diagnosis, treatment, and efficacy monitoring of D3R-related diseases.

[0023] Beneficial effects of the invention:

[0024] Currently, the lack of highly selective dopamine D3R molecular probes in clinical and commercial applications severely hinders research on the distribution and function of dopamine D3 receptors. The 18F-labeled molecular probe targeting D3R of this invention exhibits good in vivo stability and meets the clinical needs for diagnosis, treatment, and efficacy monitoring of D3R-related diseases.

[0025] Fluorine-18 has a relatively long half-life (t). 1 / 2 =110 minutes), which is more suitable for more complex multi-step organic synthesis and clinical applications.

[0026] The preparation method of the dopamine D3R molecular probe of this invention is simple, without special requirements for high temperature, high pressure, or sensitive reagents, and can be completed with ordinary reaction equipment. Product purification uses solvent extraction, column chromatography, and high-performance liquid chromatography (HPLC), which are simple and easy to implement, resulting in high product yield and purity (including radiochemical purity). Experiments show that the product of this invention, [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene, has good in vitro stability, low radioactive uptake in the skull, and greater than 90% stability after incubation in physiological saline for 5 hours. It also exhibits good in vivo stability. [Fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene has good in vitro stability, low radioactive uptake in the skull, and greater than 90% stability after incubation in physiological saline for 5 hours. 18 The effect of F is negligible; it specifically binds to the dopamine D3 receptor at the animal level; with a logP value of 1.97, it can cross the blood-brain barrier and enter the brain, thereby enabling tracking and imaging of the dopamine D3 receptor in the brain. It is a specific dopamine D3 receptor molecular probe. Attached Figure Description

[0027] The present invention will be further described below with reference to the accompanying drawings.

[0028] Figure 1 drug[ 18 Synthesis route of F] standard.

[0029] Figure 2 HPLC chromatogram of the standard.

[0030] Figure 3 drug[ 18 The radioactive HPLC spectrum of the F standard.

[0031] Figure 4 drug[ 18 [F] Radiometric HPLC spectrum of the standard after standing in physiological saline solution for 5 hours.

[0032] Figure 5 Rats were injected with the drug via the tail vein. 18 F] standard, and tail vein injection drugs [ 18 F] Head and whole-body PET imaging results after standard and D3 receptor blocker BP897.

[0033] Figure 6 Rats were injected with the drug via the tail vein. 18 F] TAC curve of the standard.

[0034] Figure 7 Tail vein injection of drugs 18 [F] TAC curves in the brain after testing the standard and the D3 receptor blocker BP897. Detailed Implementation

[0035] Example 1:

[0036] [ 18 Synthesis of F] Standards

[0037] (1) 3.6 g (20 mmol) of 7-methoxytetrahydronaphthone and 5 mL of n-propylamine were dissolved in ethanol, followed by the addition of 1.5 g of sodium cyanoborohydride and 4 mL of acetic acid. The reaction was carried out under inert gas protection at room temperature with stirring for 72 h. After the reaction was completed, concentrated hydrochloric acid was added dropwise to adjust the pH to 2. After vacuum distillation, a light yellow solid was obtained. After separation, the pH was adjusted to ≥9 with saturated sodium bicarbonate solution, and the solid was extracted with dichloromethane. After separation and drying with anhydrous sodium sulfate, the solid was purified by column chromatography to obtain 3.5 g of the light yellow solid 7-methoxy-2-(N-propyl)aminotetrahydronaphthone, i.e., 7-methoxy-2-(N-propyl)aminotetrahydronaphthone, with a yield of 78%. The synthetic route is shown in [reference needed]. Figure 1 Compound 1: 1H NMR(500MHz,Chloroform-d)δ6.99(d,J=8.3Hz,1H),6.68(dd,J=8.4,2.8Hz,1H),6.61(d,J=2.7Hz,1H),3.76(s,3H),3.05–2.87(m,2H),2.82(dt,J=16.4, 5.0Hz,1H),2.75(td,J=10.9,5.4Hz,1H),2.68(t,J=7.4Hz,2H),2.59(dd,J=1 5.8,9.4Hz,1H),2.09–2.00(m,1H),1.64–1.49(m,3H),0.95(t,J=7.4Hz,3H).

[0038] (2) The 7-methoxy-2-(N-propyl)aminotetrahydronaphthyl (438 mg, 2 mmol) obtained in step (1) was reacted with 5-bromopentanoyl chloride (396 mg, 2 mmol) in 10 mL of dichloromethane. 306 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 4 h. The mixture was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 678 mg of the light yellow solid 7-methoxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthyl, with a yield of 81%. The synthetic route is shown below. Figure 1 .

[0039] Compound 3: 1 H NMR(500MHz,Chloroform-d)δ7.00(dd,J=19.5,8.4Hz,2H),6.71(ddd,J=22.0,8.5, 2.7Hz,2H),6.64–6.56(m,2H),3.79–3.72(m,7H),3.19–3.08(m,3H),3.08–2.89(m, 4H),2.92–2.82(m,3H),2.82–2.76(m,2H),2.48–2.32(m,4H),2.05–1.94(m,1H),1. 98–1.87(m,6H),1.88–1.75(m,3H),1.69–1.55(m,2H),0.92(dt,J=18.1,7.4Hz,6H).

[0040] (3) The 7-methoxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthyl (765 mg 2 mmol) obtained in step (2) was dissolved in 8 mL of dichloromethane. After cooling the reaction flask to -78°C, 16 mL of 1 M BBr3 dichloromethane solution was slowly added dropwise. After slowly restoring to room temperature, the mixture was stirred for 12 h. Then, 15 mL of methanol was added dropwise, and the reaction was continued for 4 h. After the reaction was completed, the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate and purified by column chromatography to obtain 477 mg of the light yellow solid 7-hydroxy-2-(N-propyl-N-5'-bromopropanoyl)aminotetrahydronaphthyl, with a yield of 65%. The synthetic route is shown in [reference needed]. Figure 1 .

[0041] 1 H NMR(500MHz,Chloroform-d)δ6.90–6.77(m,1H),6.69(ddd,J=11.3,8.1,2.6Hz,1H),6.65–6.59(m,1H),3.48–3.03(m,4H),2.93–

[0042] 2.62(m,4H),2.53–2.29(m,2H),2.00–1.47(m,8H),0.90(dt,J=23.1,7.4Hz,3H).

[0043] (4) Dissolve 368 mg of 7-hydroxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthalene obtained in step (3) in 5 ml of dichloromethane, then add 113 μL of DHP and 25 mg of PPTS. Stir the mixture at room temperature for 24 h. After the reaction is complete, extract and separate the organic layer with dichloromethane. Dry the organic layer with anhydrous sodium sulfate and then purify it by column chromatography to obtain 225 mg of colorless solid 7-tetrahydropyrano-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthalene, with a yield of 50%. The synthetic route is shown in [reference needed]. Figure 1 .

[0044] 1 H NMR(500MHz,Chloroform-d)δ7.02(dd,J=19.6,8.4Hz,1H),6.91–6.80(m,2H),3.92(ddd,J=11.6,9 .6,3.0Hz,1H),3.61(dq,J=12.1,4.2Hz,1H),3.46(dt,J=8.8,6.7Hz,2H),3.27–3.14(m,2H),3.06–

[0045] 2.97(m,0H),2.95–2.79(m,4H),2.01–1.89(m,6H),1.84(ddd,J=

[0046] 22.5,11.2,6.0Hz,4H),1.70–1.61(m,6H),0.93(dt,J=17.0,7.3Hz,3H).

[0047] M(C 22 H 34 BrNO3) = 452.26 (M + H) + 474.25 (M+Na) +

[0048] (5) Dissolve 4 mg of the 7-tetrahydropyrano-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthalene obtained in step (4) in 1 mL of ultrapure acetonitrile solution, and then add 20 mL of [unclear text - likely a typo, should be removed]. 18 F - The solution (prepared using a GE PETtrace cyclotron) was reacted at 100°C for 20 min, followed by the addition of 0.2 mL of 1 M hydrochloric acid, and the reaction was continued at 100°C for another 10 min. After the reaction was complete, the pH was adjusted to neutral using saturated sodium bicarbonate solution, and the product was purified and separated by high performance liquid chromatography (HPLC) to obtain 0.457 mg of [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene, with a yield of 16.86%. The synthetic route is shown below. Figure 1 .

[0049] (6) Dissolve 368 mg of 7-hydroxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthalene obtained in step (3) in tetrahydrofuran, add 1.16 g of KF and 20 mL of Bu4NF tetrahydrofuran solution, stir at room temperature for 24 h, then quench with water, dry the organic layer with anhydrous sodium sulfate and separate and purify by column chromatography to obtain 122 mg of pale yellow product, namely 7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene, with a yield of 40%. The synthetic route is shown in [reference needed]. Figure 1 .

[0050] Standard products: 1H NMR(500MHz,Chloroform-d)δ6.98(d,J=8.3Hz,1H),6.90(d,J=8.2Hz,1H),6.74–6.44(m,3H),4.58 –4.51(m,2H),4.44(dt,J=13.9,5.8Hz,2H),3.18(dd,J=10.2,6.5Hz,2H),3.13(ddd,J=13.5,10.7,5 .3Hz,1H),2.99–2.85(m,4H),2.84–2.69(m,4H),2.52–2.36(m,J=8.2Hz,4H),2.04–1.99(m,1H),1. 93(dq,J=11.1,6.2,4.4Hz,3H),1.89–1.71(m,9H),1.70–1.56(m,5H),0.93(dt,J=20.0,7.3Hz,6H).

[0051] 19 F NMR (471MHz, Chloroform-d) δ-218.17 (d, J = 72.1Hz).

[0052] M(C 18 H 26 FNO2) = 308.29(M+H) + 330.26 (M+Na) +

[0053] Example 2: [ 18 Radioactive purity analysis and structural verification of F] standards

[0054] The purity and retention time of the standards were determined using analytical HPLC. A Kromasil 100-5-C18 column (4.6 × 250 mm, 5 μm) was used with a detection wavelength of 254 nm. The mobile phase consisted of water (phase A) and acetonitrile (phase B) at a ratio of 55% to 45%, with a flow rate of 1 mL / min. This mobile phase was used for subsequent analysis in radiolabeling experiments. The labeled products were first analyzed using analytical Radio-HPLC to determine the success of the reaction. If successful, they were then separated using separating Radio-HPLC at a flow rate of 5 mL / min, with all other conditions remaining the same.

[0055] from Figure 2 As can be seen from this, the retention time of the standard is 8.9 min. Figure 2 After labeling and separating the precursor, the retention time of the pure labeled product was 9.1 min, which is similar to the retention time of the standard, indicating that the labeled product was obtained. Figure 3 As shown, the drug [ 18The retention time of the F standard was around 9 minutes, which corresponds to the chromatographic peak of the compound standard, indicating that the two have the same chemical structure.

[0056] Example 3: In vitro stability experiment of a drug targeting dopamine D3 receptor

[0057] Take 100 μL 18 The labeled product of F (approximately 100 μCi) was added to 1 mL of physiological saline and stored at room temperature for 5 h. Stability was observed using Radio-HPLC. The Radio-HPLC chromatogram after 5 h incubation at room temperature in physiological saline is shown below. Figure 4 When the labeled product was left to stand for 5 hours, a Radio-HPLC analysis was performed again, and the retention time was still 9.1 min, which proves that the labeled product has good stability.

[0058] Example 4: Lipid-water partition coefficient experiment of drugs targeting dopamine D3 receptor

[0059] Mix 8 mL of PBS and 8 mL of n-octanol in a 20 mL centrifuge tube, vortex thoroughly for about 15 min, and let stand overnight to allow for phase separation. After separation, the upper layer will be a water-saturated n-octanol solution, and the lower layer will be a n-octanol-saturated aqueous solution. Take 0.5 mL of n-octanol and 0.5 mL of PBS buffer solution into a 1.5 mL centrifuge tube, add 50 μCi and 10 μL of the formulation-labeled product targeting the dopamine D3 receptor molecular probe, vortex for 10 min, centrifuge at 4000 rpm for 10 min, and after the two phases separate, take 0.1 mL of the n-octanol phase from the top, measure the gamma count, and record the value N1 and time (the pipette tip used for taking the liquid should also be measured). Then take 0.25 mL of the n-octanol phase into a second 1.5 mL centrifuge tube for later use. Aspirate the remaining n-octanol to leave the centrifuge tube with a pure aqueous phase. Take 0.4 mL of the aqueous phase, measure the gamma count, and record the value N2 and time (the pipette tip used for taking the liquid should also be measured). P = N1 / N2, where logP is the lipid-water partition coefficient. Add 0.25 mL of n-octanol and 0.5 mL of water to the second centrifuge tube, and repeat the above steps (take 0.1 mL of the n-octanol phase for counting, take 0.25 mL of the n-octanol phase to the third centrifuge tube, remove excess n-octanol, and take the aqueous phase for counting). Continue this cycle until the measured P value stabilizes, obtaining the final lipid-water partition coefficient. The measured lipid-water partition coefficient of the labeled product was 1.97, indicating that the labeled product has suitable lipophilicity.

[0060] Example 5: PET (microPET) imaging experiment of a drug targeting the dopamine D3 receptor

[0061] Two rats were prepared and weighed. A mixture of 10% ethanol, 200 μCi, and 1 mL of saline containing the labeled product was injected into the rats via the tail vein. Following injection, small animal PET dynamic scanning was performed, with imaging occurring 40 minutes later. Mice were anesthetized with 3.5% isoflurane and transferred to the scanning bed. The isoflurane concentration was adjusted to 2.5%, and the oxygen flow rate was 0.6-0.8 mL / min to ensure the mice were healthy and maintained in a mildly anesthetized state. A whole-body PET scan was then performed on the other rat. For the receptor blocking experiment, the above injection anesthesia procedure was repeated. After anesthesia, the rat was first injected with BP897 (1 mg / kg), followed by the labeled product 10 minutes later, to determine the specificity of the labeled product binding. The obtained images were reconstructed using a 3D mapping and analysis algorithm, and the data were processed using PMOD software to obtain in vivo PET images of the rats.

[0062] In PET imaging, the Time Activity Curve (TAC) describes the activity of a radiotracer within a living organism over time. The Standardized Uptake Value (SUV) is an indicator used to describe the distribution of the radiotracer within the organism during PET imaging. It is calculated by dividing the radioactivity of the region of interest by the tissue mass of that region, and then multiplying this ratio by the activity of the injected radiopharmaceutical (typically MBq, megabecquerels). The formula for calculating the SUV is as follows:

[0063]

[0064] In the formula, ROI represents the radioactivity within the Region of Interest (ROI). m represents the tissue mass of the ROI, and C represents the activity of the injected drug. PET images are reconstructed using a workstation, then the ROI is plotted and quantitatively analyzed. A time-activity curve is plotted with time as the independent variable and SUV values ​​as the dependent variable.

[0065] Figure 5 These are PET images of the brain of a normal rat. Figures a through c show the images 10 min, 20 min, and 40 min after injection of the labeled product, respectively. The images show that at 10 min, the radioactive signal in the metabolic region of the head is significantly higher than that of the surrounding tissue, indicating the presence of the labeled product signal in the rat brain. This suggests a high initial uptake of the labeled product in the D2 / D3 region. At 20 min, the signal in the brain weakens, indicating that the labeled product is quickly cleared from the brain, with most of it being expelled. At 40 min, the activity of the labeled product in the brain is very low, which is consistent with... Figure 6The TAC data of the brains of normal rats are consistent. Figures d-f show the images 10 min, 20 min, and 40 min after injection of the labeled product, respectively. The images show that at 10 min, the radioactive signal in the metabolic region of the head is higher than that of the surrounding tissue, and the rat brain shows a signal of the labeled product. This indicates that the probe may be taken up by the D2 / D3 region. However, compared with the normal rat group, the ROI intensity is weaker, and the brain uptake intensity is reduced, indicating that the inhibitor may have reduced the uptake of the labeled product by dopamine receptors. The reduced brain uptake intensity may be related to the inhibition of dopamine D3 receptors, i.e., the molecular probe specifically binds to the D3 receptor. At 20 min, the signal in the brain weakens, indicating that the labeled product is quickly cleared from the brain, and most of the labeled product has been expelled. At 40 min, the labeled product in the brain is very low, which is consistent with... Figure 7 The data from TAC in the brain of the inhibited rats are consistent. Figures g-i and j-l show images of normal and inhibited rats after systemic injection of the labeled product at 10, 20, and 40 minutes, respectively. The images show that at 10 minutes, the radioactive signal in the liver and intestinal metabolic regions is significantly higher than that in surrounding tissues. Between 20 and 40 minutes, the activity of the liver and intestines decreases, which is consistent with... Figure 6 The liver TAC data of rats were consistent. To further evaluate the specific binding of the labeled product in the brain, rats underwent PET imaging, followed by time-activity curve (TAC) data analysis.

[0066] Figure 6 This is TAC from the brain of a normal rat. The curve shows that in the first 28 seconds, after injection of the labeled product, normal rats quickly cross the blood-brain barrier, and the radioactive material rapidly accumulates in the brain, reaching its peak at 28 seconds, and then rapidly declines. This is consistent with... Figure 6 This aligns with the trend observed in PET imaging.

[0067] Figure 7 It is a TAC that inhibits the rat brain. The curve shows that within the first 30 seconds, the radioactive material rapidly accumulates in the brain, quickly crosses the blood-brain barrier, reaches its peak at the 30th second, and then declines rapidly, with the trend of change being similar to... Figure 7 The trend is consistent with that shown in the PET images.

Claims

1. A molecular probe targeting the dopamine D3 receptor, characterized in that: The molecular probe is [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene, and its structural formula is as follows:

2. The method for preparing the molecular probe targeting the dopamine D3 receptor according to claim 1, characterized in that: The synthesis route is shown below: Includes the following steps: (1) Dissolve 7-methoxytetrahydronaphthone and n-propylamine in ethanol, then add reducing agent and acid. Under inert gas protection, stir the reaction at room temperature for 72 h. After the reaction is completed, add acid dropwise to adjust pH=2. After vacuum distillation, a light yellow solid is obtained. After separation, adjust pH≥9 with saturated sodium bicarbonate solution, extract with organic solvent, separate, dry with anhydrous sodium sulfate, and then purify by column chromatography to obtain a light yellow solid 7-methoxy-2-(N-propyl)aminotetrahydronaphthone. (2) Dissolve the 7-methoxy-2-(N-propyl)aminotetrahydronaphthyl chloride obtained in step (1) in an organic solvent, add alkali, stir at room temperature for 4 hours, extract and separate with organic solution, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a light yellow solid 7-methoxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthyl chloride; (3) Dissolve the 7-methoxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthalene obtained in step (2) in an organic solvent. Then, cool the reaction flask to -78°C and slowly add a demethylating agent. After slowly returning to room temperature, stir the reaction for 12 hours. Then add alcohol and react for 4 hours. After the reaction is complete, extract and separate with an organic solution. Dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a light yellow solid 7-hydroxy-2-(N-propyl-N-5'-bromopentanoyl)aminotetrahydronaphthalene. (4) Dissolve the 7-hydroxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl obtained in step (3) in an organic solvent, then add DHP and PPTS, stir at room temperature for 24 h, after the reaction is completed, extract and separate with organic solution, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain colorless solid 7-tetrahydropyranyl-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl; (5) Dissolve the 7-tetrahydropyrano-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthalene obtained in step (4) in 1 mL of ultrapure acetonitrile solution, then add... 18 F - The solution (prepared using a GE PETtrace cyclotron) was reacted at 110°C for 10 min, followed by the addition of hydrochloric acid and a further reaction at 110°C for 10 min. After the reaction was completed, the pH was adjusted to neutral using an alkali, and the product was purified and separated by high performance liquid chromatography to obtain [fluoro-18]7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthalene. (6) Dissolve the 7-hydroxy-2-(N-propyl-N-5'-bromopropionyl)aminotetrahydronaphthyl obtained in step (3) in an organic solvent, add potassium fluoride and tetrabutylammonium fluoride, stir at room temperature for 24 h, then quench with water, dry the organic layer with anhydrous sodium sulfate and then separate and purify by column chromatography to obtain a pale yellow product, namely 7-hydroxy-2-(N-propyl-N-5'-fluoro-pentanoyl)aminotetrahydronaphthyl.

3. The method for preparing the fluorine-18 labeled dopamine D3 receptor molecular probe according to claim 2, characterized in that: The organic solvent mentioned in step (1) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; the reducing agent is one of lithium aluminum hydride, sodium borohydride, sodium triacetyl borohydride and sodium cyanoborohydride; the acid is one of acetic acid, hydrochloric acid and sulfuric acid.

4. The preparation method of the molecular probe targeting dopamine D3 receptor according to claim 2, characterized in that: The organic solvent mentioned in step (2) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; the base is one of potassium carbonate, sodium carbonate and sodium bicarbonate.

5. The preparation method of the molecular probe targeting dopamine D3 receptor according to claim 2, characterized in that: The organic solvent in step (3) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene; the demethylating agent is one of boron tribromide, boron trichloride and aluminum tribromide; and the alcohol is one of methanol, ethanol and propanol.

6. The method for preparing the molecular probe targeting the dopamine D3 receptor according to claim 2, characterized in that: The organic solvent mentioned in step (4) is one of dichloromethane, acetonitrile, acetone, ethyl acetate and toluene.

7. The method for preparing the molecular probe targeting the dopamine D3 receptor according to claim 2, characterized in that: The acid mentioned in step (5) is one of acetic acid, hydrochloric acid, and sulfuric acid; the base is one of potassium carbonate, sodium carbonate, and sodium bicarbonate.

8. The method for preparing the molecular probe targeting the dopamine D3 receptor according to claim 2, characterized in that: The organic solvent mentioned in step (6) is one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate and toluene.

9. The application of the molecular probe targeting dopamine D3 receptor according to claim 1, characterized in that: The 18F-labeled molecular probe targeting D3R with good in vivo stability is used to prepare reagents for clinical diagnosis, treatment and efficacy monitoring of D3R-related diseases.

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