A labeled fatty acid derivative, precursor compounds thereof and use thereof in imaging agents

Abstract

The present application relates to a kind of marked fatty acid derivatives, precursor compounds and its application in imaging agent, its general formula is as shown in formula I: Wherein, M is 99m Tc or Re;R, R 1 , R 2 , R 3 , R 4 and R 5 And A1-A 12 Independently be H, aliphatic chain or alicyclic;J, X, Y independently be nothing, -O-, -S-, and J, X, Y are not simultaneously nothing, R 6 ~R 14 Independently be H or aliphatic chain, and R 13 With R 14 Cannot be simultaneously H;Z is 1-6, a is 0-5, b is 0-5, c is 0-3;D is 0-27, e is 0-27, f is 0-28, g is 0-7, and in d, e, f and g, at least two are not 0.The present application provides a completely new type of structure, which can be used as a new type of myocardial metabolism imaging agent, and has important clinical application prospect.

Description

Technical Field

[0001] This invention relates to the fields of medicine and chemistry, specifically to a class of labeled isocyanate-containing fatty acid derivatives, their precursor compounds, and their applications in imaging agents. Background Technology

[0002] Fatty acids are the simplest type of lipid, and they are the building blocks of many more complex lipids. Under sufficient oxygen supply, fatty acids can be oxidized and broken down into CO2 and H2O, releasing a large amount of energy. Therefore, fatty acids are one of the body's main energy sources, especially the primary energy source for myocardial contraction.

[0003] The role of fatty acids in the myocardium: Muscle contraction requires high energy levels, thus necessitating a continuous and efficient supply of ATP to maintain contractile function, basal metabolism, and ion exchange balance. In normal human myocardium, fatty acid oxidation provides 60%-80% of the energy required for myocardial function. Additionally, the myocardium can obtain energy for physiological activities by oxidizing energy substances such as glucose, pyruvate, amino acids, and lactate. When the body is in a state of low blood glucose concentration or fasting, the heart's ability to take up fatty acids is very high; at this time, almost all of the myocardium's oxygen consumption is used for fatty acid oxidation.

[0004] When myocardial oxygen supply is sufficient, fatty acids can efficiently provide energy to the myocardium through β-oxidation; when myocardial ischemia or low oxygen supply occurs, β-oxidation of fatty acids is inhibited, and glucose metabolism is used to provide energy for myocardial metabolism, resulting in a decrease in the utilization rate of fatty acids by the myocardium.

[0005] The metabolic pathway of myocardial fatty acid imaging agents is basically similar to that of free fatty acids. Fatty acid oxidation occurs in three steps: the first step is the activation of fatty acids in the cytosol, where fatty acids are catalyzed by acyl-CoA synthase to produce acyl-CoA; the second step is the transport of acyl-CoA into the mitochondria; and the third step is the β-oxidation of acyl-CoA. After one β-oxidation, long-chain fatty acids lose two carbons from acetyl-CoA starting at the β-carbon atom, generating acyl-CoA with two fewer carbons, releasing a large amount of energy in this process.

[0006] Acyl-CoA undergoes β-oxidation in the myocardium in four steps: removal of an H atom at the α and β positions, addition of water, dehydrogenation to generate β-acyl-CoA, and thiolysis. Each step corresponds to a different enzyme: acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-OH acyl-CoA dehydrogenase, and β-ketoacyl-CoA thiolysis enzyme.

[0007] Currently, the myocardial metabolic imaging agents used clinically mainly include: those used for PET imaging. 11 [C]-palmitate and [ 18 F]-FDG, and [F]-FDG for SPECT imaging123 I]-IPPA and [ 123 I]BMIPP. (Among them) 11 The half-life of C is only 110 minutes, which places high demands on the speed of labeling and imaging. 18 F-FDG is relatively expensive, while radioactive iodine-labeled drugs are prone to deiodination in the body and must be purchased from specialized companies. Each of these different drugs has its own insurmountable drawbacks. 99m Tc possesses excellent radionuclide properties; its half-life is 6 hours, facilitating drug labeling, transportation, and use. Furthermore, it is inexpensive and readily available. Another extremely important advantage is... 99m Tc has different valences (+1 to +7), which can form various coordination structures, with coordination numbers mostly at 5, 6, and 7. Some labeling methods have been implemented for drug delivery, facilitating clinical application. However, currently there is still no... 99m Tc-labeled myocardial metabolic imaging agents have been successfully used in clinical practice.

[0008] Then in 2008, Byung Chul Lee et al. published a paper on compound […]. 99m Based on the structure of Tc]CpTT-PA, a carbonyl group was introduced to design and synthesize a compound. 99m Tc-CpTT-16-oxo-HAD aims to increase hydrophilicity and reduce hepatic uptake. This compound is metabolized in the myocardium via β-oxidation, ultimately forming the compound... 99m Tc-CpTT-4-oxo-butyric acid, compared to compound [ 99m The myocardial uptake of Tc]CpTT-PA was higher, but the background values ​​of liver, lung and kidney were also higher, and the ideal target-to-non-target ratio was not obtained.

[0009] In 2012, Zeng Huahui et al. published their findings on compounds. 99m Based on the long-chain structure of Tc-CpTT-16-oxo-HAD, an amide bond was introduced to synthesize a compound. 99m Tc-CpTT-6-oxo-HAUA, this compound is reduced in the liver, but the myocardial uptake is relatively low, with myocardial uptake at only 4.37% ID / g at 1 min.

[0010] To address the aforementioned technical problems, the applicant / inventor also investigated isocyanate-containing (labeled) aliphatic compounds. While the overall effect was significantly improved, shortcomings remained, including high background levels in the liver and lungs, and poor imaging results in the myocardium, which collectively affected further drug development. Therefore, to better realize true clinical application, the inventor's research group has been conducting research in different directions and structures for the past three years. Through these efforts, they discovered the structure in this application, which exhibits superior overall performance. Summary of the Invention

[0011] In view of this, the object of the present invention is to provide a labeled fatty acid derivative, its precursor compound, and its application in a developer, overcoming the shortcomings of the prior art. The object of the present invention is achieved through the following technical solution:

[0012] One inventive aspect of this invention is to provide a labeled fatty acid derivative, the general formula of which is shown in Formula I:

[0013]

[0014] Where M is 99m Tc or Re; R, R 1 R 2 R 3 R 4 and R 5 Independently, these six groups are H, aliphatic chains, or alicyclic groups, and may be completely identical, completely different, or partially identical groups; A1~A 12 (i.e. A1, A2, A3, A4, A5, A6, A7, A8, A9, A 10 A 11 A 12 J, X, and Y are independently H, aliphatic chains, or alicyclic chains; J, X, and Y are independently none, -O- (oxygen atom), -S- (sulfur atom), sulfone group), (sulfoxide), (sulfonic acid group) (urea bridge) Furthermore, J, X, and Y cannot all be zero simultaneously, and R... 6 ~R 14 Independently, it is an H or aliphatic chain, and R 13 ~R 14 The following cannot all be H simultaneously; z is an integer from 1 to 6, a is an integer from 0 to 5, b is an integer from 0 to 5, and c is from 0 to 3, preferably b and c are not both 0. d is an integer from 0 to 27, e is an integer from 0 to 27, f is an integer from 0 to 28, and g is an integer from 0 to 7. In a specific compound, at least two of d, e, f, and g are not 0. That is, preferably, in the structure to the right of M, the ether oxygen groups O, J, X, Y, and COOR are not directly connected to each other, but are connected through at least one C atom. For example, if J and X are absent, there is no direct connection between O and Y, or between Y and COOR.

[0015] Furthermore, at least one of J, X, and Y is an etheroxy group or a group containing an S atom. Groups containing an S atom include -S-, At least one of them.

[0016] Furthermore, J, X, and Y are independently none, -O-, -S-, and Preferably, J is none. X represents nothing. Y is -O-, -S-, More preferably, at least one of J, X, and Y is a group containing an S atom or Groups containing an S atom include -S- or

[0017] More preferably, in general formula I, J, X, and Y are more preferably any of the following combinations: J and X are both none, and Y is -S- or Alternatively, J can be none, and X can be -SO2- or Y is -S- or Or, J and X are both Y is -S- or Alternatively, J is none, X is... Y is -S- or

[0018] Furthermore, R, R 1 R 2 R 3 R 4 and R 5 All are H or aliphatic chains. Preferably, the aliphatic chain includes aliphatic hydrocarbons. More preferably, the aliphatic chain is an aliphatic hydrocarbon with 1-28 carbon atoms.

[0019] Further, a is an integer from 1 to 3 (such as 1, 2 or 3, more preferably 1); b is an integer from 1 to 3 (such as 1, 2 or 3, more preferably 1); c is an integer from 1 to 3 (such as 1, 2 or 3, more preferably 1).

[0020] R, R 1 ~R 14 and A1~A 12 (i.e., R, R) 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14,A1,A2,A3,A4,A5,A6,A7,A8,A9,A 10 A 11 A 12 Aliphatic hydrocarbons that are independently -H or have 1-5 carbon atoms, i.e., independently -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)CH3, -C(CH3)2CH2CH3, -CH2C(CH3)2CH3 or -CH(CH3)CH(CH3)CH3, and R 13 ~R 14 They cannot both be H.

[0021] d is an integer from 0 to 14, e is an integer from 0 to 14, f is an integer from 1 to 15, and g is an integer from 1 to 4.

[0022] Furthermore, the general structural formula of a labeled precursor of a fatty acid compound on the right side of Formula I is an isocyanate monomer, which is... Among them, J, X, Y, R 4 R 5 R, A3~A 12 b, c, d, e, f, and g are all consistent with those defined in any of the above paragraphs, and will not be repeated here; then the isocyanate monomer can be directly synthesized into general formula I by a one-step labeling method.

[0023] Furthermore, another labeled precursor of the fatty acid compound on the right side of Formula I has the general structural formula of an isocyanate metal salt, namely... Wherein, Q is a metal cation, preferably copper ion, cuprous ion, calcium ion, potassium ion, sodium ion, magnesium ion, or aluminum ion, more preferably copper ion or cuprous ion; E is an anion, preferably tetrafluoroborate ion (BF4). - ), hexafluorophosphate ions (PF6) - ), trifluoroacetate ion (CF3COO) - ), perchlorate ions (ClO4) - Fluoride ions, chloride ions, bromide ions, iodide ions, and more preferably tetrafluoroborate ions (BF4). - ); J, X, Y, R 4 R 5 R, A3~A 12z, b, c, d, e, f, and g are all consistent with those defined in any of the above paragraphs, and will not be repeated here; then, this isocyanate metal salt can be directly synthesized into general formula I via a one-step labeling method. Preferably, the precursor isocyanate metal salt is a copper isocyanate. Then, the isocyanocopper salt can be directly synthesized into general formula I via a one-step labeling method. Previously, similar isocyanate-containing fatty acid structures involved a two-step labeling process: first, labeling a precursor with an isocyanate carboxylic acid ester monomer to form a rhenium or technetium complex in carboxylic acid ester form, followed by hydrolysis under alkaline conditions to the final rhenium or technetium complex in carboxylic acid form. Therefore, the method of this invention significantly shortens the intermediate labeling steps and time, and in particular overcomes the instability of the previous isocyanate carboxylic acid ester monomer labeling precursor, as well as the destructive effect of the hydrolysis step under alkaline conditions on the chemical stability of these isocyanate-containing technetium complexes.

[0024] Furthermore, M is 99m Tc or Re, z is an integer from 1 to 6, a and b are both 1, c is 1, R, R 1 R 2 R 3 R 4 and R 5 Independently -H, -CH3, or -CH2CH3, A1~A 12 If all are H, then general formula I includes the following compounds:

[0025] ① When d and e are both 0, J and X are both non-existent, f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is a sulfur atom (-S-), then formula I is the following general formula II:

[0026] ②When d and e are both 0, J and X are both absent, f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is a sulfone group. When, Equation I is equivalent to the following general Equation III:

[0027] ③ When d is 0, J is absent, e is an integer from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and X is a sulfone group. When Y is a sulfur atom (-S-), Formula I is equivalent to the following general formula IV:

[0028] ④ When d and e are both integers from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and J is a sulfone group. When X is a sulfone group When Y is a sulfur atom (-S-), Formula I is equivalent to the following general formula V:

[0029] ⑤ When d is 0, J is none, e is an integer from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and X is a urea bridge. When Y is a sulfur atom (-S-), Formula I is equivalent to the following general formula VI:

[0030] ⑥ When d and e are both 0, J and X are both non-existent, f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is... When, Equation I is equivalent to the following general formula VII:

[0031] ⑦ When d and e are both 0, J and X are both non-existent, f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is... When, Equation I is the following general formula VIII:

[0032] Furthermore, when z is an integer from 1 to 6, c is 1, a and b are both 1, d and e are both 0 (i.e., excluding J and X), f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is -S-, general formula II includes, but is not limited to, the following compounds:

[0033]

[0034] When z is an integer from 1 to 6, c is 1, a and b are both 1, d and e are both 0 (i.e., excluding J and X), f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is... At that time, general formula III includes, but is not limited to, the following compounds:

[0035]

[0036]

[0037] When z is an integer from 1 to 6, c is 1, a and b are both 1, d is 0 (i.e., excluding J), e is an integer from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and X is... When Y is -S-, general formula IV includes, but is not limited to, the following compounds:

[0038]

[0039] When z is an integer from 1 to 6, c is 1, a and b are both 1, d and e are both integers from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and J is... When X is When Y is -S-, general formula V includes, but is not limited to, the following compounds:

[0040]

[0041] When z is an integer from 1 to 6, c is 1, a and b are both 1, d is 0 (i.e., excluding J), e is an integer from 1 to 14, f is an integer from 1 to 15, g is an integer from 1 to 6, and X is a urea bridge. When Y is a sulfur atom (-S-), general formula VI includes, but is not limited to, the following compounds:

[0042]

[0043] When z is an integer from 1 to 6, c is 1, a and b are both 1, d and e are both 0 (i.e., excluding J and X), f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is... At that time, the general formula VⅡ includes, but is not limited to, the following compounds:

[0044]

[0045] When z is an integer from 1 to 6, c is 1, a and b are both 1, d and e are both 0 (i.e., excluding J and X), f is an integer from 1 to 15, g is an integer from 1 to 6, and Y is... At that time, the general formula VIII includes, but is not limited to, the following compounds:

[0046]

[0047] Where M is the marked technetium 99m Tc or Re, R, R 1 R 2 R 3 R 4 and R 5 All are aliphatic hydrocarbons with H or 1-4 carbon atoms, where d is an integer from 0 to 14, e is an integer from 0 to 14, f is an integer from 1 to 15, and g is an integer from 1 to 6.

[0048] Another inventive aspect of this invention is to provide a precursor compound for preparing labeled fatty acid derivatives, wherein the precursor compound is an isocyanate monomer, and the structure of the isocyanate monomer is as follows: Among them, J, X, Y, R 4 R 5 R, A3~A 12 z, b, c, d, e, f, and g are all consistent with those defined in any of the above paragraphs, and will not be repeated here. General formula I can be synthesized from this precursor in one step.

[0049] Another inventive aspect of this invention is to provide another precursor compound for preparing labeled fatty acid derivatives, said precursor compound being an isocyanate metal salt, the structure of which is as follows: Wherein, Q is a metal cation, preferably copper ion, cuprous ion, calcium ion, potassium ion, sodium ion, magnesium ion, or aluminum ion, more preferably copper ion or cuprous ion; E is an anion, preferably tetrafluoroborate ion (BF4). - ), hexafluorophosphate ions (PF6) - ), trifluoroacetate ion (CF3COO) - ), perchlorate ions (ClO4) - Fluoride ions, chloride ions, bromide ions, iodide ions, and more preferably tetrafluoroborate ions (BF4). - ); J, X, Y, R 4 R 5 A3~A 12 z, b, c, d, e, f, and g are all consistent with those defined in any of the above paragraphs, and will not be repeated here. General formula I can be synthesized in one step from this precursor.

[0050] Another inventive point of this invention is to provide the application of a labeled fatty acid derivative according to any of the above paragraphs in a myocardial imaging agent.

[0051] The final inventive point of this invention is to provide a myocardial imaging agent comprising the general formula I described in any of the preceding paragraphs.

[0052] The main beneficial effects of this application are as follows: This invention presents a completely new structure, which creatively adds a novel and unique group to the structure of isocyanate-containing aliphatic compounds. Specifically, it adds at least one of the structures J, X, and Y in general formula I, while simultaneously modifying other parts of the structure, resulting in a completely new structural type. In this fatty acid compound, when at least one ligand terminal in the new structure is a carboxylic acid or ester group (i.e., z is not equal to 0), and a simple sulfur atom, oxygen atom, sulfone group, or similar group is added at a suitable position away from the carboxylic acid or ester group, or further, a sulfone group, urea bridge, or similar structure is added at a suitable position, this enables the fatty acid imaging agent to have high uptake and long retention time in the myocardium, low background levels in the lungs, blood, and liver, and improves the water solubility of this imaging agent.

[0053] Specifically, using the compound of this application, lung and blood background levels are very low throughout the entire process; initially, myocardial absorption is weak, while liver background is relatively high; as time progresses, liver background gradually decreases, while myocardial absorption gradually increases; especially around 60 minutes after tail vein injection, liver uptake is barely observable, while myocardial absorption is strongest at this time, resulting in very clear myocardial imaging; thereafter, with further extension of time after intravenous injection, myocardial absorption gradually weakens again until it essentially disappears. This demonstrates the characteristics of myocardial metabolic imaging agents, which are superior to traditional myocardial perfusion imaging agents, such as... 99mCompared to Tc-MIBI (which has consistently shown strong myocardial uptake), this type of imaging agent in the present invention may be able to better reflect the vitality and metabolic state of the myocardium, and be better used for the diagnosis of heart diseases and the assessment of myocardial cell survival, making it a promising candidate for myocardial fatty acid metabolism imaging agents with significant clinical application potential. Attached Figure Description

[0054] Figure 1 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 78 and its corresponding Re complex 69 co-injected; Figure 2 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 79 and its corresponding Re complex 71 co-injected; Figure 3 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 80 and its corresponding Re complex 72 co-injected; Figure 4 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 81 and its corresponding Re complex 73 co-injected; Figure 5 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 82 and its corresponding Re complex 74 co-injected; Figure 6 It is as described in Embodiment 1 of the present invention. 99m Liquid phase spectrum of Tc radioactive complex 83 and its corresponding Re complex 75 co-injected; Figure 7 The radioactivity described in Embodiment 3 of the present invention 99m Representative dynamic SPECT / CT images of Tc complex 79 in female SD rats ( Figure 7 A, Figure 7 B and Figure 7 C represents 99m (Coronal, sagittal, and cross-sectional views of dynamic SPECT / CT imaging of Tc complex 79 at 56-64 min after tail vein injection in female SD rats); Figure 8 The radioactivity described in Embodiment 3 of the present invention 99m Representative dynamic SPECT / CT images of Tc complex 80 in female SD rats ( Figure 8 A, Figure 8 B and Figure 8 C represents 99m (Coronal, sagittal, and cross-sectional views of dynamic SPECT / CT imaging of Tc complex 80 at 66-72 min after tail vein injection in female SD rats); Figure 9 It is as described in Embodiment 6 of the present invention. 99mLiquid phase spectrum of Tc radioactive complex 130 and its corresponding Re complex 127 co-injected; Figure 10 This is as described in Embodiment 10 of the present invention. 99m Liquid phase spectra of Tc radioactive complex 158 co-injected with the corresponding Re complex 157. Figure 1 , 4 In 6, compounds with shorter elution times (i.e., earlier elution times) correspond to the peaks on the left, while compounds with longer elution times (i.e., later elution times) correspond to the peaks on the right. Detailed Implementation

[0055] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention provided below is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0056] The specific synthesis processes of the compounds in categories II, III, IV, V, VI, VII, and VIII, which are individually defined in this invention, are described below. Since it is impossible to exhaustively list the synthesis processes for every protected compound, those not listed can be referred to the following methods, which are entirely feasible for those skilled in the art. Furthermore, due to space limitations, this application only describes the effects of a few structures; however, structures not listed also have similar effects.

[0057] Example 1

[0058] Organic synthetic routes and methods for labeled precursors 59-68 of typical compounds of general formula II selected in this application, as well as Re(rhenium-186) complexes 69-77 of some typical compounds and their corresponding radioactive compounds. 99m The marking routes and methods for Tc(Technetium-99m) complexes 78-83 are listed below, including cases where f in general formula II is 2, 3, 4, 5, 6, 7, 11, and g is 4; cases where f is 2 and g is 6; cases where f is 3 and g is 5; and cases where f is 6 and g is 2.

[0059] (1) The synthesis and labeling route is as follows:

[0060]

[0061]

[0062] (2) The synthesis and labeling process is as follows:

[0063] Synthesis of Intermediate 2: Starting material 1 (48.7460 g) was added to starting material 0 (39.0000 g) at 0 °C. The mixture was then stirred at 60 °C for 3 h. The reaction solution was concentrated under vacuum to obtain 50.1200 g of concentrate, yielding intermediate 2. Its characterization data are as follows: 1 HNMR (400MHz, CDCl3, δppm): 8.23 ​​(s, 1H), 6.52 (brs, 1H), 4.86 (s, 2H), 3.83 (d, J = 7.5Hz, 2H), 1.75 (s, 3H).

[0064] Synthesis of Intermediate 5: Starting material 3 (100.0000 g) was dissolved in anhydrous ethanol, and then thiourea (63.0720 g) was added. The mixture was refluxed and stirred for 20 h. After cooling to room temperature, the ethanol was removed by rotary evaporation. A 7.5 mol / L sodium hydroxide aqueous solution (1001.6756 mL) was added to the resulting mother liquor, and the mixture was heated at 90 °C for 16 h. After cooling, a 2 mol / L sulfuric acid aqueous solution was added dropwise to adjust the pH of the mixture to approximately 2. The mixture was extracted twice with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate to obtain intermediate 5 (58.6516 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ11.09 (brs, 1H), 2.55 (q, J = 7.4Hz, 2H), 2.38 (t, J = 7.0Hz, 2H), 1.64-1.79 (m, 4H), 1.37 (t, J = 7.8Hz, 1H).

[0065] Synthesis of intermediate 6: For details, please refer to "Synthesis of intermediate 5". Intermediate 12 (47.9633 g) was obtained from raw material 4 (100.0000 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ11.09 (brs, 1H), 2.53 (q, J = 7.4Hz, 2H), 2.36 (t, J = 7.4Hz, 2H), 1.58-1.69 (m, 4H), 1.31-1.45 (m, 5H).

[0066] Synthesis of Intermediate 7: Intermediate 5 (58.6520 g) was dissolved in anhydrous methanol, and then p-toluenesulfonic acid (7.5265 g) was added. The mixture was refluxed and stirred overnight. After cooling, it was concentrated under vacuum, quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, and concentrated under vacuum to obtain Intermediate 7 (45.2640 g). Its characterization data are as follows: 1H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 2.54 (q, J = 7.2Hz, 2H), 2.33 (t, J = 7.0Hz, 2H), 1.61-1.83 (m, 4H), 1.36 (t, J = 7.8Hz, 1H).

[0067] Synthesis of intermediate 8: For details, please refer to "Synthesis of intermediate 7". Intermediate 12 (42.5464 g) was obtained from starting material 6 (47.9633 g) and p-toluenesulfonic acid (5.0905 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ11.09 (brs, 1H), 2.53 (q, J = 7.4Hz, 2H), 2.36 (t, J = 7.4Hz, 2H), 1.58-1.69 (m, 4H), 1.31-1.45 (m, 5H).

[0068] Synthesis of Intermediate 10: Starting material 9 (30.0000 g) was dissolved in anhydrous ethanol, and then thiourea (13.2158 g) was added. The mixture was refluxed and stirred for 18 h. After cooling to room temperature, the ethanol was removed by rotary evaporation. An aqueous solution of sodium hydroxide (7.5670 g) was added to the resulting mother liquor, and the mixture was refluxed and stirred for another 1 h. After cooling, the mixture was extracted twice with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate to obtain intermediate 10 (7.0458 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.59 (s, 3H), 2.46 (t, J = 7.2Hz, 2H), 2.25 (t, J = 7.5Hz, 2H), 1.52-1.61 (m, 4H), 1.32-1.39 (m, 2H).

[0069] Synthesis of Intermediate 19: Starting material 12 (12.0000 g), intermediate 7 (17.0790 g), and anhydrous potassium carbonate (16.8546 g) were stirred overnight at room temperature. The mixture was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain intermediate 19 (14.6364 g). Characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.72(t,J=6.4Hz,2H),3.67(s,3H),2.70(t,J=6.5Hz,2H),2 .55(t,J=7.2Hz,2H),2.34(t,J=7.3Hz,2H),1.67-1.77(m,2H),1.57-1.67(m,2H).

[0070] Synthesis of Intermediate 20: For details, please refer to "Synthesis of Intermediate 19". Intermediate 20 (13.3987 g) was obtained from raw material 13 (15.0000 g), intermediate 7 (19.1953 g), and anhydrous potassium carbonate (18.9431 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.69(t,J=6.2Hz,2H),3.67(s,3H),2.61(t,J=7.3Hz,2H),2.53(t,J= 7.2Hz,2H),2.34(t,J=7.3Hz,2H),1.78-1.86(m,2H),1.68-1.77(m,2H),1.57-1.67(m,2H).

[0071] Synthesis of Intermediate 21: For details, please refer to "Synthesis of Intermediate 19". Intermediate 21 (6.6741g) was obtained from raw material 14 (8.8499g), intermediate 7 (10.2868g), and anhydrous potassium carbonate (10.1516g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.66 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 2.50-2.55 (m, 4H), 2.34 (t, J = 7.2 Hz, 2H), 1.57-1.76 (m, 8H).

[0072] Synthesis of Intermediate 22: For details, please refer to "Synthesis of Intermediate 19". Intermediate 22 (24.6306 g) was obtained from raw material 15 (15.0000 g), intermediate 7 (23.9565 g), and anhydrous potassium carbonate (23.6417 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),3.37(t,J=8.6Hz,2H),3.18(t,J=7.3Hz,1H),2.29-2. 33(m,4H),2.15(t,J=5.4Hz,2H),1.48-1.54(m,2H),1.34-1.41(m,6H),1.22-1.28(m,2H).

[0073] Synthesis of Intermediate 23: For details, please refer to "Synthesis of Intermediate 19". Intermediate 23 (18.0194 g) was obtained from raw material 16 (15.0000 g), intermediate 7 (14.7344 g), and anhydrous potassium carbonate (14.5408 g). Its characterization data are as follows: 1H NMR (400MHz, CDCl3, CDCl3): δ3.67(s,3H),3.61(t,J=5.2Hz,2H),2.49-2.53(m,4H),2.45(t, J=7.3Hz,1H),2.34(t,J=7.3Hz,2H),1.69-1.76(m,2H),1.53-1.65(m,6H),1.37-1.46(m,4H).

[0074] Synthesis of Intermediate 24: For details, please refer to "Synthesis of Intermediate 19". Intermediate 24 (12.8443 g) was obtained from raw material 17 (23.7877 g), intermediate 7 (23.3666 g), and anhydrous potassium carbonate (23.0595 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 3.64 (t, J = 6.6Hz, 2H), 2.51 (q, J = 7.0Hz, 4H) ,2.34(t,J=7.3Hz,2H),1.70-1.76(m,2H),1.54-1.65(m,6H),1.30-1.43(m,6H).

[0075] Synthesis of Intermediate 25: For details, please refer to "Synthesis of Intermediate 19". Intermediate 25 (19.9610 g) was obtained from raw material 18 (34.3875 g), intermediate 7 (24.3474 g), and anhydrous potassium carbonate (24.0274 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 3.64 (t, J = 6.6Hz, 2H), 2.48-2.53 (m, 4H), 2 .33(t,J=7.2Hz,2H),1.70-1.77(m,2H),1.53-1.65(m,6H),1.29-1.39(m,15H).

[0076] Synthesis of Intermediate 26: For details, please refer to "Synthesis of Intermediate 19". Intermediate 26 (5.4869 g) was obtained from raw material 12 (5.7779 g), intermediate 8 (9.7797 g), and anhydrous potassium carbonate (8.1154 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.72(t,J=6.2Hz,2H),3.67(s,3H),2.71(t,J=6.2Hz,2H),2 .52(t,J=7.4Hz,2H),2.31(t,J=7.5Hz,2H),1.54-1.67(m,4H),1.30-1.44(m,4H).

[0077] Synthesis of Intermediate 27: For details, please refer to "Synthesis of Intermediate 19". Intermediate 27 (5.7569 g) was obtained from raw material 13 (10.0000 g), intermediate 10 (14.0082 g), and anhydrous potassium carbonate (12.6287 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.66(t,J=6.1Hz,2H),3.60(s,3H),2.55(t,J=7.1Hz,2H),2.46(t,J= 7.3Hz,2H),2.25(t,J=7.5Hz,2H),1.72-1.81(m,2H),1.50-1.62(m,4H),1.30-1.40(m,2H).

[0078] Synthesis of Intermediate 28: For details, please refer to "Synthesis of Intermediate 19". Intermediate 28 (9.9812 g) was obtained from raw material 16 (10.0260 g), intermediate 11 (7.9847 g), and anhydrous potassium carbonate (9.7191 g). Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.84(brs,1H),3.70(s,3H),3.59(t,J=6.6Hz,2H),2.77(t,J=7.4H z, 2H), 2.61 (t, J = 7.4Hz, 2H), 2.53 (t, J = 7.4Hz, 2H), 1.51-1.63 (m, 4H), 1.33-1.45 (m, 4H).

[0079] Synthesis of Intermediate 29: Intermediate 2 (5.0308 g), Intermediate 19 (14.6364 g), and mercuric acetate (20.0543 g) were dissolved in dichloromethane. The mixture was stirred overnight at room temperature, filtered, and the filtrate was concentrated under vacuum. The concentrate was dissolved in methanol, and sodium borohydride (2.0350 g) was added. The mixture was stirred at room temperature for 60 min, filtered, and the filtrate was concentrated under vacuum. The concentrate was redissolved in dichloromethane, filtered again, and concentrated under vacuum. Separation was performed using silica gel column chromatography to obtain relatively pure Intermediate 29 (3.4613 g).

[0080] Synthesis of intermediate 30: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 30 (1.2856g) was obtained from intermediate 2 (4.2922g), intermediate 20 (13.3987g), mercuric acetate (17.1099g) and sodium borohydride (1.7363g).

[0081] Synthesis of intermediate 31: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 31 (1.4626 g) was obtained from intermediate 2 (2.0019 g), intermediate 21 (6.6741 g), mercuric acetate (7.9800 g), and sodium borohydride (0.8098 g). Its characterization data are: HRMS: calcd 342.1715 (M+Na), found 342.1710 (M+Na).

[0082] Synthesis of intermediate 32: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 32 (2.4097g) was obtained from intermediate 2 (4.6169g), intermediate 22 (16.3720g), mercuric acetate (18.4044g) and sodium borohydride (1.8676g).

[0083] Synthesis of intermediate 33: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 33 (3.7046g) was obtained from intermediate 2 (4.7944g), intermediate 23 (18.0194g), mercuric acetate (19.1121g) and sodium borohydride (1.9394g).

[0084] Synthesis of Intermediate 34: For details, please refer to "Synthesis of Intermediate 29". Relatively pure Intermediate 34 (1.8431 g) was obtained from Intermediate 2 (1.6048 g), Intermediate 24 (6.3720 g), mercuric acetate (6.3971 g), and sodium borohydride (0.6492 g). Its characterization data: HRMS: calcd 362.2365 (M+H) + Found 362.2484(M+H) + ,calcd 384.2184(M+Na) + Found 384.2306(M+Na) + .

[0085] Synthesis of Intermediate 35: For details, please refer to "Synthesis of Intermediate 29". Relatively pure Intermediate 35 (1.3249 g) was obtained from Intermediate 2 (1.3669 g), Intermediate 25 (6.5880 g), mercuric acetate (5.4488 g), and sodium borohydride (0.5529 g). Its characterization data: HRMS: calcd 418.2991 (M+H) + Found 418.2993(M+H) + ,calcd440.2810(M+Na) + Found 440.2809(M+Na) + .

[0086] Synthesis of intermediate 36: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 36 (1.3966g) was obtained from intermediate 2 (1.6458g), intermediate 26 (5.4869g), mercuric acetate (6.5605g) and sodium borohydride (0.6657g).

[0087] Synthesis of intermediate 37: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 37 (2.9145g) was obtained from intermediate 2 (1.7267g), intermediate 27 (5.7569g), mercuric acetate (6.8834g) and sodium borohydride (0.6985g).

[0088] Synthesis of intermediate 38: For details, please refer to "Synthesis of intermediate 29". Relatively pure intermediate 38 (2.9414g) was obtained from intermediate 2 (2.9938g), intermediate 28 (9.9812g), mercuric acetate (11.9342g) and sodium borohydride (1.2110g).

[0089] Synthesis of isocyanate intermediate 39: Intermediate 29 (3.4613 g) was dissolved in dichloromethane, and then triethylamine (3.3293 g) and phosphorus oxychloride (2.0032 g) were added. The mixture was then stirred at room temperature for 20–30 min. The solution was then quenched with a 20% (w / w) potassium carbonate aqueous solution, extracted with dichloromethane, concentrated under vacuum, and separated by silica gel column chromatography to obtain isocyanate intermediate 39 (0.4163 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),3.55(t,J=6.8Hz,2H),3.38(s,2H),2.66(t,J=6.8Hz,2H),2 .59(t,J=7.2Hz,2H),2.34(t,J=7.3Hz,2H),1.70-1.75(m,2H),1.60-1.66(m,2H),1.29(s,6H).

[0090] Synthesis of isocyanate intermediate 40: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 40 (0.3249 g) was obtained from intermediate 30 (1.2856 g), triethylamine (1.1798 g), and phosphorus oxychloride (0.7099 g). Characterization data: 1H NMR (400MHz, CDCl3): δ3.67(s,3H),3.46(t,J=6.0Hz,2H),3.37(s,2H),2.60(t,J=7.1Hz,2H),2.52(t,J= 7.2Hz,2H),2.34(t,J=7.3Hz,2H),1.77-1.85(m,2H),1.69-1.77(m,2H),1.60-1.66(m,2H),1.28(s,6H).

[0091] Synthesis of isocyanate intermediate 41: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 41 (0.6590 g) was obtained from intermediate 31 (1.4626 g), triethylamine (1.2833 g), and phosphorus oxychloride (0.7721 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 3.33-3.41 (m, 4H), 2.48-2.57 (m, 4H), 2.34 (t, J = 7.3Hz, 2H), 1.70-1.78 (m, 2H), 1.60-1.67 (m, 6H), 1.27 (s, 6H).

[0092] Synthesis of isocyanate intermediate 42: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 42 (0.6418 g) was obtained from intermediate 32 (2.4097 g), triethylamine (2.0253 g), and phosphorus oxychloride (1.2186 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),3.33-3.39(m,4H),2.48-2.54(m,4H),2.34(t,J =7.3Hz,2H),1.69-1.76(m,2H),1.53-1.64(m,6H),1.42-1.49(m,2H),1.27(s,6H).

[0093] Synthesis of isocyanate intermediate 43: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 43 (1.0299 g) was obtained from intermediate 33 (3.7046 g), triethylamine (2.9881 g), and phosphorus oxychloride (1.7979 g). Characterization data: 1H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 3.32-3.39 (m, 4H), 2.47-2.55 (m, 4H), 2.34 (t, J = 7.3Hz ,2H),1.69-1.77(m,2H),1.51-1.65(m,6H),1.35-1.44(m,J=4.5,3.4Hz,4H),1.27(s,6H).

[0094] Synthesis of isocyanate intermediate 44: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 44 (0.8140 g) was obtained from intermediate 34 (1.8431 g), triethylamine (1.4289 g), and phosphorus oxychloride (0.8598 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.67 (s, 3H), 3.31-3.38 (m, 4H), 2.50 (q, J = 7.3Hz, 4H), 2.33 (t ,J=7.3Hz,2H),1.69-1.77(m,2H),1.50-1.64(m,6H),1.31-1.42(m,6H),1.27(s,6H).

[0095] Synthesis of isocyanate intermediate 45: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 45 (0.9372 g) was obtained from intermediate 35 (1.3249 g), triethylamine (1.4289 g), and phosphorus oxychloride (0.8598 g). Characterization data: 1 H NMR(400MHz, CDCl3): δ3.67(s,3H),3.31-3.39(m,4H),2.46-2.54(m,4H), 2.33(t,J=7.3Hz,2H),1.42-1.81(m,9H),1.27-1.41(m,13H),1.27(s,6H).

[0096] Synthesis of isocyanate intermediate 46: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 46 (0.4487 g) was obtained from intermediate 36 (1.3966 g), triethylamine (1.2254 g), and phosphorus oxychloride (0.7373 g). Characterization data: 1H NMR (400MHz, CDCl3): δ3.67(s,3H),3.55(t,J=6.8Hz,2H),3.38(s,2H),2.66(t,J=6.9Hz,2H),2 .56(t,J=7.4Hz,2H),2.31(t,J=7.5Hz,2H),1.56-1.66(m,4H),1.33-1.43(m,4H),1.29(s,6H).

[0097] Synthesis of isocyanate intermediate 47: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 47 (0.9000 g) was obtained from intermediate 37 (2.9145 g), triethylamine (2.5572 g), and phosphorus oxychloride (1.5386 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.46(t,J=6.1Hz,2H),3.37(s,2H),2.60(t,J=7.1Hz,2H),2.51(t,J=7.4Hz ,2H),2.32(t,J=7.5Hz,2H),1.85–1.77(m,2H),1.67–1.58(m,4H),1.46–1.39(m,2H),1.28(s,6H).

[0098] Synthesis of isocyanate intermediate 48: For details, please refer to "Synthesis of isocyanate intermediate 39". Isocyanate intermediate 48 (1.2494 g) was obtained from intermediate 38 (2.9414 g), triethylamine (2.5808 g), and phosphorus oxychloride (1.5528 g). Characterization data: 1 H NMR (400MHz, CDCl3): δ3.70(s,3H),3.31-3.39(m,4H),2.78(t,J=7.4Hz,2H),2.61(t,J =7.4Hz,2H),2.53(t,J=7.4Hz,2H),1.51-1.62(m,4H),1.34-1.42(m,4H),1.27(s,6H).

[0099] Synthesis of copper methyl ester intermediate 49: Isocyanomethyl ester intermediate 39 (0.4163 g) and tetra(acetonitrile)copper(I) tetrafluoroborate (0.1197 g) were stirred in dichloromethane at room temperature for 30-60 min, filtered, concentrated under vacuum, and separated by silica gel column chromatography to obtain relatively pure copper methyl ester intermediate 49 (0.1560 g). Alternatively, isocyanomethyl ester intermediate 39 (1.00 equivalent) and cuprous chloride (0.25 equivalent) were stirred in a mixed solvent of ethanol and dichloromethane at room temperature for 15 min, then ammonium tetrafluoroborate (1.06 equivalent) was added and stirred at 60 °C for 15 min, filtered, concentrated under vacuum, and separated by silica gel column chromatography, which also yielded relatively pure copper methyl ester intermediate 49.

[0100] Synthesis of copper salt methyl ester intermediate 50: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 50 (0.1799g) was obtained by reacting isocyanate methyl ester intermediate 40 (0.3249g) with tetra(acetonitrile)copper(I)tetrafluoroborate (0.0889g).

[0101] Synthesis of copper salt methyl ester intermediate 51: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 51 (0.5048 g) was obtained from isocyanomethyl ester intermediate 41 (0.6590 g).

[0102] Synthesis of copper salt methyl ester intermediate 52: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 52 (405.6 mg) was obtained from isocyanomethyl ester intermediate 42 (0.6418 g).

[0103] Synthesis of copper salt methyl ester intermediate 53: For details, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 53 (0.3732 g) was obtained from isocyanomethyl ester intermediate 43 (1.0229 g).

[0104] Synthesis of copper salt methyl ester intermediate 54: For details, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 54 (0.5547 g) was obtained from isocyanomethyl ester intermediate 44 (0.8140 g).

[0105] Synthesis of copper salt methyl ester intermediate 55: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 55 (0.7437 g) was obtained from isocyanomethyl ester intermediate 45 (0.9372 g).

[0106] Synthesis of copper salt methyl ester intermediate 56: For details, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 56 (0.5368g) was obtained from isocyanomethyl ester intermediate 46 (0.4487g).

[0107] Synthesis of copper salt methyl ester intermediate 57: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 57 (0.7204 g) was obtained from isocyanomethyl ester intermediate 47 (0.9000 g).

[0108] Synthesis of copper salt methyl ester intermediate 58: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49". Relatively pure copper salt methyl ester intermediate 58 (1.3991 g) was obtained from isocyanomethyl ester intermediate 48 (1.2494 g).

[0109] Synthesis of copper salt carboxylic acid labeled precursor 59: Copper salt methyl ester intermediate 49 (0.1560 g) was mixed with sodium hydroxide (0.0201 g) in a mixed solvent of tetrahydrofuran and water at a volume ratio of 4:1 and stirred at room temperature for 5-6 h. The mixture was then acidified with dilute hydrochloric acid, extracted with dichloromethane, concentrated under vacuum, and separated by silica gel column chromatography to obtain relatively pure copper salt carboxylic acid labeled precursor 59 (0.0575 g). Its characterization data are as follows: 1 H NMR (400MHz, CD3OD): δ3.78(s,8H),3.60(t,J=6.5Hz,8H),2.69(t,J=6.5Hz,8H) ,2.64(t,J=7.0Hz,8H),2.20(t,J=7.0Hz,8H),1.63-1.72(m,16H),1.30(s,24H); 13 C NMR (101MHz, CD3OD): δ174.34,162.55,73.24,62.14,32.49,32.37,29.45,25.46,22.04; 19 F NMR (376MHz, CD3OD): δ-155.44.

[0110] Synthesis of copper salt carboxylic acid labeled precursor 60: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 60 (0.1168 g) was obtained from copper salt methyl ester intermediate 50 (0.1799 g) and sodium hydroxide (0.0221 g). Characterization data: 1H NMR (400MHz, CD3OD): δ3.76(s,8H),3.51(t,J=5.8Hz,8H),2.64(t,J=7.2Hz,8H),2.56(t, J=7.1Hz,8H),2.21(t,J=7.2Hz,8H),1.77-1.86(m,8H),1.59-1.73(m,16H),1.28(s,24H); 13 C NMR (101MHz, CD3OD): δ179.88,157.70,72.79,59.89,51.05,36.33,31.42,29.90,29.26,28.49,25.23,22.09; 19 F NMR (376MHz, CD3OD): δ-155.67.

[0111] Synthesis of copper salt carboxylic acid labeled precursor 61: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 61 (0.2552 g) was obtained from copper salt methyl ester intermediate 51 (0.5048 g) and sodium hydroxide (0.0596 g). Characterization data: 1 H NMR (400MHz, CD3OD): δ3.71(s,8H),3.34(t,J=5.6Hz,8H),2.48-2.57(m,16H),2.11(t,J=7.2Hz,8H),1.54-1.67(m,32H),1.18(s,24H); 13 C NMR (101MHz, CD3OD): δ172.96,157.45,72.61,61.40,60.33,50.85,50.39,36.63,34.26,3 2.77,32.03,31.79,31.38,29.36,29.09,28.90,28.52,26.48,25.32,25.23,24.72,22.30; 19 F NMR (376MHz, CD3OD): δ-155.47; HRMS: calcd 350.0846 (M+Cu) + Found 350.0520(M+Cu) + ; calcd 637.2401(2M+Cu) + Found 637.1989(2M+Cu) + When the compound is a copper salt, the "M" in this section refers to the precise mass of the isocyanate monomer in the copper salt, and the same applies below.

[0112] Synthesis of copper salt carboxylic acid labeled precursor 62: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 62 (0.0967 g) was obtained from copper salt methyl ester intermediate 52 (0.1516 g) and sodium hydroxide (0.0596 g). Characterization data: 1 H NMR (400MHz, CD3OD): δ3.76 (s, 8H), 3.43 (t, J = 5.6Hz, 8H), 2.60 (q, J = 7.2Hz, 16H ),2.21(t,J=6.8Hz,8H),1.62-1.75(m,24H),1.50-1.62(m,16H),1.27(s,24H); 13 C NMR (101MHz, CD3OD): δ179.96,146.11,72.74,61.24,51.09,36.36,32.95,32.93,29.16,28.97,28.57,25.74,25.22,22.01; 19 F NMR (376MHz, CD3OD): δ-155.47; HRMS: calcd364.1002 (M+Cu) + Found 364.0928(M+Cu) + ; calcd 665.2714 (2M+Cu) + Found 665.2706(2M+Cu) + .

[0113] Synthesis of copper salt carboxylic acid labeled precursor 63: For details, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 63 (0.2106 g) was obtained from copper salt methyl ester intermediate 53 (0.3732 g) and sodium hydroxide (0.0407 g). Its characterization data: HRMS: calcd 378.1159 (M+Cu) + ,found378.1063(M+Cu) + ; calcd 693.3027 (2M+Cu) + Found 693.3050(2M+Cu) + .

[0114] Synthesis of copper salt carboxylic acid labeled precursor 64: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 64 (0.1134 g) was obtained from copper salt methyl ester intermediate 54 (0.3017 g) and sodium hydroxide (0.0582 g). Its characterization data: HRMS: calcd 392.1315 (M+Cu) + ,found392.1039(M+Cu)+ ;calcd 721.3340(2M+Cu) + Found 721.3295(2M+Cu) + .

[0115] Synthesis of copper salt carboxylic acid labeled precursor 65: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 65 (0.2530 g) was obtained from copper salt methyl ester intermediate 55 (0.7437 g) and sodium hydroxide (0.0680 g). Its characterization data: HRMS: calcd 448.1941 (M+Cu) + ,found448.1981(M+Cu) + .

[0116] Synthesis of copper salt carboxylic acid labeled precursor 66: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 66 (0.2180 g) was obtained from copper salt methyl ester intermediate 56 (0.5368 g) and sodium hydroxide (0.0633 g). Characterization data: 1 H NMR (400MHz, CD3OD): δ3.74(s,8H),3.59(t,J=6.8Hz,8H),2.67(t,J=6.8Hz,8H),2.61(t,J=7.5Hz ,8H),2.16-2.27(m,8H),1.56-1.64(m,16H),1.39-1.45(m,8H),1.33-1.38(m,8H),1.28(s,24H).

[0117] Synthesis of copper salt carboxylic acid labeled precursor 67: For detailed procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 67 (0.0424 g) was obtained from copper salt methyl ester intermediate 57 (0.7204 g) and sodium hydroxide (0.0850 g). Characterization data: 1 H NMR (400MHz, CD3OD): δ3.67 (s, 8H), 3.42 (t, J = 5.8Hz, 8H), 2.55 (t, J = 7.2Hz, 8H), 2.46 (t, J = 7.4Hz, 8H), 2.10 (t, J = 7.5Hz, 8H), 1.69-1.76 (m, 8H), 1.49-1.56 (m, 16H), 1.32-1.39 (m, 8H), 1.19 (s, 24H); 13 C NMR (101MHz, CD3OD): δ180.62,157.70,72.80,59.87,51.06,36.97,31.72,29.92,29.23,28.65,28.59,25.69,22.09;19 F NMR (376MHz, CD3OD): δ-155.68.

[0118] Synthesis of copper salt carboxylic acid labeled precursor 68: For details, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59". Copper salt carboxylic acid labeled precursor 68 (0.4857 g) was obtained from copper salt methyl ester intermediate 58 (1.3991 g) and sodium hydroxide (0.1651 g). Its characterization data: HRMS: calcd 350.0846 (M+Cu) + ,found350.0732(M+Cu) + ; calcd 637.2401(2M+Cu) + Found 637.2467(2M+Cu) + .

[0119] Synthesis of Re(rhenium-186) complex 69:

[0120] (1) Preparation of lyophilized kit: Tetra(2-methoxyisobutylisocyanate)copper(I)tetrafluoroborate (1.0 mg), copper salt carboxylic acid labeled precursor 59 (0.8-2.4 mg), stannous chloride dihydrate (0.025-0.075 mg), cysteine ​​hydrochloride monohydrate (0.5-1.0 mg), sodium citrate dihydrate (1.0-2.6 mg) and D-mannitol (5-20 mg) were dissolved in an appropriate amount of ultrapure water, the pH was adjusted to 5-6, and the kit was lyophilized in vials for later use.

[0121] (2) Synthesis of Re complex: The above-mentioned lyophilized reagent kit was dissolved in a mixed solvent of ethanol and water in a volume ratio of 1:1. Ammonium perperurate (2.5–3.9 mg) and stannous chloride dihydrate (2.1–3.3 mg) were then added, and the mixture was reacted at 100 °C for 30 min. After cooling, the mixture was filtered, and the filtrate was separated using a C-18 reversed-phase semi-preparative column for HPLC (high-performance liquid chromatography) to obtain Re complex 69. Its characterization data were: HRMS: calcd 1011.4997 (M). + Found 1011.5006(M) + .

[0122] Synthesis of Re complex 70: For details, please refer to "Labeling of Re complex 69". Re complex 70 was obtained from copper salt carboxylic acid-labeled precursor 60 (0.8–2.5 mg). Its characterization data: HRMS: calcd 1025.5154 (M). + ,found1025.5131(M) + .

[0123] Synthesis of Re complex 71: For details, please refer to "Labeling of Re complex 69". Re complex 71 was obtained from copper salt carboxylic acid-labeled precursor 61 (0.9–2.6 mg). Its characterization data: HRMS: calcd 1039.5283 (M) + ,found1039.5326(M) + .

[0124] Synthesis of Re complex 72: For details, please refer to "Labeling of Re complex 69". Re complex 72 was obtained from copper salt carboxylic acid-labeled precursor 62 (0.9–2.7 mg). Its characterization data: HRMS: calcd 1053.5439 (M) + ,found1053.5449(M) + .

[0125] Synthesis of Re complex 73: For details, please refer to "Labeling of Re complex 69". Re complex 73 was obtained from copper salt carboxylic acid-labeled precursor 63 (0.9–2.8 mg). Its characterization data: HRMS: calcd 1067.5629 (M). + ,found1067.5637(M) + .

[0126] Synthesis of Re complex 74: For details, please refer to "Labeling of Re complex 69". Re complex 74 was obtained from copper salt carboxylic acid-labeled precursor 64 (1.0–2.9 mg). Its characterization data: HRMS: calcd 1081.5752 (M) + ,found1081.5608(M) + .

[0127] Synthesis of Re complex 75: For details, please refer to "Labeling of Re complex 69". Re complex 75 was obtained from copper salt carboxylic acid labeled precursor 66 (0.9–2.6 mg). Its characterization data: HRMS: calcd 1039.5283 (M) + ,found1039.4426(M) + .

[0128] Synthesis of Re complex 76: For details, please refer to "Labeling of Re complex 69". Re complex 76 was obtained from copper salt carboxylic acid labeled precursor 67 (0.9–2.6 mg). Its characterization data: HRMS: calcd 1039.5283 (M) + ,found1039.4634(M) + .

[0129] Synthesis of Re complex 77: For details, please refer to "Labeling of Re complex 69". Re complex 77 was obtained from copper salt carboxylic acid labeled precursor 68 (0.9–2.6 mg). Its characterization data: HRMS: calcd 1039.5283 (M) + ,found1039.4918(M) + .

[0130] 99m Marking of Tc(Technetium-99m) complex 78: In this embodiment, due to the marking... 99m Tc complexes are radioactive, and their mass spectra cannot usually be measured directly. Therefore, it is common practice to first synthesize the corresponding Re(rhenium-186) complex using an HPLC C-18 reversed-phase semi-preparative column and measure its mass spectrum. If the product is acceptable, the same method is used to prepare... 99m Tc complexes, then compare Re complexes with the corresponding Tc complexes. 99m The liquid phase elution time of the Tc-labeled target product is used to confirm... 99m The correctness of the chemical structure of the Tc-labeled target product was confirmed using this method in other embodiments of the present invention.

[0131] (1) Preparation of lyophilized kit: Tetra(2-methoxyisobutylisocyanate)copper(I)tetrafluoroborate (1.0 mg), copper salt carboxylic acid labeled precursor 59 (0.8-2.4 mg), stannous chloride dihydrate (0.025-0.075 mg), cysteine ​​hydrochloride monohydrate (0.5-1.0 mg), sodium citrate dihydrate (1.0-2.6 mg) and D-mannitol (5-20 mg) were dissolved in an appropriate amount of ultrapure water, the pH was adjusted to 5-6, and the kit was lyophilized in vials for later use.

[0132] (2) 99m Radioactive labeling of Tc: The above-mentioned lyophilized kit was dissolved in a mixed solvent of ethanol and water in a volume ratio of 1:1, and then mixed with freshly rinsed Na... 99m TcO4 (37–3700 MBq) was reacted at 100 °C for 30 min. After cooling, the mixture was filtered, and the filtrate was separated using an HPLC (high-performance liquid chromatography) C-18 reversed-phase semi-preparative column to obtain... 99m Tc radioactive complex 78, and 99m Liquid chromatography-mass spectra of co-injection of Tc radioactive complex 78 and the corresponding Re complex 69 (methanol / water containing 1 / 1000 trifluoroacetic acid = 70 / 30, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) are shown below. Figure 1 As shown in the figure (blue text and curves represent Re complexes, red text and curves represent...), 99m Tc radioactive complex), then 99mThe elution time of Tc radiocomplex 78 (61.531 min) was basically the same as that of the corresponding Re complex 69 (63.056 min).

[0133] 99m Marking of Tc complex 79: See "" for specific procedures 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 61 (0.9–2.6 mg). 99m The liquid chromatography spectrum of Tc complex 79 co-injected with the corresponding Re complex 71 (methanol / water containing 1 / 1000 trifluoroacetic acid = 70 / 30, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 2 As shown, then 99m The elution time of Tc radiocomplex 79 (89.958 min) was basically the same as that of the corresponding Re complex 71 (91.575 min).

[0134] 99m Marking of Tc complex 80: See "" for specific procedures 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 62 (0.9–2.7 mg). 99m The liquid chromatography spectrum of Tc radioactive complex 80 and its corresponding Re complex 72 (methanol / water containing 1 / 1000 trifluoroacetic acid = 73 / 27, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 3 As shown, then 99m The elution time of Tc radiocomplex 80 (80.675 min) is basically the same as that of the corresponding Re complex 72 (82.108 min).

[0135] 99m Marking of Tc complex 81: See "" for specific procedures 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 63 (0.9–2.8 mg). 99m The liquid chromatography spectrum of Tc radioactive complex 81 and its corresponding Re complex 73 (methanol / water containing 1 / 1000 trifluoroacetic acid = 75.5 / 24.5, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 4 As shown, then 99m The elution time of Tc radioactive complex 81 (67.651 min) was basically the same as that of the corresponding Re complex 73 (69.084 min).

[0136] 99m Marking of Tc complex 82: See "" for specific procedures 99mThe labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 64 (1.0–2.9 mg). 99m The liquid chromatography spectrum of Tc radioactive complex 82 and its corresponding Re complex 74 (methanol / water containing 1 / 1000 trifluoroacetic acid = 78 / 22, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 5 As shown, then 99m The elution time of Tc radiocomplex 82 (70.350 min) was basically the same as that of the corresponding Re complex 74 (71.583 min).

[0137] 99m Marking of Tc complex 83: See "" for specific procedures 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 66 (0.9–2.6 mg). 99m The liquid chromatography spectrum of Tc radioactive complex 83 and its corresponding Re complex 76 (methanol / water containing 1 / 1000 trifluoroacetic acid = 73 / 27, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 6 As shown, then 99m The elution time of Tc radiocomplex 83 (73.083 min) was basically the same as that of the corresponding Re complex 75 (74.477 min).

[0138] Example 2

[0139] Select the corresponding radioactivity of some typical compounds of general formula II in this application. 99m The in vivo biodistribution of Tc complex 78-81 in female Sprague-Dawley (SD) rats was studied, as shown below:

[0140] (1) The experimental method is as follows:

[0141] Female SD rats (180-220g, n=3) were fasted for 12 hours before the experiment. The purified radioactive... 99mTc complexes 78-81 were prepared into physiological saline (containing 10% ethanol) solutions of approximately 250-350 μCi / mL. Female SD rats were euthanized by cervical dislocation at five time points (15, 30, 60, 120, and 240 min) after tail vein injection, via 200 μL of the above solution. Blood, brain, heart, liver, spleen, lung, kidney, muscle, bone, large intestine, small intestine, stomach, and tail were collected, weighed, and counted. The count distribution of each tissue and organ was calculated (unit: %ID / g; for large intestine, small intestine, and stomach, the unit is %ID). The data are the mean ± standard deviation of three mice at each time point. Simultaneously, 200 μL of the above solution was diluted to 20 mL to obtain the %ID before tail count deduction.

[0142] (2) Radioactivity 99m The biodistribution of Tc complex 78-81 in female Kunming mice is as follows:

[0143] Table 1 Radioactivity 99m Biodistribution data of Tc complex 79 in female SD rats (n=3, ID% / g)

[0144]

[0145] Regarding absolute myocardial uptake, our radioactivity 99m At 15, 30, 60, 120, and 240 min after tail vein injection, the absolute myocardial uptake values ​​of Tc complex 79 in female SD rats were 1.50±0.27, 2.24±0.31, 2.45±0.35, 1.54±0.45, and 0.60±0.04%ID / g, respectively. The peak absolute myocardial uptake was reached at 60 min after tail vein injection, at 2.45±0.35%ID / g. This peak value was consistent with... 99m Tc-MIBI (currently the most widely used myocardial perfusion imaging agent in the world) and [ 123 While the peak absolute myocardial uptake of BMIPP (the world's only approved fatty acid imaging agent for clinical use) varied in rats, the values ​​were generally good and acceptable. Furthermore, our radiopharmaceutical exhibited a long myocardial retention time within 15-240 minutes after tail vein injection, but also showed a clear dynamic trend of initial increase followed by decrease. 99m The absolute myocardial uptake value of Tc-MIBI changed very little with the extension of time after injection, therefore, compared with... 99m Compared to Tc-MIBI, our radioactivity 99m Tc complex 79 better reflects the strength of myocardial vitality and metabolic function.

[0146] According to literature, myocardial perfusion imaging agents99m The absolute myocardial uptake values ​​of Tc-MIBI in female SD rats were as follows: at 10, 30, and 60 min after injection, the values ​​were 3.70, 3.16, and 3.04%Dose / g, respectively (see reference 1); at 10, 20, 30, and 60 min after injection, the values ​​were 3.26±0.18, 3.07±0.21, 3.13±0.12, and 3.29±0.12%ID / g, respectively (see reference 2); at 30, 60, and 120 min after injection, the values ​​were 3.16±0.56, 3.14±0.42, and 2.83±0.25%ID / g, respectively (see reference 3). Fatty acid imaging agent [ 123 I] Absolute myocardial uptake of BMIPP in rats: at 30, 60 and 240 min after injection, the values ​​were 3.63, 4.26 and 2.27% ID / g, respectively, see reference 4.

[0147] Within 15-120 minutes after tail vein injection, our radioactivity... 99m In female SD rats, the baseline levels of Tc complex 79 in the liver and lungs gradually decreased, while the heart / liver ratio gradually increased. In particular, within 60-120 minutes after tail vein injection, the absolute myocardial uptake in female SD rats significantly exceeded the baseline level in the liver.

[0148] Our radioactivity 99m At 60 and 120 min after tail vein injection of Tc complex 79 in female SD rats, the heart / liver ratios were 3.82±1.21 and 5.55±1.38, respectively. The heart / liver ratios were high, exceeding [the expected values]. 99m The corresponding values ​​of Tc-MIBI at the same time point after tail vein injection in female SD rats, and [ 123 The corresponding value of I]BMIPP in rats 60 min after tail vein injection.

[0149] According to literature, myocardial perfusion imaging agents 99m Heart / liver ratios of Tc-MIBI in female SD rats: At 60 and 120 min post-injection, the values ​​were 2.04±0.17 and 2.96±0.34, respectively (see reference 1); at 60 min post-injection, the value was 2.65±0.22 (see reference 2); at 60 and 120 min post-injection, the values ​​were 4.25±0.84 and 4.52±1.57, respectively (see reference 3). Fatty acid imaging agent [ 123 I] BMIPP heart / liver ratio in rats: at 60 and 240 min after injection, the values ​​were 2.22 and 2.39, respectively (see reference 4).

[0150] Our radioactivity was measured at 30, 60, 120, and 240 minutes after intravenous injection.99m The heart / lung ratios of Tc complex 79 were 8.21±0.51, 17.12±3.09, 15.05±5.27, and 6.66±0.60, respectively, which were very high, exceeding [the threshold]. 99m The corresponding values ​​of Tc-MIBI at 30, 60, and 120 min after tail vein injection in female SD rats also far exceeded [ 123 [I] The corresponding values ​​of BMIPP at 30, 60 and 240 min after tail vein injection in rats.

[0151] Myocardial perfusion imaging agent 99m The heart / lung ratios of Tc-MIBI in female SD rats were as follows: at 30, 60, and 120 min post-injection, the values ​​were 5.17±0.39, 6.77±0.55, and 6.48±0.51, respectively (see reference 1); at 30 and 60 min post-injection, the values ​​were 4.66±0.24 and 7.32±0.28, respectively (see reference 2); and at 30, 60, and 120 min post-injection, the values ​​were 3.57±0.72, 6.41±1.25, and 7.97±1.89, respectively (see reference 3). Fatty acid imaging agent [ 123 I] BMIPP heart / lung ratio in rats: at 30, 60 and 240 min after injection, the values ​​were 3.16, 3.52 and 2.49, respectively, see reference 4.

[0152] Our radioactivity 99m The heart / blood ratio of Tc complex 79 was very high, with values ​​of 25.88±5.10, 56.19±13.56, 118.25±44.79, and 24.36±1.72 at 30, 60, 120, and 240 min after tail vein injection, respectively, far exceeding [ 123 [I] The corresponding values ​​of BMIPP at 30, 60, and 240 min after tail vein injection in rats, although our radiopharmaceutical heart / blood ratio is lower than that of [I] 99m The corresponding values ​​of Tc-MIBI at 30 and 60 min after tail vein injection in female SD rats were shown, but the heart / blood ratio was still very high. This is because when the heart / blood ratio is greater than 10, the difference in heart / blood ratio has almost negligible effect on myocardial imaging.

[0153] According to literature, myocardial perfusion imaging agents 99m Heart / blood ratios of Tc-MIBI in female SD rats: At 30 and 60 min post-injection, the values ​​were 104.30 and 164.50, respectively (see reference 2); at 30, 60, and 120 min post-injection, the values ​​were 114.6±34.70, 137.80±35.00, and 209.00±12.40, respectively (see reference 3). Fatty acid imaging agent [123 I] BMIPP heart / blood ratio in rats: at 30, 60 and 240 min after injection, the values ​​were 2.27, 2.51 and 2.01, respectively, see reference 4.

[0154] The above-mentioned documents 1 are: Boschi, A.; Uccelli, L.; Bolzati, C.; Duatti, A.; Sabba, N.; Moretti, E.; Di Domenico, G.; Zavattini, G.; Refosco, F.; Giganti, M.Synthesis and Biologic Evaluation of Monocationic Asymmetric 99m Tc-Nitride HeterocomplexesShowing High Heart Uptake and Improved Imaging Properties. 99m Tc-N-DBODC5,a NewMyocardial Perfusion Imaging Agent with Rapid Liver Clearance:Comparison with 99m Tc-Sestamibi and 99m Tc-Tetrofosmin in Rats. J. Nucl. Med. 2004, 45(12), 2095-2101. Reference 3 above is: Liu, S.; He, Z.-J.; Hsieh, W.-Y.; Kim, Y.-S. Evaluation of Novel Cationic 99mTc-Nitrido Complexes as Radiopharmaceuticals for Heart Imaging: Improving Liver Clearance with Crown Ether Groups. Nucl. Med. Bio. 2006, 33 (3), 419-432. The above-mentioned documents 4 are: Goodman, MM; Kirsch, G.; Knapp Jr., FFSynthesis and Evaluation of Radioiodinated Terminal p-Iodophenyl-Substitutedα-andβ-Methyl-branched FattyAcids. J. Med. Chem. 1984, 27(3), 390-397.

[0155] Table 2 Radioactivity 99m Biodistribution data of Tc complex 80 in female SD rats (n=3, ID% / g)

[0156]

[0157] Regarding myocardial perfusion imaging agents 99m The absolute myocardial uptake, heart / liver ratio, heart / liver ratio, and heart / blood ratio of Tc-MIBI in female SD rats, as well as the fatty acid imaging agent [ 123 [I] Absolute myocardial uptake values ​​of BMIPP in rats: absolute myocardial uptake values, heart / liver ratio, heart / liver ratio, and heart / blood ratio. Please refer to Table 1 in this embodiment for information on radioactivity. 99m The relevant section discusses the biodistribution results of Tc complex 79.

[0158] Regarding absolute myocardial uptake, our radioactivity 99m At 15, 30, 60, 120, and 240 min after tail vein injection, the absolute myocardial uptake values ​​of Tc complex 80 in female SD rats were 0.94±0.16, 1.42±0.32, 2.06±0.06, 1.73±0.09, and 0.93±0.09%ID / g, respectively. The peak absolute myocardial uptake was reached at 60 min after tail vein injection, at 2.06±0.06%ID / g. This peak value was consistent with... 99m Tc-MIBI (currently the most widely used myocardial perfusion imaging agent in the world) and [ 123 While the peak absolute myocardial uptake of BMIPP (the world's only approved fatty acid imaging agent for clinical use) varied in rats, the absolute myocardial uptake values ​​were still acceptable. Furthermore,99m Tc complex 80, when injected via the tail vein, produces the effects described above within 15-240 minutes. 99m Like Tc complex 79, it also has a long retention time in the myocardium, but it also shows a clear dynamic trend of first increasing and then decreasing (among which, 99m (The absolute myocardial uptake of Tc complex 80 decreased by 54.9% within 60-240 minutes after tail vein injection, a relatively significant decrease.) 99m The absolute myocardial uptake value of Tc-MIBI changed very little with the extension of time after injection, therefore, compared with... 99m Compared to Tc-MIBI, our radioactivity 99m Tc complex 80 also better reflects the strength of myocardial vitality and metabolic function.

[0159] Within 30-120 minutes after tail vein injection, our radioactivity... 99m In female SD rats, the baseline levels of Tc complex 80 in the liver and lungs gradually decreased, while the heart / liver ratio gradually increased. In particular, within 60-120 minutes after tail vein injection, the absolute myocardial uptake of Tc complex 80 in female SD rats significantly exceeded the baseline level in the liver.

[0160] 99m In female SD rats, Tc complex 80, administered via tail vein injection, resulted in heart / liver ratios of 6.43±1.85, 9.68±0.76, and 5.56±1.30 at 60, 120, and 240 min, respectively. These ratios were high and significantly exceeded the normal range. 99m The corresponding values ​​of Tc-MIBI at the same time point after tail vein injection in female SD rats, and [ 123 [I] The corresponding values ​​of BMIPP at 60 and 240 min after tail vein injection in rats.

[0161] At 60, 120, and 240 minutes after intravenous injection 99m The heart / lung ratios of Tc complex 80 were 9.48±1.39, 11.40±3.06, and 15.00±3.18, respectively, which were very high and significantly exceeded [the threshold]. 99m The corresponding values ​​of Tc-MIBI at 30, 60, and 120 min after tail vein injection in female SD rats also far exceeded [ 123 [I] The corresponding values ​​of BMIPP at 30, 60 and 240 min after tail vein injection in rats.

[0162] radioactivity 99mThe heart / blood ratio of Tc complex 80 was also very high, with values ​​of 54.80±11.86, 164.01±43.51, 197.36±32.29, and 141.90±22.86 at 30, 60, 120, and 240 min after tail vein injection, respectively, which far exceeded […]. 123 [I] The corresponding values ​​of BMIPP at 30, 60, and 240 min after tail vein injection in rats. 99m The cardiac / blood values ​​of Tc complexes are also close to those of... 99m The corresponding values ​​of Tc-MIBI at 30 and 60 min after tail vein injection in female SD rats were 104.30 and 164.50, respectively, indicating that the heart / blood ratio was still very high. This is because when the heart / blood ratio is greater than 10, the difference in heart / blood ratio has almost negligible effect on myocardial imaging.

[0163] Trimetazidine hydrochloride (TMZ) is a widely used antianginal drug and an inhibitor of fatty acid β-oxidation. TMZ directly inhibits fatty acid oxidation (FAO) in the β-oxidation pathway because it strongly inhibits long-chain 3-ketoacyl-CoA (CoA) thioase (the enzyme that catalyzes the final step of fatty acid β-oxidation). It can also inhibit medium-chain or short-chain 3-ketoacyl-CoA thioases to some extent. Therefore, it is used in the study of radioactivity. 99m To assess the sensitivity of Tc complex 80 to fatty acid β-oxidation, we first conducted a TMZ blocking experiment from a biodistribution perspective. In this experiment, SD rats sacrificed 60 minutes after injection were divided into two groups: one group consisted of fasted female SD rats that were simultaneously injected with a 0.2 mL solution of physiological saline containing TMZ (40 mg / kg) and our radioactive tracer. 99m Tc complex 80 (TMZ-treated group), another group of fasted female SD rats were injected with radioactive material only. 99m Tc complex 80 (control group). Absolute myocardial uptake was compared between control group SD rats and TMZ-treated SD rats 60 min after tail vein injection of our radiotracer 80 (corresponding to the time point of peak absolute myocardial uptake). Table 2 shows that at 60 min after injection, 99m The absolute uptake of Tc complex 80 in TMZ-treated SD rats was significantly lower in myocardial form compared to the corresponding value in the control group, with a decrease of 51% (significant P < 0.01). This indicates that the radioactive... 99m Tc complex 80 is quite sensitive to myocardial fatty acid β-oxidation. TMZ administration is radioactive. 99m The impact of the metabolic fate of Tc complex 80 will also be discussed in Example 4 below.

[0164] Table 3 Radioactivity 99mBiodistribution data of Tc complex 81 in female SD rats (n=3, ID% / g)

[0165]

[0166] Regarding myocardial perfusion imaging agents 99m The absolute myocardial uptake, heart / liver ratio, heart / liver ratio, and heart / blood ratio of Tc-MIBI in female SD rats, as well as the fatty acid imaging agent [ 123 [I] Absolute myocardial uptake values ​​of BMIPP in rats: absolute myocardial uptake values, heart / liver ratio, heart / liver ratio, and heart / blood ratio. Please refer to Table 1 in this embodiment for information on radioactivity. 99m The relevant section discusses the biodistribution results of Tc complex 79.

[0167] radioactivity 99m At 15, 30, 60, 120, and 240 min after tail vein injection, the absolute myocardial uptake values ​​of Tc complex 81 in female SD rats were 3.37±0.15, 3.45±0.19, 3.98±0.25, 2.83±0.25, and 2.29±0.05%ID / g, respectively, indicating generally high myocardial uptake. A peak value of 3.98±0.25%ID / g was observed at 60 min after tail vein injection. This peak value was consistent with... 99m Tc-MIBI (currently the most widely used myocardial perfusion imaging agent in the world) and [ 123 [I]BMIPP (the world's only approved fatty acid imaging agent for clinical use) showed a near-peak absolute myocardial uptake in rats. Furthermore, our radiopharmaceutical, after tail vein injection, exhibited a long myocardial retention time within 15-240 minutes, but also showed a relatively obvious dynamic trend of initial increase followed by decrease. 99m The absolute myocardial uptake value of Tc-MIBI changed very little with the extension of time after injection, therefore, compared with... 99m Compared to Tc-MIBI, our radioactivity 99m Tc complex 81 better reflects the strength of myocardial vitality and metabolic function.

[0168] Within 15-240 minutes after tail vein injection, the radioactivity... 99m Similar to complex 79, Tc complex 81 gradually decreased the baseline levels of liver and lung function in female SD rats, while the heart / liver ratio gradually increased. In particular, within 60-240 minutes after tail vein injection, its absolute myocardial uptake in female SD rats significantly exceeded that of the liver and lung baseline levels.

[0169] radioactivity 99mIn female SD rats, Tc complex 81, administered via tail vein injection, resulted in heart / liver ratios of 6.87±1.56, 7.91±0.50, and 11.82±1.15 at 60, 120, and 240 min, respectively. These ratios were high and significantly exceeded the normal range. 99m The corresponding values ​​of Tc-MIBI at the same time point after tail vein injection in female SD rats, and [ 123 [I] The corresponding values ​​of BMIPP at 60 and 240 min after tail vein injection in rats.

[0170] Our radioactivity was measured at 30, 60, 120, and 240 minutes after intravenous injection. 99m The heart / liver ratios of Tc complex 81 were 6.00±0.31, 14.35±2.38, 10.43±0.62, and 15.97±2.41, respectively. The heart / lung ratio was very high, significantly exceeding [the threshold]. 99m The corresponding values ​​of Tc-MIBI at 30, 60, and 120 min after tail vein injection in female SD rats also far exceeded [ 123 [I] The corresponding values ​​of BMIPP at 30, 60 and 240 min after tail vein injection in rats.

[0171] Our radioactivity 99m The heart / blood ratio of Tc complex 81 was very high, with values ​​of 220.61±45.73, 449.52±67.26, 146.14±22.27, and 143.42±25.82 at 30, 60, 120, and 240 min after tail vein injection, respectively, far exceeding [ 123 [I] The corresponding values ​​of BMIPP at 30, 60, and 240 min after tail vein injection in rats, although our radiopharmaceutical heart / blood ratio is lower than that of [I] 99m The corresponding values ​​of Tc-MIBI at 30 and 60 min after tail vein injection in female SD rats were shown, but the heart / blood ratio was still very high. This is because when the heart / blood ratio is greater than 10, the difference in heart / blood ratio has almost negligible effect on myocardial imaging.

[0172] radioactivity 99m The absolute myocardial uptake and heart / liver ratio of Tc complex 78 were lower than the values ​​mentioned above.

[0173] In summary, the test results of this embodiment show that, in the case of radioactivity... 99m Among Tc complexes 78-81, the peak absolute uptake of fatty acids in the myocardium of female SD rats generally increased with increasing fatty acid carbon chain length. Especially... 99m Tc complex 81, with peak absolute myocardial uptake comparable to the most widely used myocardial perfusion imaging agent in clinical practice worldwide. 99mThe corresponding values ​​for Tc-MIBI are close. 99m The peak absolute uptake of Tc complex 79-80 in the myocardium was also good. 99m Tc complexes 79-81 all showed a trend of gradually increasing total myocardial uptake values ​​15-60 min after injection, followed by a gradual decrease 60-240 min after injection, exhibiting dynamic changes in myocardial absorption. Furthermore, these three complexes showed high heart / liver, heart / lung, and heart / blood ratios 30-120 min after injection, demonstrating excellent overall biodistribution results.

[0174] Example 3

[0175] The corresponding radioactivity of some typical compounds of general formula II in this application is selected. 99m Tc complex 79-80 was used in small animal SPECT / CT imaging studies of female SD rats, as shown below:

[0176] (1) The experimental method is as follows:

[0177] 180g female SD rats (fasted overnight) were anesthetized with 2% isoflurane gas and initially injected with 800 μCi of radioactive gas via the tail vein. 99m Tc complex 39-40 (dissolved in physiological saline containing 10% EtOH, 1000 μL) was then subjected to SPECT / CT scan.

[0178] (2) Experimental results:

[0179] Figure 7 Corresponding to radioactivity 99m Representative dynamic SPECT / CT images of Tc complex 79 in female SD rats ( Figure 7 A, Figure 7 B and Figure 7 C represents 99m (Coronal, sagittal, and cross-sectional views of dynamic SPECT / CT imaging of Tc complex 79 at 56-64 min after tail vein injection in female SD rats);

[0180] Figure 8 Corresponding to radioactivity 99m Representative dynamic SPECT / CT images of Tc complex 80 in female SD rats ( Figure 8 A, Figure 8 B and Figure 8 C represents 99m (Coronal, sagittal, and cross-sectional views of dynamic SPECT / CT imaging of Tc complex 80 at 66-72 min after tail vein injection in female SD rats);

[0181] from Figure 7 and Figure 8 It can be seen that radioactivity 99m Tc complex 79 was observed in SD rats 56-64 min after tail vein injection, and 99m At 66-72 min after tail vein injection of Tc complex 80 in SD rats, the two radioactive... 99m Tc complexes are clearly visualized in the myocardium, while the lungs, blood, and liver background are almost undetectable, indicating that the two aforementioned radioactive compounds... 99m Tc complexes produce excellent myocardial imaging quality.

[0182] Example 4

[0183] The corresponding radioactivity of some typical compounds of general formula II in this application is selected. 99m The metabolism of Tc complex 80 in female SD rats was studied, as shown below:

[0184] (1) The experimental method is as follows:

[0185] Female SD rats (180-220g, fasted overnight) were injected intravenously with 800 μCi of radioactive material via the tail vein. 99m Tc complex 80 (200-300 μCi, dissolved in physiological saline containing 10% EtOH, 1000 μL) (n=3). Heart, intestinal, and liver samples were collected at 60 and 120 min post-injection. SD rats euthanized 60 min post-injection were divided into two groups: one group of fasted female SD rats was simultaneously injected with physiological saline (0.2 mL) containing the fatty acid β-oxidation inhibitor TMZ (40 mg / kg) and our radiotracer (TMZ administration group); the other group of fasted female SD rats was injected only with the radiotracer. 99m Tc complex 80 (control group). Heart, intestinal, or liver samples were homogenized in a 2:1 volume ratio of CHCl3-CH3OH, then 40% urea and 5% sulfuric acid aqueous solution were added, followed by sonication and centrifugation at 2000 rpm for 10 min (a modified Folch extraction method). The resulting aqueous phase, organic phase, and residual tissue particles were then separated. 99m Tc radioactive gamma count (n=3).

[0186] In addition, after radioactivity counting of residual tissue particles obtained from heart samples, they were dissolved in 1 mol / L NaOH solution at 90°C for 1 h, cooled, and then treated with 50% trichloroacetic acid (TCA). After centrifugation at 2000 rpm for 10 min, the supernatant and precipitate were separated. 9m Tc radioactive gamma count.

[0187] (2) The experimental results are as follows:

[0188] Table 4. The aqueous phase, organic phase, and residual granular phase of the heart, liver, and intestine of fasted female SD rats after tissue extraction using a modified Folch extraction method. 99m Distribution of Tc radioactivity (as a percentage of total) 99m Percentage of Tc radioactivity count (intravenous injection) 99m At 60 and 120 min after Tc complex 80, n=3)

[0189] Table 4 Radioactivity 99m Metabolism of Tc complex 80 in female SD rats

[0190]

[0191] The results of modified Folch extraction analysis of tissue extracts, as shown in Table 4, indicate that after intravenous injection... 99m At 60 and 120 minutes after Tc complex 80, most of the heart, intestines and liver... 99m Tc radioactivity was present in the granular phase of residual tissue. The granular phase of residual tissue was also present in heart samples from control SD rats at these two time points. 99m The proportions of Tc radioactive counts were 68.54±3.66% and 66.27±4.54% of the total count, respectively, with corresponding values ​​of 64.04±4.90% and 67.23±4.08% in liver samples and 60.70±5.71% and 65.55±3.54% in intestinal samples. Furthermore, for 99m In heart samples from control group SD rats 60 minutes after Tc complex 80, when the residual tissue particles were dissolved in 1 mol / L NaOH aqueous solution at 90°C for 1 hour, followed by the addition of 50% trichloroacetic acid, most of the residual tissue particles were... 99m Tc radioactivity re-precipitates (the precipitated material) 99m Tc radioactivity count as a percentage of residual tissue granular phase 99m (86.0% of the Tc radioactivity count). Furthermore, compared to the control group, SD rats in the TMZ-treated group were injected with... 99m At 60 min after Tc complex 80, the residual tissue granular phase 99m The percentage of Tc radioactive count (as a percentage of the total radioactive count) decreased significantly from 68.54 ± 3.66% (heart samples from control group SD rats) to 26.60 ± 2.09% (heart samples from TMZ-treated group SD rats), a decrease of 61% (significant P < 0.01). Injection 99mAt 60 min after Tc complex administration, the organic fraction content of the heart samples increased from 31.38 ± 2.48% (heart samples from control group SD rats) to 73.11 ± 2.03% (heart samples from TMZ-treated group SD rats), with a significant difference (P < 0.01) compared to the control group SD rats. The results of the above metabolic analysis, combined with the TMZ inhibition test results from a biodistribution perspective in Example 2, indicate that radioactivity... 99m Tc complex 80 is highly sensitive to myocardial fatty acid β-oxidation. Moreover, most of it... 99m Tc complex 80 was partially β-oxidized to radioactive metabolites that can bind tightly to tissue proteins, providing strong evidence for the β-oxidation of our radiotracer in the myocardium.

[0192] Examples 2, 3, and 4 clearly demonstrate that the addition of a compound with a thioether at position J significantly reduces lung and blood background levels compared to the absence of the compound; liver background clearance is extremely rapid, almost completely absent after approximately 60 minutes of intravenous injection; while myocardial imaging is very clear, and water solubility is enhanced—effects not seen in previous studies of fatty acid compounds, which is very surprising. The metabolic characteristics of the structure in this application are very similar to those of an ideal imaging agent, fully embodying the characteristics of a myocardial metabolic imaging agent. The imaging agent in this invention can better reflect myocardial vitality and metabolic state, and is better suited for the diagnosis of heart diseases and the assessment of myocardial cell viability. Therefore, it can serve as a myocardial fatty acid metabolism imaging agent with significant clinical application prospects.

[0193] Example 5

[0194] Organic synthetic routes and methods for labeled precursors 96-98 of typical compounds of general formula III in this application, and labeled routes and methods for Re(rhenium-186) complexes 99 of some typical compounds (when f is 5, 7, and 11 in general formula III, and g is 4 in all cases) are shown below:

[0195] (1) The synthesis and labeling route is as follows:

[0196]

[0197]

[0198] (2) The synthesis and labeling process is as follows:

[0199] Synthesis of Intermediate 84: At 0°C, m-chloroperoxybenzoic acid (1.0859 g) was added in portions to a dichloromethane solution of intermediate 22 (2.0846 g) described in this application, and the mixture was stirred at room temperature for 1 hour or overnight. The mixture was quenched sequentially with saturated sodium bicarbonate aqueous solution and saturated sodium thiosulfate aqueous solution, filtered, extracted with dichloromethane, and concentrated under reduced pressure to obtain intermediate 84 (1.4418 g). The product was used directly in the next reaction without further purification.

[0200] Synthesis of intermediate 85: For specific procedures, please refer to "Synthesis of intermediate 84" in this example. Intermediate 85 (6.8010g) was obtained by reacting intermediate 24 (6.3720g) with m-chloroperoxybenzoic acid (14.3523g). The product was used directly in the next reaction without further purification.

[0201] Synthesis of intermediate 86: For specific procedures, please refer to "Synthesis of intermediate 84" in this example. Intermediate 86 (6.6374 g) was obtained by reacting intermediate 25 (6.4185 g) with m-chloroperoxybenzoic acid (11.9103 g). The product was used directly in the next reaction without further purification.

[0202] Synthesis of intermediate 87: For specific procedures, please refer to “Synthesis of intermediate 29” in Example 1. Relatively pure intermediate 87 (0.6449g) was obtained from intermediate 2 (0.3577g), intermediate 84 (1.4418g), mercuric acetate (1.4261g) and sodium borohydride (0.1447g).

[0203] Synthesis of Intermediate 88: For specific procedures, please refer to "Synthesis of Intermediate 29" in Example 1. Relatively pure Intermediate 88 (1.2788 g) was obtained from Intermediate 2 (1.5266 g), Intermediate 85 (6.8010 g), mercuric acetate (6.0856 g), and sodium borohydride (0.6175 g). Its data characterization: HRMS: calcd 394.2263 (M+H) + Found 394.2410(M+H) + ,calcd 416.2083(M+Na) + Found 416.2247(M+Na) + .

[0204] Synthesis of intermediate 89: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1. Relatively pure intermediate 89 (1.7163g) was obtained from intermediate 2 (1.2514g), intermediate 86 (6.6374g), mercuric acetate (4.9886g) and sodium borohydride (0.5062g).

[0205] Synthesis of isocyanate intermediate 90: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 133 (0.3714 g) was obtained from intermediate 87 (0.6449 g), triethylamine (0.4946 g), and phosphorus oxychloride (0.2976 g). Its data characterization is as follows: 1 H NMR (400MHz, CD3OD): δ3.67 (s, 3H), 3.52 (s, 2H), 3.43 (t, J = 5.6Hz, 2H), 3.04-3.13 (m,4H),2.41(t,J=7.0Hz,2H),1.74-1.87(m,6H),1.52-1.62(m,4H),1.25(s,6H); 13 C NMR (101MHz, CD3OD): δ61.00,52.03,51.59,32.68,29.25,24.92,23.35,21.92,21.22,20.93.

[0206] Synthesis of isocyanate intermediate 91: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 91 (0.5546 g) was obtained from intermediate 88 (1.2788 g), triethylamine (0.9108 g), and phosphorus oxychloride (0.5480 g). Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.68 (s, 3H), 3.34-3.37 (m, 4H), 2.92-2.98 (m, 4H), 2.38 (t, J = 7.2Hz, 2 H),1.77-1.92(m,6H),1.49-1.55(m,2H),1.42-1.47(m,2H),1.36-1.38(m,4H),1.26(s,6H).

[0207] Synthesis of isocyanate intermediate 92: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 135 (0.5976 g) was obtained from intermediate 89 (1.7163 g), triethylamine (1.0699 g), and phosphorus oxychloride (0.6437 g). Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.68 (s, 3H), 3.33-3.37 (m, 4H), 2.92-2.98 (m, 4H), 2.38 (t, J = 7.1Hz, 2 H),1.77-1.92(m,6H),1.49-1.56(m,2H),1.44-1.45(m,2H),1.28-1.37(m,12H),1.27(s,6H).

[0208] Synthesis of copper salt methyl ester intermediate 93: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49" in Example 1. Relatively pure copper salt methyl ester intermediate 93 (0.1434g) was obtained by reacting isocyanate methyl ester intermediate 90 (0.3714g) with tetra(acetonitrile)copper(I)tetrafluoroborate (0.0841g).

[0209] Synthesis of copper methyl ester intermediate 94: For specific procedures, please refer to "Synthesis of copper methyl ester intermediate 49" in Example 1. Relatively pure copper methyl ester intermediate 94 (0.2530 g) was obtained from isocyanate methyl ester intermediate 91 (0.5546 g) and tetra(acetonitrile)copper(I) tetrafluoroborate (0.1161 g). Its data characterization: HRMS: calcd 438.1370 (M+Cu) + ,found438.1492(M+Cu) + ;calcd 813.3449(2M+Cu) + Found 813.3667(2M+Cu) + When the compound is a copper salt, "M" here refers to the precise mass of the isocyanate monomer in the copper salt, and the same applies below.

[0210] Synthesis of copper methyl ester intermediate 95: For specific procedures, please refer to "Synthesis of copper methyl ester intermediate 49" in Example 1. Relatively pure copper methyl ester intermediate 95 (0.2695 g) was obtained from isocyanate methyl ester intermediate 92 (0.5576 g) and tetra(acetonitrile)copper(I) tetrafluoroborate (0.1010 g); HRMS: calcd 494.2164 (M+Cu) + Found 494.1996(M+Cu) + ; calcd 925.470 (2M+Cu) + Found 925.5005(2M+Cu) + .

[0211] Synthesis of copper salt carboxylic acid labeled precursor 96: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in section 1. Relatively pure copper salt carboxylic acid labeled precursor 96 (0.0479 g) was obtained from copper salt methyl ester intermediate 93 (0.1434 g) and sodium hydroxide (0.0149 g). Its data characterization is as follows: 1H NMR (400MHz, CD3OD): δ3.74(s,8H),3.43(t,J=5.9Hz,8H),3.07-3.11(m,16H),2.23(t,J=7.6 Hz,8H),1.79-1.85(m,16H),1.70-1.77(m,8H),1.56-1.60(m,16H),1.27(s,24H); HRMS:calcd 396.0900(M+Cu) + Found 396.0519(M+Cu) + ; calcd 729.2510(2M+Cu) + Found 729.2190(2M+Cu) + .

[0212] Synthesis of copper salt carboxylic acid labeled precursor 97: For specific procedures, refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in section 1. Relatively pure copper salt carboxylic acid labeled precursor 97 (0.1134 g) was obtained from copper salt methyl ester intermediate 94 (0.2530 g) and sodium hydroxide (0.0245 g); HRMS: calcd 424.1213 (M+Cu). + Found 424.1282(M+Cu) + ; calcd 785.3136(2M+Cu) + Found 785.3275(2M+Cu) + .

[0213] Synthesis of copper salt carboxylic acid labeled precursor 98: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1. Relatively pure copper salt carboxylic acid labeled precursor 98 (0.1642 g) was obtained from copper salt methyl ester intermediate 95 (0.2695 g) and sodium hydroxide (0.0230 g); HRMS: calcd 480.1839 (M+Cu) + Found 480.1938(M+Cu) + ; calcd 897.3888(2M+Cu) + Found 897.4505(2M+Cu) + .

[0214] Synthesis of Re complex 99: For specific procedures, please refer to "Synthesis of Re complex 69" in Example 1. Re complex 99 was obtained from copper salt carboxylic acid-labeled precursor 96 (1.0–3.0 mg). Its characterization data is as follows: HRMS: calcd 1085.5371 (M). + Found 1085.5135 (M) + .

[0215] Furthermore, this embodiment is radioactive. 99m The labeling routes and methods for Tc complexes are the same as the corresponding steps in the above embodiments, and will not be repeated here.

[0216] Example 6

[0217] Organic synthetic routes and methods for labeled precursors 124-126 of typical compounds of general formula IV selected in this application, as well as Re(rhenium-186) complexes 127-129 of some typical compounds and their corresponding radioactive components. 99m The marking route and method for Tc(Technetium-99m) complex 130 (in this embodiment, e in general formula IV is always 3, f is 5, 6, or 8, and g is always 4) are as follows:

[0218] (1) The synthesis and labeling route is as follows:

[0219]

[0220] (2) The synthesis and labeling process is as follows:

[0221] Synthesis of Intermediate 101: For specific procedures, please refer to "Synthesis of Intermediate 7" in Example 1. Intermediate 101 (213.7000 g) was obtained by reacting starting material 100 (200.0000 g), anhydrous ethanol, and p-toluenesulfonic acid (9.7340 g). Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ4.17 (q, J = 7.1Hz, 2H), 2.78 (q, J = 7.0Hz, 2H), 2.64 (t, J = 6.7Hz, 2H), 1.65 (t, J = 8.3Hz, 1H), 1.27 (t, J = 7.2Hz, 3H).

[0222] Synthesis of Intermediate 102: Lithium aluminum hydride (259.5824 g) was added in portions to a tetrahydrofuran solution of intermediate 101 (203.4000 g), and the mixture was stirred overnight at room temperature. After quenching, the mixture was extracted with ethyl acetate and concentrated under reduced pressure to obtain intermediate 102 (129.7912 g). The product was used directly in the next reaction without further purification. Its data characterization is as follows: 1 H NMR (400MHz, CDCl3, CDCl3): δ3.77 (t, J = 6.1 Hz, 2H), 2.65 (q, J = 7.0 Hz, 2H), 1.83-1.90 (m, 2H), 1.41 (t, J = 8.1 Hz, 1H).

[0223] Synthesis of intermediate 106: Intermediate 102 (35.0000 g), starting material 103 (87.3253 g), and 1,8-diazabicycloundec-7-ene (i.e., DBU, 153.6052 g) were stirred at room temperature for 1 h. The mixture was quenched with water, extracted with dichloromethane, and concentrated under reduced pressure to obtain crude intermediate 106. The product was used directly in the next reaction without further purification.

[0224] Synthesis of intermediate 107: For details, please refer to "Synthesis of intermediate 106". After reacting intermediate 102 (40.7420 g) and starting material 104 (107.8540 g), intermediate 107 (31.9044 g) was obtained by silica gel column chromatography. Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.76(t,J=5.2Hz,2H),3.41(t,J=6.8Hz,2H),2.64(t,J=7.0Hz,2H),2.54( t,J=7.3Hz,2H),1.82-1.89(m,4H),1.65(t,J=7.0Hz,1H),1.57-1.62(m,2H),1.42-1.50(m,4H).

[0225] Synthesis of intermediate 108: For details, please refer to "Synthesis of intermediate 106". Intermediate 108 (23.0627 g) was obtained by reacting intermediate 102 (33.0430 g) and starting material 105 (97.5299 g) with silica gel column chromatography. Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ3.66(t,J=6.0Hz,2H),3.35(t,J=6.8Hz,2H),2.56(t,J=7.1Hz,2H),2.46( t,J=7.6Hz,2H),2.40(t,J=7.0Hz,1H),1.76-1.81(m,4H),1.49-1.54(m,2H),1.28-1.37(m,8H).

[0226] Synthesis of intermediate 109: For specific procedures, please refer to "Synthesis of intermediate 84" in Example 5. After reacting the crude product intermediate 106 (converted to the molar amount of intermediate 102), intermediate 109 (22.6074 g) was obtained by silica gel column chromatography. Its data characterization is as follows: 1H NMR (400MHz, CDCl3): δ3.79(t,J=5.8Hz,2H),3.43(t,J=6.7Hz,2H),3.14(t,J=7.6Hz,2H),3.02( t,J=7.9Hz,2H),2.80(t,J=6.2Hz,1H),2.05-2.12(m,2H),1.85-1.95(m,4H),1.59-1.66(m,2H).

[0227] Synthesis of intermediate 110: For specific procedures, please refer to "Synthesis of intermediate 84" in Example 5. Intermediate 110 (33.0875 g) was obtained from intermediate 107 (31.9044 g). The product was used directly in the next reaction without further purification.

[0228] Synthesis of intermediate 111: For specific procedures, please refer to "Synthesis of intermediate 84" in Example 5. Intermediate 111 (25.1807g) was obtained from intermediate 108 (23.0627g). The product was used directly in the next reaction without further purification.

[0229] Synthesis of intermediate 112: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1. Intermediate 112 (15.5740 g) was obtained from intermediate 109 (22.6074 g), and its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.78(t,J=5.6Hz,2H),3.67(s,3H),3.13(t,J=7.4Hz,2H),3.00(t,J=7.8Hz,2H),2.50-2 .54(m,5H),2.34(t,J=7.2Hz,2H),2.05-2.11(m,2H),1.83-1.91(m,2H),1.67-1.76(m,2H),1.54-1.66(m,6H).

[0230] Synthesis of intermediate 113: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1. Relatively pure intermediate 113 (17.8940 g) was obtained from intermediate 110 (33.0875 g), and its data characterization is as follows: 1H NMR (400MHz, CDCl3): δ3.81(t,J=5.6Hz,2H),3.67(s,3H),3.13(t,J=7.4Hz,2H),2.97-3.01(m,2H),2.45-2.53(m,4H) ,2.34(t,J=7.2Hz,2H),2.07-2.14(m,2H),1.82-1.90(m,3H),1.71-1.77(m,2H),1.61-1.68(m,4H),1.42-1.49(m,4H).

[0231] Synthesis of intermediate 114: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1. Relatively pure intermediate 114 (10.9546 g) was obtained from intermediate 111 (25.1807 g), and its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.73(t,J=5.9Hz,2H),3.66(s,3H),3.12(t,J=7.6Hz,2H),2.97-3.01(m,2H),2.47-2.52(m,4H) ,2.33(t,J=7.2Hz,2H),2.01-2.08(m,2H),1.79-1.90(m,2H),1.69-1.76(m,2H),1.53-1.64(m,4H),1.25-1.46(m,8H).

[0232] Synthesis of intermediate 115: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1. Relatively pure intermediate 115 (2.6092 g) was obtained from intermediate 2 (3.0230 g) and intermediate 112 (15.5740 g). Its data characterization is as follows: HRMS: calcd 440.2141 (M+H), found 440.2153 (M+H), calcd 462.1960 (M+Na), found 462.1957 (M+Na).

[0233] Synthesis of intermediate 116: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1. Relatively pure intermediate 116 (2.3764g) was obtained from intermediate 2 (3.3357g) and intermediate 113 (17.8940g). Its data characterization is as follows: HRMS: calcd 454.2297 (M+H), found 454.2280 (M+H), calcd 476.2116 (M+Na), found 476.2101 (M+Na).

[0234] Synthesis of intermediate 117: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1. Relatively pure intermediate 117 (1.0537g) was obtained from intermediate 2 (1.8920g) and intermediate 114 (10.9546g). Its data characterization is as follows: HRMS: calcd 482.2610 (M+H), found 482.2572 (M+H), calcd 504.2429 (M+Na), found 504.2376 (M+Na).

[0235] Synthesis of isocyanate intermediate 118: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 118 (869.4 mg) was obtained from intermediate 115 (2.6092 g), and its data characterization is as follows: 1 HNMR (400MHz, CDCl3): δ3.67(s,3H),3.53(t,J=5.7Hz,2H),3.38(s,2H),3.11(t,J=7.4Hz,2H),2.99(t,J=7.9Hz,2H),2.49- 2.54(m,4H),2.34(t,J=7.2Hz,2H),2.06-2.13(m,2H),1.83-1.91(m,2H),1.67-1.77(m,2H),1.53-1.64(m,6H),1.28(s,6H).

[0236] Synthesis of isocyanate intermediate 119: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 119 (956.2 mg) was obtained from intermediate 116 (2.3764 g), and its data characterization is as follows: 1 HNMR (400MHz, CDCl3): δ3.60(s,3H),3.46(t,J=5.7Hz,2H),3.31(s,2H),3.03(t,J=7.4Hz,2H),2.89-2.93(m,2H),2.42-2.46(m,4H) ,2.27(t,J=7.2Hz,2H),2.00-2.06(m,2H),1.75-1.83(m,2H),1.63-1.70(m,2H),1.47-1.58(m,4H),1.36-1.39(m,4H),1.28(s,6H).

[0237] Synthesis of isocyanate intermediate 120: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1. Isocyanate intermediate 120 (675.7 mg) was obtained from intermediate 117 (1.0537 g), and its data characterization is as follows: 1HNMR (400MHz, CDCl3): δ3.60(s,3H),3.46(t,J=5.6Hz,2H),3.31(s,2H),3.03(t,J=7.4Hz,2H),2.90(t,J=7.8Hz,2H),2.41-2.46(m,4 H), 2.27 (t, J = 7.3Hz, 2H), 1.99-2.06 (m, 2H), 1.73-1.81 (m, 2H), 1.63-1.70 (m, 2H), 1.46-1.58 (m, 4H), 1.26-1.39 (m, 8H), 1.21 (s, 6H).

[0238] Synthesis of copper methyl ester intermediate 121: For specific procedures, please refer to "Synthesis of copper methyl ester intermediate 49" in Example 1. Relatively pure copper methyl ester intermediate 121 (742.5 mg) was obtained from isocyanate methyl ester intermediate 118 (869.4 mg). Its data characterization: HRMS: calcd 484.1247 (M+Cu), found 484.0943 (M+Cu). When the compound is a copper salt, "M" here refers to the precise mass of the isocyanate monomer in the copper salt, and the same applies below.

[0239] Synthesis of copper methyl ester intermediate 122: For specific procedures, please refer to "Synthesis of copper methyl ester intermediate 49" in Example 1. Relatively pure copper methyl ester intermediate 165 (344.0 mg) was obtained from isocyanate methyl ester intermediate 119 (956.2 mg). Its data characterization: HRMS: calcd 498.1404 (M+Cu), found 498.1386 (M+Cu).

[0240] Synthesis of copper methyl ester intermediate 123: For specific procedures, please refer to "Synthesis of copper methyl ester intermediate 49" in Example 1. Relatively pure copper methyl ester intermediate 166 (499.1 mg) was obtained from isocyanate methyl ester intermediate 120 (675.7 mg). Its data characterization: HRMS: calcd 526.1717 (M+Cu), found 526.1777 (M+Cu).

[0241] Synthesis of copper salt carboxylic acid labeled precursor 124: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1. Relatively pure copper salt carboxylic acid labeled precursor 124 (205.0 mg) was obtained from copper salt methyl ester intermediate 121 (742.5 mg). Its data characterization: HRMS: calcd 470.1091 (M+Cu), found 470.1076 (M+Cu).

[0242] Synthesis of copper salt carboxylic acid labeled precursor 125: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1. Relatively pure copper salt carboxylic acid labeled precursor 125 (176.0 mg) was obtained from copper salt methyl ester intermediate 122 (344.0 mg). Its data characterization: HRMS: calcd 484.1247 (M+Cu), found 484.1274 (M+Cu).

[0243] Synthesis of copper salt carboxylic acid labeled precursor 126: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1. Relatively pure copper salt carboxylic acid labeled precursor 126 (238.1 mg) was obtained from copper salt methyl ester intermediate 123 (499.1 mg). Its data characterization: HRMS: calcd 512.1560 (M+Cu), found 512.1562 (M+Cu).

[0244] Synthesis of Re complex 127: For specific procedures, please refer to “Labeling of Re complex 69” in Example 1. Re complex 127 was obtained by labeling the copper salt carboxylic acid precursor 124 (1.2-3.5 mg). Its data characterization: HRMS: calcd 1159.5528 (M), found 1159.5609 (M).

[0245] Synthesis of Re complex 128: For specific procedures, please refer to “Labeling of Re complex 69” in Example 1. Re complex 128 was obtained by labeling the copper salt carboxylic acid precursor 125 (1.2-3.7 mg). Its data characterization: HRMS: calcd 1173.5684 (M), found 1173.5747 (M).

[0246] Synthesis of Re complex 129: For specific procedures, please refer to "Labeling of Re complex 69" in Example 1. Re complex 129 was obtained by labeling the copper salt carboxylic acid precursor 126 (1.3-3.9 mg). Its data characterization: HRMS: calcd 120 1.5997 (M), found 120 1.6062 (M).

[0247] 99m Synthesis of Tc complex 130: For specific procedures, please refer to Example 1. 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid-labeled precursor 124 (1.2–3.5 mg). 99m The liquid chromatography spectrum of Tc complex 130 co-injected with the corresponding Re complex 127 (methanol / water containing 1 / 1000 trifluoroacetic acid = 70 / 30, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) is shown below. Figure 9 As shown, then 99mThe elution time of Tc radiocomplex 130 (75.075 min) was basically the same as that of the corresponding Re complex 127 (76.425 min).

[0248] Example 7

[0249] Select the corresponding radioactive compounds of typical compounds in part IV of the general formula in this application. 99m The biodistribution of Tc complex 130 in female Kunming mice was studied, as shown below:

[0250] (1) The experimental method is as follows:

[0251] Female Kunming mice (20-22g, n=3) were fasted for 12 hours before the experiment. The purified radioactive... 99m Tc complex 130 was prepared into physiological saline (containing 10% ethanol) solutions of approximately 100 μCi / mL. Female Kunming mice were euthanized by cervical dislocation at five time points (5, 15, 30, 60, and 120 min) after tail vein injection, via 100 μL of the above solution. Blood, brain, heart, liver, spleen, lung, kidney, muscle, bone, large intestine, small intestine, stomach, and tail were collected, weighed, and counted. The count distribution of each tissue and organ was calculated (unit: %ID / g; for large intestine, small intestine, and stomach, the unit is %ID). The data are the mean ± standard deviation of three mice at each time point. Simultaneously, 100 μL of the above solution was diluted to 10 mL to obtain the %ID before tail count deduction.

[0252] (2) Radioactivity 99m The biodistribution of Tc complex 130 in female Kunming mice is as follows:

[0253] Table 5 Radioactivity 99m Biodistribution data of Tc complex 130 in female Kunming mice (n=3, ID% / g)

[0254]

[0255]

[0256] radioactivity 99m After intravenous injection of Tc complex 130, the absolute absorption by the myocardium is relatively low over time.

[0257] Example 8

[0258] Furthermore, the structures of the typical compound of general formula IV in this application—its isocyanomethyl ester intermediate 131, its copper salt carboxylic acid labeled precursor 132, and its corresponding Re complex 133—are shown below (in this embodiment, e is 6, f is 5, and g is 4 in general formula IV). Its organic synthesis route and method, labeling route and method are completely consistent with those in Example 7 above. The final steps are also referred to in Example 1 respectively for “synthesis of isocyanomethyl ester intermediate 39”, “synthesis of copper salt carboxylic acid labeled precursor 59”, and “labeling of Re complex 69”. The specific process will not be repeated here.

[0259]

[0260] Isocyanomethyl ester intermediate 131, its data characterization: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),3.34-3.38(m,4H),2.93-2.97(m,4H),2.49-2.54(m,4H), 2.34(t,J=7.8Hz,2H),1.82-1.90(m,4H),1.67-1.77(m,2H),1.42-1.63(m,12H),1.27(s,6H).

[0261] The copper salt carboxylic acid-labeled precursor 132 was characterized by the following data: HRMS: calcd 512.1560 (M+Cu). + ,found512.1545(M+Cu) + When the compound is a copper salt, "M" here refers to the precise mass of the isocyanate monomer in the copper salt.

[0262] Re complex 133, characterized by: HRMS: calcd 1201.6030 (M) + Found 1201.5981(M) + .

[0263] Example 9

[0264] Furthermore, the synthetic routes and methods for intermediates 97-98 of the labeled precursors of typical compounds of general formula IV selected in this application (in this embodiment, e is always 2, f is always 2, and g is 2 and 4 respectively) are as follows:

[0265] (1) The synthesis and labeling route is as follows:

[0266]

[0267]

[0268] (2) The synthesis method is as follows:

[0269] Synthesis of intermediate 134: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1 above. Relatively pure intermediate 134 (51.7092g) was obtained from intermediate 2 (39.6520g) and starting material 12 (74.9760g). Without further purification, it was directly added to the next reaction step.

[0270] Synthesis of intermediate 136: For specific procedures, please refer to "Synthesis of Intermediate 106" in Example 6 above. After reacting relatively pure intermediate 134 (47.5935 g), 2-mercaptoethanol (135, 18.2522 g), and DBU (39.2512 g), the relatively pure intermediate 136 (11.0177 g) was obtained by silica gel column chromatography. Its characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.25 (s, 1H), 6.52 (brs, 1H), 3.75-3.79 (m, 3H), 3.54 (t, J = 5.8Hz ,2H),3.35(d,J=6.0Hz,2H),2.79(t,J=5.8Hz,2H),2.74(t,J=5.8Hz,1H),1.21(s,6H).

[0271] Synthesis of intermediate 137: Phosphorus tribromide (14.9029 g) was added to a relatively pure dichloromethane solution of intermediate 136 (11.0177 g), and the mixture was stirred overnight at room temperature. The mixture was then quenched with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried, and concentrated under vacuum to obtain a concentrate containing intermediate 137 (9.3624 g). This product was used directly in the next reaction without further purification.

[0272] Synthesis of intermediate 138: For specific procedures, please refer to "Synthesis of intermediate 84" in Example 5 above. A concentrate containing intermediate 138 (10.4163g) was obtained from the concentrate containing intermediate 137 (9.3624g). The product was used directly in the next reaction without further purification.

[0273] Synthesis of intermediate 139: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1 above. Intermediate 138 (3.5466 g) was reacted with starting material 11 (1.6174 g) to obtain intermediate 139 (2.8267 g). Its data characterization is as follows: 1H NMR (400MHz, CDCl3): δ8.22(s,1H),6.93(brs,1H),3.82(t,J=5.3Hz,2H),3.24-3.50(m,6H),2.93- 2.99(m,2H),2.84(t,J=7.1Hz,2H),2.65(t,J=7.1Hz,2H),1.22(s,6H); HRMS:calcd356.1202(M+H) + ,found 356.1206(M+H) + ,calcd 378.1021(M+Na) + ,found 378.1010(M+Na) + .

[0274] Synthesis of intermediate 140: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1 above. Intermediate 138 (3.2899 g) reacted with intermediate 7 (1.8505 g) to obtain intermediate 140 (2.6050 g). Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ8.23(s,1H),6.82(brs,1H),3.82(t,J=5.2Hz,2H),3.32-3.43(m,4H),3.30(t,J=5.4Hz,2H),2.87- 2.98(m,2H),2.59(t,J=7.1Hz,2H),2.35(t,J=7.1Hz,2H),1.69-1.77(m,2H),1.59-1.67(m,2H),1.22(s,6H); HRMS:calcd 384.1515(M+H) + ,found384.1450(M+H) + ,calcd 406.1334(M+Na) + Found 406.1317(M+Na) + .

[0275] Synthesis of isocyanate monomer methyl ester intermediate 141: For specific procedures, refer to "Synthesis of Intermediate 39" in Example 1 above. Intermediate 139 (2.0180 g) was obtained from intermediate 139 (2.8267 g), and its data characterization is as follows: 1H NMR (400MHz, CDCl3): δ3.78 (t, J=5.3Hz, 2H), 3.64 (s, 3H), 3.29-3.39 (m, 4H), 3.19 (t, J= 5.3Hz,2H),2.87-2.94(m,2H),2.78(t,J=7.2Hz,2H),2.57(t,J=7.2Hz,2H),1.26(s,6H); 13 C NMR (101MHz, CDCl3): δ171.04,157.39,73.41,59.37,55.66,54.26,53.06,50.90,49.78,49.71,49.65,33.32,25.98,22.97,21.69,20.04,13.19.

[0276] Synthesis of isocyanate monomer methyl ester intermediate 142: For specific procedures, please refer to "Synthesis of intermediate 39" in Example 1 above. Intermediate 140 (1.3060 g) was obtained from intermediate 140 (2.6050 g), and its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.85(t,J=5.3Hz,2H),3.67(s,3H),3.34-3.45(m,4H),3.26(t,J=5.3Hz,2H),2.89-2 .98(m,2H),2.59(t,J=7.1Hz,2H),2.34(t,J=7.2Hz,2H),1.69-1.79(m,2H),1.59-1.68(m,2H),1.33(s,6H); 13 C NMR (101MHz, CDCl3): δ173.65,158.36,74.34,56.62,55.37,53.94,51.54,50.68,50.61,50.55,33.43,31.76,28.61,23.90,23.81,22.70.

[0277] Synthesis of copper salt methyl ester intermediate 143: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49" in Example 1 above. Relatively pure copper salt methyl ester intermediate 143 (1.5498g) was obtained from isocyanate monomer intermediate 141 (2.0180g).

[0278] Synthesis of copper methyl ester intermediate 144: For specific procedures, please refer to “Synthesis of copper methyl ester intermediate 49” in Example 1 above. Relatively pure copper methyl ester intermediate 144 (1.0444 g) was obtained from isocyanate monomer intermediate 142 (1.3060 g).

[0279] Synthesis of copper salt carboxylic acid labeled precursor 145: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1 above. Relatively pure copper salt carboxylic acid labeled precursor 145 (0.3596 g) was obtained from copper salt methyl ester intermediate 143 (1.5498 g). Its data characterization is as follows: 1 H NMR(400MHz,CD3OD)δ3.74-3.93(m,16H),3.44-3.53(m,8H),3.35-3.40(m,8H) ,2.95-3.05(m,8H),2.86(t,J=7.4Hz,8H),2.47(t,J=7.4Hz,8H),1.32(s,24H).

[0280] Synthesis of copper salt carboxylic acid labeled precursor 146: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1 above. Relatively pure copper salt carboxylic acid labeled precursor 146 (0.3856 g) was obtained from copper salt methyl ester intermediate 144 (1.0444 g). Its data characterization: HRMS: calcd 414.0465 (M+Cu) + Found 414.0432(M+Cu) + When the compound is a copper salt, "M" here refers to the precise mass of the isocyanate monomer in the copper salt.

[0281] Synthesis of Re complex 147: For specific procedures, please refer to "Synthesis of Re complex 69" in Example 1 above. Re complex 147 was obtained from copper salt carboxylic acid-labeled precursor 146 (1.0–3.1 mg). Its data characterization: HRMS: calcd 1103.4935 (M) + Found 1103.4958 (M) + .

[0282] In addition, radioactivity 99m Tc complex (in this embodiment, when e is always 2, f is always 2, g is 2 and 4 respectively, M is...) 99m The marking route and method (when Tc) are the same as the corresponding steps in the above embodiments, and will not be repeated here.

[0283] Example 10

[0284] Organic synthetic routes and methods for labeled precursor 108 of typical compounds of general formula V selected in this application, as well as Re complexes 109 of typical compounds and their corresponding radioactive compounds. 99m The marking route and method for Tc complex 110 (in this embodiment, d is 3, e is 5, f is 3, and g is 4 in general formula V) are as follows:

[0285] (1) The synthesis and labeling route is as follows:

[0286]

[0287] (2) The synthesis and labeling methods are as follows:

[0288] Synthesis of intermediate 150: For specific procedures, please refer to "Synthesis of intermediate 106" in Example 6 above. After reacting raw materials 13 (96.8007g), 148 (94.9063g), 149 (140.6079g), and DBU (257.4380g), the mixture was separated by silica gel column chromatography to obtain relatively pure intermediate 150 (69.7249g). The product was used directly in the next reaction without further purification.

[0289] Synthesis of intermediate 151: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1 above. After reacting intermediate 2 (14.6129 g) and relatively pure intermediate 150 (69.7249 g), the mixture was separated by silica gel column chromatography to obtain relatively pure intermediate 151 (17.2080 g). The product was used directly in the next reaction without further purification.

[0290] Synthesis of Intermediate 152: Relatively pure intermediate 151 (17.2080 g) was dissolved in a mixed solvent of 1,4-dioxane and water. Oxone (potassium peroxymonosulfonate, 118.0222 g) was then added in portions, and the mixture was stirred overnight at room temperature. The mixture was then quenched with water, extracted with dichloromethane, dried, concentrated under vacuum, and separated by silica gel column chromatography to obtain intermediate 152 (2.4834 g). Its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ8.24(brs,1H),6.25(brs,1H),3.56(t,J=6.2Hz,2H),3.49(t,J=5.7Hz,2H),3.32(d,J=6.0H z,2H),3.00-3.18(m,8H),2.38-2.44(m,2H),2.05-2.11(m,2H),1.89-1.97(m,4H),1.64-1.72(m,2H),1.17(s,6H).

[0291] Synthesis of intermediate 153: For specific procedures, please refer to "Synthesis of intermediate 19" in Example 1 above. Intermediate 152 (2.4834 g) reacts with intermediate 7 (0.9231 g) to obtain intermediate 153 (1.5640 g), whose data characterization is as follows: 1HNMR (400MHz, CDCl3): δ8.23(brs,1H),6.45(brs,1H),3.67(s,3H),3.50(t,J=5.6Hz,2H),2.99-3.18(m,8H),2.67(t,J=6.7 Hz,2H),2.53(t,J=7.1Hz,2H),2.34(t,J=7.3Hz,2H),2.05-2.16(m,4H),1.89-1.95(m,4H),1.59-1.77(m,8H),1.18(s,6H).

[0292] Synthesis of isocyanate intermediate 154: For specific procedures, please refer to "Synthesis of isocyanate intermediate 39" in Example 1 above. Isocyanate intermediate 154 (1.3280 g) was obtained from intermediate 153 (1.7249 g), and its data characterization is as follows: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),3.53(t,J=5.6Hz,2H),3.38(s,2H),3.09-3.14(m,4H),2.98-3.03(m,4H),2.67(t,J=6.9 Hz,2H),2.53(t,J=7.2Hz,2H),2.34(t,J=7.1Hz,2H),2.07-2.16(m,4H),1.88-1.96(m,4H),1.60-1.75(m,6H),1.28(s,6H).

[0293] Synthesis of copper salt methyl ester intermediate 155: For specific procedures, please refer to "Synthesis of copper salt methyl ester intermediate 49" in Example 1 above. Relatively pure copper salt methyl ester intermediate 155 (1.0637g) was obtained from isocyanomethyl ester intermediate 154 (1.3280g).

[0294] Synthesis of copper salt carboxylic acid labeled precursor 156: For specific procedures, please refer to "Synthesis of copper salt carboxylic acid labeled precursor 59" in Example 1 above. Relatively pure copper salt carboxylic acid labeled precursor 156 (0.4610 g) was obtained from copper salt methyl ester intermediate 155 (1.0637 g). Its data characterization is as follows: 1 H NMR (400MHz, CD3OD): δ3.79(s,8H),3.56(t,J=5.2Hz,8H),3.13-3.31(m,32H),2.69(t,J=6.8Hz,8H),2.56(t,J =7.1Hz,8H),2.17(t,J=6.7Hz,8H),1.94-2.11(m,16H),1.80-1.93(m,16H),1.55-1.73(m,24H),1.29(s,24H); 13C NMR (101MHz, CD3OD): δ181.16,154.10,73.12,59.65,51.76,51.44,50.87,49.5 6,37.31,31.16,29.94,29.31,26.83,25.53,22.97,22.04,21.63,21.12,21.06; 19 F NMR (376MHz, CD3OD): δ-155.4; HRMS: calcd 576.1179 (M+Cu) + Found 576.1184(M+Cu) + .

[0295] Labeling of Re complex 157: For specific procedures, refer to "Labeling of Re complex 69" in Example 1 above. Re complex 157 was obtained by labeling precursor 156 with copper salt carboxylic acid; HRMS: calcd 1265.5649 (M). + Found 1265.5552(M) + .

[0296] 99m The marking of Tc complex 158: For specific procedures, please refer to the "..." section of Example 1 above. 99m The labeling of Tc complex 78 was obtained from copper salt carboxylic acid labeled precursor 156. 99m Tc radioactive complex 158. 99m Liquid chromatography-mass spectra of Tc radioactive complex 158 and its corresponding Re complex 157 co-injected (methanol / water containing 1 / 1000 trifluoroacetic acid = 67.5 / 32.5, total flow rate 1.0 mL / min, C-18 reversed-phase semi-preparative column) are shown below. Figure 10 As shown, then 99m The elution time of Tc radiocomplex 158 (62.125 min) was basically the same as that of the corresponding Re complex 157 (63.192 min).

[0297] Example 11

[0298] Select the corresponding radioactivity of some typical compounds of general formula V in this application. 99m The in vivo biodistribution of Tc complex 158 in female Kunming mice was studied. For specific experimental methods, please refer to the "Radioactive" section in Example 7 above. 99m The experimental method and results of the study on the biodistribution of Tc complex 130 in female Kunming mice are as follows:

[0299] Table 6 Radioactivity 99m Biodistribution data of Tc complex 158 in female Kunming mice (n=3, ID% / g)

[0300]

[0301] radioactivity 99m After tail vein injection, Tc complex 158 showed low absolute myocardial absorption and rapid myocardial clearance over time. Furthermore, the cardiac / blood and cardiac / lung values ​​remained at moderate levels after tail vein injection.

[0302] Example 12

[0303] Furthermore, the synthetic route and method for intermediate 163, a labeled precursor of a typical compound of general formula VI in this application (in this embodiment, e is 2, f is 2, and g is 4 in general formula VI), are as follows:

[0304] (1) The synthetic route is as follows:

[0305]

[0306] (2) The synthesis method is as follows:

[0307] Synthesis of intermediate 160: Pyridine (3.1456 g) was added to a dichloromethane solution of starting material 159 (2.5090 g), and the mixture was cooled to -30 °C. Then, triphosgene (1.2998 g) was added to the mixture, and the mixture was stirred in an ice bath for 4 h. The reaction solution was quenched with hydrochloric acid, extracted with dichloromethane, dried, and concentrated under vacuum to obtain a concentrate containing intermediate 160 (1.4693 g). The product was used directly in the next reaction without further purification.

[0308] Synthesis of Intermediate 161: 2-Aminoethanol (0.4603 g) and DIPEA (diisopropylethylamine, 1.9586 g) were added sequentially to a dichloromethane solution containing a concentrate of intermediate 160 (1.4693 g) under ice bath conditions. The mixture was stirred under ice bath conditions for 0.5 h, then stirred overnight at room temperature. The mixture was concentrated under vacuum and separated by silica gel column chromatography to obtain intermediate 161 (0.9288 g), whose data characterization is as follows: 1 H NMR (400MHz, CD3OD): δ4.84 (t, J = 8.4 Hz, 2H), 3.94 (t, J = 8.6 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H).

[0309] Synthesis of Intermediate 162: For specific procedures, please refer to "Synthesis of Intermediate 19" in Example 1 above. Intermediate 161 (0.9288 g) reacted with Intermediate 7 (0.7827 g) to obtain Intermediate 162 (122.3 mg). Its data characterization is as follows: 1H NMR (400MHz, CD3OD): δ3.65(s,3H),3.56(t,J=5.6Hz,2H),3.28(t,J=7.2Hz,2H),3.22(t,J= 5.6Hz,2H),2.53-2.61(m,4H),2.35(t,J=7.2Hz,2H),1.67-1.74(m,2H),1.57-1.63(m,2H).

[0310] Synthesis of intermediate 163: For specific procedures, please refer to "Synthesis of intermediate 29" in Example 1 above. After reacting intermediate 2 (29.0 mg) and intermediate 162 (122.3 mg), a concentrate containing intermediate 163 (147.5 mg) was obtained. Its data characterization: HRMS: calcd 378.2063 (M+H) + ,found 378.1202(M+H) + ,calcd 400.1882(M+Na) + Found 400.1918(M+Na) + .

[0311] Furthermore, the synthetic route and method for converting intermediate 163 into the corresponding copper salt carboxylic acid-labeled precursor via the corresponding isocyanate monomer methyl ester intermediate and the subsequent copper salt methyl ester intermediate; and its corresponding rhenium Re complex (in this embodiment, when e is 2, f is 2, g is 4, and M is Re in general formula VI) and radioactive 99m Tc complex (in this embodiment, when e is 2, f is 2, g is 4, and M is...) 99m The marking route and method (when Tc) are the same as the corresponding steps in the above embodiments, and will not be repeated here.

[0312] Example 12

[0313] The synthetic route and method for labeled precursor 180 of a typical compound of general formula VII in this application are described (in this embodiment, f is 12 and g is 1 in general formula VII). Furthermore, following the synthetic route for labeled precursor 180, there are methods for increasing the value of g when f is small, as shown below:

[0314] (1) The synthetic route is as follows:

[0315]

[0316]

[0317] (2) The preliminary synthesis steps are as follows:

[0318] First, 6-caprolactone (164) is ring-opened with sodium hydroxide and then acidified to give intermediate 165;

[0319] Then, intermediate 165 is reacted with tert-butyldiphenylchlorosilane (TBDPSCl) in DMF (imidazolium participates in the reaction as a base), and the alcohol hydroxyl group of intermediate 165 is protected by tert-butyldiphenylchlorosilane, transforming it into intermediate 166.

[0320] Next, intermediate 166 reacts with oxalyl chloride in toluene, and the carboxyl group of intermediate 166 is converted to acyl chloride to give intermediate 167.

[0321] Next, intermediate 167 undergoes a Friedel-Crafts reaction with thiophene (168) in dichloromethane (tin tetrachloride participates in the reaction as a Lewis acid) to give intermediate 169;

[0322] Next, intermediate 169 reacts with potassium hydroxide and hydrazine in ethylene glycol. After a Wolff-Kisher-Huang Minglong reduction reaction, the carbonyl group on intermediate 169 is reduced to a methylene group to give intermediate 170.

[0323] Subsequently, intermediate 170 reacts with 3-methylglutaric anhydride (171) in nitrobenzene to undergo a Friedel-Crafts reaction (aluminum trichloride participates in the reaction as a Lewis acid) to give intermediate 172;

[0324] Next, intermediate 172 undergoes a Wolff-Kisher-Huang Minglong reduction reaction, where the carbonyl group on intermediate 172 is reduced to a methylene group, yielding intermediate 173.

[0325] Then, the thiophene ring on intermediate 173 is reduced to four methylene-(CH2)4- by Raney nickel to obtain intermediate 174;

[0326] Next, intermediate 174 was subjected to a methyl esterification reaction in methanol catalyzed by p-toluenesulfonic acid to obtain intermediate 175;

[0327] Subsequently, intermediate 175 was subjected to a deprotection reaction of the tert-butyldiphenylchlorosilyl protecting group in a mixed solvent of tetrahydrofuran and acetic acid by the action of tetrabutylammonium fluoride (TBAF) to obtain intermediate 176.

[0328] Then, referring to the specific operation steps in "Synthesis of Intermediate 29" in Example 1 of this invention, intermediate 176 and intermediate 2 undergo an alkoxymercuration-demercuration reaction under the action of mercuric acetate and subsequently sodium borohydride to obtain intermediate 177.

[0329] Next, referring to the specific operation steps in "Synthesis of Isocyanomethyl Ester Intermediate 39" in Example 1 of this invention, intermediate 177 was dehydrated under the action of triethylamine and phosphorus oxychloride to obtain isocyanomethyl ester intermediate 178.

[0330] Subsequently, isocyanate intermediate 178 undergoes a ligand exchange reaction with tetra(acetonitrile)copper(I)tetrafluoroborate to obtain copper salt methyl ester intermediate 179.

[0331] Next, copper salt methyl ester intermediate 179 was hydrolyzed and acidified to obtain copper salt carboxylic acid labeled precursor 180;

[0332] Following this, the copper salt carboxylic acid-labeled precursor 180 was labeled according to "labeling of Re complex 69" in Example 1 above. 99m The corresponding steps for labeling Tc complex 69 can yield its rhenium complex and... 99m Tc complexes. Further details will not be provided here.

[0333] At this point, f = 12 and g = 1. If we want the methyl group to move away from the carboxyl group (i.e., appropriately increase the g value in formula VII and appropriately decrease the f value in formula VII), we can start from an intermediate similar to position 174 and adopt the following strategy: First, the carboxylic acid is reduced to a primary alcohol by lithium aluminum hydride. The primary alcohol reacts with thionyl chloride to become a chlorinated product. The chlorinated product reacts with sodium cyanide and sodium iodide to become a cyano group, which is then hydrolyzed to a carboxylic acid. This increases the g value in formula VII and yields a product with the methyl substituent moving away from the carboxyl group.

[0334] Example 13

[0335] Furthermore, the synthetic route and method for the labeled precursor 190 of a typical compound of general formula VIII in this application (in this embodiment, f is 12 and g is 1 in general formula VIII) are also described below, following the synthetic route for the labeled precursor 190, as well as methods for increasing the value of g when f is small:

[0336] (1) The synthetic route is as follows:

[0337]

[0338]

[0339] (2) The preliminary synthesis steps are as follows: The reaction steps from intermediate 170 to copper salt carboxylic acid labeled precursor 190 are completely similar to the reaction steps from intermediate 170 to copper salt carboxylic acid labeled precursor 180 in Example 12 above, and need not be repeated here.

[0340] Following this, the copper salt carboxylic acid-labeled precursor 190 was labeled according to "labeling of Re complex 69" in Example 1 above.99m The corresponding steps for labeling Tc complex 69 can yield its rhenium complex and... 99m Tc complexes. Further details will not be provided here.

[0341] In addition, at this time, f = 12 and g = 1; if you want the methyl group to move away from the carboxyl group (i.e., appropriately increase the g value in general formula VIII and appropriately decrease the f value in general formula VIII), you can start from an intermediate similar to 184 and take a reaction step that is completely similar to that in Example 12 above, starting from intermediate 174 to increase the g value, thereby increasing the g value in general formula VII, and obtaining a product in which the methyl substituent is away from the carboxyl group.

[0342] In this invention, "calcd" refers to the predicted value of the molecular ion peak of the target molecule using Chemdraw software, "found" refers to the measured value of the molecular ion peak of the target molecule using a mass spectrometer, "HRMS" refers to high-resolution mass spectrometry characterization, and the letter "M" in the HRMS characterization data of the copper salt methyl ester intermediate and the copper salt carboxylic acid labeled precursor refers to the Exact Mass (precise molecular ion peak) of the corresponding isocyanate monomer. In the positive ion characterization mode of the mass spectrometer, the copper salt methyl ester intermediate and the copper salt carboxylic acid labeled precursor can only show the molecular ion peaks of "M+Cu" (corresponding isocyanate monomer plus copper atom) or "2M+Cu" (2 corresponding isocyanate monomers plus copper atom).

[0343] It should also be noted that this application conducted efficacy tests using both mice and rats. This is because rat experiments are closer to human trials, and therefore, rat experiments are more accurate and have greater reference value. Thus, rat experiments were added to the mouse study. Furthermore, due to space limitations, the structural characterization in this application only describes specific characterization data and omits accompanying figures.

[0344] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can be modified and varied in various ways. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of protection of the present invention.

Claims

1. A labeled fatty acid derivative, characterized in that: Its general formula is shown in Formula I: Where M is 99m Tc or Re; R, R 1 R 2 R 3 R 4 and R 5 Independently H, aliphatic chain; A1~A 12 Independently, it is an H, an aliphatic chain; the aliphatic chain is an aliphatic hydrocarbon chain with 1-28 carbon atoms; J and X do not exist, and Y is -S- or or ; Where z is an integer from 1 to 6; a is an integer from 1 to 3; b is an integer from 1 to 3; c is an integer from 1 to 3; d is an integer from 0 to 14, e is an integer from 0 to 14, f is an integer from 1 to 15, and g is an integer from 1 to 6.

2. The labeled fatty acid derivative according to claim 1, characterized in that: R, R 1 R 2 R 3 R 4 and R 5 and A1~A 12 An aliphatic hydrocarbon chain that is independently -H or has 1-5 carbon atoms.

3. The labeled fatty acid derivative according to claim 1, characterized in that: Formula I is general formula II, where, M, z, f, g, R, R 1 R 2 R 3 R 4 R 5 All are consistent with those defined in claim 1. 。 4. The labeled fatty acid derivative according to claim 1, characterized in that: Formula I is general formula III, where, M, z, f, g, R, R 1 R 2 R 3 R 4 R 5 All are consistent with those defined in claim 1. 。 5. A precursor compound for preparing labeled fatty acid derivatives, characterized in that: The precursor compound is an isocyanate monomer, and the structure of the isocyanate monomer is... Among them, J, X, Y, R 4 R 5 R, A3~A 12 b, c, d, e, f, and g are all consistent with those defined in any one of claims 1-2.

6. A precursor compound for preparing labeled fatty acid derivatives, characterized in that: The precursor compound is an isocyanate metal salt, and the structure of the isocyanate metal salt is as follows: Wherein, Q is a metal cation, which is copper ion, cuprous ion, calcium ion, potassium ion, sodium ion, magnesium ion, or aluminum ion; E is an anion, which is tetrafluoroborate ion (BF4). - ), hexafluorophosphate ions (PF6) - ), trifluoroacetate ion (CF3COO) - ), perchlorate ions (ClO4) - ), fluoride ions, chloride ions, bromide ions, iodide ions; J, X, Y, R 4 R 5 R, A3~A 12 z, b, c, d, e, f, and g are all consistent with those defined in any one of claims 1-2.

7. The precursor compound according to claim 6, characterized in that, Q represents copper ions or cuprous ions; E represents tetrafluoroborate ions (BF4). - ).

8. A myocardial imaging agent, characterized in that, The myocardial imaging agent comprises the general formula I as described in any one of claims 1-2.

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