Phenoxyalkyl guanidine derivative of targeted noradrenaline transporter and preparation method and application of phenoxyalkyl guanidine derivative

Abstract

The invention relates to the technical field of biological medicines, in particular to a noradrenaline transporter-targeting phenoxy alkyl guanidine derivative as well as a preparation method and application of the noradrenaline transporter-targeting phenoxy alkyl guanidine derivative. The structure of the phenoxyalkyl guanidine derivative is shown as a formula (I): # imgabs0 #, wherein R1 is 19F, 18F or 131I; r2 is hydrogen, a hydroxyl group, fluorine, chlorine, bromine, a C1-C6 alkoxy group or a C1-C6 substituted alkoxy group; l is a linker and is C2-C10 alkyl, C2-C10 substituted alkyl, C3-C10 cycloalkyl or C3-C10 substituted cycloalkyl. The F-18 or I-131 labeled phenoxy alkyl guanidine derivative provided by the invention can be used as a NET targeted radioactive diagnosis or treatment drug with higher affinity and better targeting property, and can be used for myocardial sympathetic nerve imaging and NET positive tumor diagnosis or treatment in nuclear medicine.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a phenoxyalkylguanidine derivative targeting norepinephrine transporter protein, and a preparation method and application thereof. Background Art

[0002] With the help of single-photon emission computed tomography (SPECT) and positron emission tomography (PET), molecular probes labeled with radionuclides can integrate specific targeted diagnosis and treatment, promoting the realization of integrated diagnosis and treatment of tumors. Norepinephrine transporter (NET) is a transmembrane protein located in the presynaptic membrane of adrenergic nerves. It terminates noradrenergic signal transduction by rapidly reuptaking norepinephrine (NE) released by neurons. Neuroendocrine tumors originating from the sympathetic nervous system (such as NB, pheochromocytoma, and paraganglioma) also highly express NET. Therefore, NET is an important target for myocardial sympathetic nerve imaging and functional imaging and radionuclide therapy of some neuroendocrine tumors. Nuclear medicine molecular probes targeting NET have been developed and applied to the diagnosis and treatment of NB. The most widely used one is radioactive iodine-123 ( 123 I) / iodine-131( 131 I) labeled NE analog meta-iodobenzylguanidine (MIBG). Diagnosis: 123 I-MIBG imaging has been recommended by the International neuroblastoma risk group (INRG) for disease staging and treatment response monitoring. 123 The I-MIBG probe has certain limitations, such as limited spatial resolution, inability to perform quantitative analysis, long half-life of the radionuclide, and cumbersome collection procedures (injection 123 I-MIBG imaging is performed 24 hours or even 48 hours after taking the drug, and patients and their families need to go back and forth to the hospital many times. 131 I-MIBG has been used for the treatment of relapsed / refractory NB for many years. 131 The response rate of I-MIBG monotherapy in patients with relapsed and / or refractory NB is only 20-40%. How to further improve the clinical treatment response rate and improve the treatment effect has been a major issue in recent years. 131 I-MIBG therapy research is the focus.123 I / 131 I-MIBG is widely used in clinical practice. In view of the above limitations, further optimization and development of new NET-targeted radioactive diagnostic and therapeutic drugs for the diagnosis and treatment of NET-positive tumors have good clinical application prospects. Summary of the invention

[0003] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a phenoxyalkylguanidine derivative targeting norepinephrine transporter and a preparation method and application thereof, so as to solve the problems of low imaging quality and poor therapeutic effect of existing NET targeted radioactive diagnostic and therapeutic drugs.

[0004] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0005] In a first aspect, a phenoxyalkylguanidine derivative is provided, the structure of which is shown in formula (I):

[0006]

[0007] Among them, R1 is 19 F. 18 F or 131 I; R2 is hydrogen, hydroxyl, fluorine, chlorine, bromine, C1-C6 alkoxy or C1-C6 substituted alkoxy; L is a linker, C2-C 10 Alkyl, C2-C 10 Substituted alkyl, C 3- C 10 Cycloalkyl or C 3- C 10 Substituted cycloalkyl.

[0008] Furthermore, the structure of formula (I) is selected from any one of the following compounds:

[0009]

[0010] In a second aspect, a method for preparing an F-18-labeled phenoxyalkylguanidine derivative is provided, wherein an F-18-labeled precursor is used for photooxidation-reduction catalysis, and after the labeling reaction, the protecting group is removed and separated and purified to obtain the derivative; the structure of the F-18-labeled precursor is shown in formula (II):

[0011]

[0012] Wherein, R29 is hydrogen or fluorine, chlorine, bromine, aldehyde, cyano, aryl, alkyl or -COR35 which may be substituted at any position; R35 is alkoxy or substituted amino; R30, R31, R32, R33 are hydrogen or a Boc protecting group;

[0013] The specific steps are as follows:

[0014]

[0015] Furthermore, the photocatalyst used for the photocatalytic labeling reaction includes 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate; and the solvent is dichloromethane or dichloroethane.

[0016] In a third aspect, a method for preparing an I-131-labeled phenoxyalkylguanidine derivative is provided, wherein an I-131-labeled precursor is subjected to a labeling reaction, and then the protecting group is removed, separated and purified to obtain the derivative; the structure of the I-131-labeled precursor is shown in formula (III):

[0017]

[0018] Wherein, R30, R31, R32, and R33 are Boc protecting groups, and R34 is trimethyltin or tributyltin;

[0019] The specific steps are as follows:

[0020]

[0021] In a fourth aspect, a pharmaceutical composition is provided, which contains an effective dose of a phenoxyalkylguanidine derivative and its F-18 and I-131 markers.

[0022] In a fifth aspect, the invention provides the use of phenoxyalkylguanidine derivatives and their F-18 and I-131 markers in the preparation of products for the diagnosis and treatment of NET-positive tumors and / or NET-positive tumor metastases.

[0023] In a sixth aspect, a phenoxyalkylguanidine derivative and its F-18, I-131 markers are provided for use in the preparation of products for imaging of myocardial sympathetic nerves and NET-positive tumors.

[0024] The beneficial effects of the present invention are:

[0025] The present invention provides a novel NET-targeted phenoxyalkylguanidine derivative, a pharmaceutical composition containing the same, and its application. The novel NET-targeted phenoxyalkylguanidine derivative can be prepared by using the labeling precursor provided by the present invention to achieve efficient F-18 or I-131 labeling. The novel F-18 or I-131-labeled phenoxyalkylguanidine derivative can be used for myocardial sympathetic nerve imaging and the diagnosis, grading and treatment of NET-positive tumors, and has broad application prospects. 18 F-MFBG( 18 Compared with F-meta-fluorobenzylguanidine), the compound disclosed in the present invention has a higher uptake and background ratio in myocardial sympathetic nerves and tumors, and can achieve accurate and efficient NET molecular function imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 18 Radio-HPLC spectrum of F-18 labeling reaction of F-1;

[0027] Figure 2 18 Radio-HPLC spectrum of F-1;

[0028] Figure 3 18 Radio-HPLC spectrum of F-2's F-18 labeling reaction;

[0029] Figure 4 18 Radio-HPLC spectrum of F-2;

[0030] Figure 5 18 Radio-HPLC spectrum of F-18 labeling reaction of F-3;

[0031] Figure 6 18 Radio-HPLC spectrum of F-3;

[0032] Figure 7 18 Radio-HPLC spectrum of F-18 labeling reaction of F-4;

[0033] Figure 8 18 Radio-HPLC spectrum of F-4;

[0034] Fig. 9 18 Radio-HPLC spectrum of F-18 labeling reaction of F-5;

[0035] Fig.10 18 Radio-HPLC spectrum of F-5;

[0036] Fig.11 18 Radio-HPLC spectrum of F-18 labeling reaction of F-6;

[0037] Fig.12 18 Radio-HPLC spectrum of F-6;

[0038] Fig.13 18 Radio-HPLC spectrum of F-18 labeling reaction of F-7;

[0039] Fig.14 18Radio-HPLC spectrum of F-7;

[0040] Fig.15 18 Radio-HPLC spectrum of F-18 labeling reaction of F-8;

[0041] Fig.16 18 Radio-HPLC spectrum of F-18 labeling reaction of F-9;

[0042] Fig.17 18 Radio-HPLC spectrum of F-9;

[0043] Fig.18 18 Radio-HPLC spectrum of F-18 labeling reaction of F-10;

[0044] Fig.19 18 Radio-HPLC spectrum of F-10;

[0045] Fig. 20 131 Radio-HPLC spectrum of I-131 labeling reaction of I-1;

[0046] Fig.21 131 Radio-HPLC spectrum of the I-131 labeling reaction of I-2;

[0047] Fig. 22 131 Radio-HPLC spectrum of I-131 labeling reaction of I-5;

[0048] Fig.23 18 F-5 PET-CT fusion image (Mip) and coronal (Cor) image 60 minutes after administration in PC12 tumor-bearing mice;

[0049] Fig.24 18 F-4 and 18 PET-CT images and tumor, muscle, and liver uptake ratios 60 minutes after administration of F-MFBG in PC12 tumor-bearing mice;

[0050] Fig.25 F-18 labeled phenoxyalkylguanidine derivatives and 18 F-OFBG (o-fluorobenzylguanidine), 18 F-MFBG (meta-fluorobenzylguanidine), 18 PET images of myocardial sympathetic nerve imaging 60 minutes after administration of F-PFBG (paraflubenzylguanidine) in SD rats;

[0051] Fig.26 18 F-1 is a schematic diagram of the distribution of PC12 in the body of tumor-bearing mice. DETAILED DESCRIPTION

[0052] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0053] Example 1

[0054] Synthesis of phenoxyalkylguanidine derivatives:

[0055]

[0056] Compound 18 Synthesis of F-1:

[0057] 2-(2-Fluorophenoxy)ethylamine (68 mg, 0.44 mmol, 1.0 eq,) and N,N'-di-Boc-1H-1-guanidinopyrazole (165 mg, 0.53 mmol, 1.2 eq) were dissolved in acetonitrile (10 mL), potassium carbonate (91 mg, 0.66 mmol, 1.5 eq) was added, and the reaction was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 15: 1) to obtain a white solid (Boc protected 18 F-1). 1 HNMR(400MHz,Chloroform-d)δ11.48(s,1H),8.73(t,J=5.7Hz,1H),7.02-6.93(m,2H),6 .92-6.83(m,2H),4.05(t,J=5.2Hz,2H),3.82(q,J=5.3Hz,2H),1.51(s,9H)1.49(s,9H). 18 F NMR(376MHz,Chloroform-d)δ-123.47. 13C NMR(10MHz,Chloroform-d)δ163.50,157.50(d,J=238.6Hz),156.38,154.66(d,J=2.1Hz),15 3.08, 115.91 (d, J = 10.8Hz), 115.75 (d, J = 4.2Hz), 83.21, 79.39, 66.99, 40.14, 28.31, 28.07.

[0058] Boc protected 18 F-1 was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 5 h. TLC showed that the reaction of the raw material was basically complete (PE:EA=5:1). The solvent was dried under reduced pressure, and the crude product was dissolved in water (1 mL) and freeze-dried to obtain 18 F-1, white solid. 1 H NMR (400MHz, Methanol-d4) δ7.18-7.08(m,3H),7.02-6.95(m,1H),4.20(t,J=5.0Hz,2H),3.65(t,J=5.0Hz,2H). 18 F NMR(377MHz,Methanol-d4)δ-77.12,-136.70. 13 CNMR(100MHz,Methanol-d4)δ157.88,152.62(d,J=244.4Hz),146.28(d,J=10.8Hz),124.35( d, J=4.0Hz), 121.70 (d, J=6.9Hz), 115.75 (d, J=18.2Hz), 115.00 (d, J=1.6Hz), 67.62, 40.85.

[0059] Compound 18 Synthesis of F-2: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.33-7.27(m,1H),6.84-6.77(m,1H),6.77-6.68(m,2H),4.14(t,J=5.0Hz,2H),3.62(t,J=5.1Hz,2H). 18 F NMR(377MHz, Methanol-d4)δ-77.23,-113.71. 13C NMR (100MHz, Methanol-d4) δ163.65 (d, J = 244.0Hz), 159.86 (d, J = 11.0Hz), 157.72, 130.29 (d ,J=10.0Hz),110.05(d,J=2.9Hz),107.51(d,J=21.5Hz),101.78(d,J=25.3Hz),66.24,40.66.

[0060] Compound 18 Synthesis of F-3: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.08-7.00(m,2H),7.00-6.93(m,2H),4.11(t,J=5.1Hz,2H),3.61(t,J=5.0Hz,2H). 18 F NMR(377MHz, Methanol-d4)δ-77.20,-125.62. 13 C NMR (100MHz, Methanol-d4) δ157.70, 157.61 (d, J = 237.6Hz), 154.65 (d, J = 2.2Hz), 115.51 (d, J = 5.2Hz), 115.36 (d, J = 10.2Hz), 66.58, 40.83.

[0061] Compound 18 Synthesis of F-4: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.14-7.08(m,3H),6.98-6.92(m,1H),4.16(q,J=5.3Hz,2H),3.50-3.39(m,2H),2.14-2.07(m,2H). 18 F NMR(377MHz, Methanol-d4)δ-76.98,-136.93. 13 C NMR (100MHz, Methanol-d4) δ157.42, 152.72 (d, J = 244.2Hz), 146.68 (d, J = 10.6Hz), 124.26 (d, J =3.8Hz), 121.22 (d, J = 7.0Hz), 115.62 (d, J = 18.3Hz), 115.03 (d, J = 1.8Hz), 66.06, 38.06, 28.27.

[0062] Compound18 Synthesis of F-5: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.29-7.23(m,1H),6.77-6.74(m,1H),6.74-6.62(m,2H),4.06(t,J=5.9Hz,2H),3.39(t,J=6.8Hz,2H),2.11-2.00(m,2H). 18 F NMR(377MHz, Methanol-d4)δ-76.94,-113.97. 13 C NMR(100MHz, Methanol-d4)δ163.68(d,J=243.5Hz),160.33,160.28(d,J=11.0Hz),130.15(d,J= 10.1Hz), 110.05 (d, J = 2.9Hz), 107.06 (d, J = 21.6Hz), 101.66 (d, J = 25.2Hz), 64.91, 38.12, 28.14.

[0063] Compound 18 Synthesis of F-5a: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ6.59-6.57(m,1H),6.51-6.46(m,2H),4.02(t,J=5.9Hz,2H),3.37(t,J=6.9Hz,2H),2.29(s,3H),2.03(p,J=6.4Hz,2H). 18 F NMR(376MHz, Methanol-d4)δ-77.08,-115.03. 13 C NMR(100MHz,Methanol-d4)δ163.53(d,J=242.9Hz),157.38,159.97(d,J=11.8Hz),141.07(d,J=9.9Hz),1 10.69(d,J=2.6Hz),107.78(d,J=21.6Hz),98.71(d,J=25.4Hz),64.81,38.13,28.15,20.14(d,J=2.2Hz).

[0064] Compound 18 Synthesis of F-6: According to 18 The synthesis method of F-1 is to replace the raw materials. 1H NMR (400MHz, Methanol-d4) δ7.05-6.95(m,2H),6.95-6.88(m,2H),4.03(t,J=5.9Hz,2H),3.39(t,J=6.8Hz,2H),2.12-1.95(m,2H). 18 F NMR(377MHz, Methanol-d4)δ-76.94,-126.06. 13 C NMR(100MHz,Methanol-d4)δ161.75(q,J=34.5Hz),157.40,157.38(d,J=237.1Hz), 155.02(d,J=2.1Hz),118.28,115.40,115.36,115.28,115.17,65.20,38.17,28.27.

[0065] Compound 18 Synthesis of F-7: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.13-7.05(m,3H),6.95-6.90(m,1H),4.11(t,J=5.9Hz,2H),3.29(t,J=6.9Hz,2H),1.95-1.76(m,4H). 18 F NMR(377MHz, Methanol-d4)δ-77.00,-137.43. 13 C NMR (100MHz, Methanol-d4) δ157.30, 152.68 (d, J = 244.0Hz), 146.90 (d, J = 10.6Hz), 124.20 (d, J = 3. 9Hz), 120.87 (d, J = 6.9Hz), 115.52 (d, J = 18.4Hz), 114.83 (d, J = 1.9Hz), 68.43, 40.79, 26.01, 25.36.

[0066] Compound 18 Synthesis of F-8: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.31-7.22(m,1H),6.74-6.73(m,1H),6.71-6.62(m,2H),4.03(t,J=6.0Hz,2H),3.27(t,J=6.9Hz,2H),1.92-1.73(m,4H). 18F NMR(377MHz,Methanol-d4)δ-77.20,-114.06. 13 C NMR (100MHz, Methanol-d4) δ163.69 (d, J = 243.6Hz), 160.50 (d, J = 10.9Hz), 157.30, 130.09 (d, J = 10. 2Hz), 110.05 (d, J = 2.9Hz), 106.80 (d, J = 21.6Hz), 101.53 (d, J = 25.1Hz), 67.32, 40.78, 25.92, 25.32.

[0067] Compound 18 Synthesis of F-9: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.06-6.95(m,2H),6.95-6.86(m,2H),4.00(t,J=5.9Hz,2H),3.27(t,J=6.8Hz,2H),1.90-1.74(m,4H). 18 F NMR(377MHz,Methanol-d4)δ77.12,-126.39. 13 C NMR (100MHz, Methanol-d4) δ157.29, 157.24 (d, J = 236.8Hz), 155.22 (d, J = 2.0Hz), 115.31 (d, J = 9.0Hz), 115.16 (d, J = 6.2Hz), 67.61, 40.81, 26.05, 25.35.

[0068] Compound 18 Synthesis of F-10: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR(400MHz, Methanol-d4)δ7.12-7.04(m,3H),6.94-6.88(m,1H),4.08(t,J=6.2Hz, 2H),3.23(t,J=6.9Hz,2H),1.91-1.81(m,2H),1.75-1.65(m,2H),1.65-1.55(m,2H). 18 F NMR(377MHz,Methanol-d4)δ-77.13,-137.16. 13C NMR (100MHz, Methanol-d4) δ157.28, 152.68 (d, J = 243.9Hz), 147.03 (d, J = 10.5Hz), 124.17 (d, J = 3.9Hz ),120.71(d,J=6.9Hz),115.49(d,J=18.4Hz),114.77(d,J=1.8Hz),68.69,40.98,28.52,28.25,22.93.

[0069] Compound 18 F- 127 Synthesis of I-11: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.28-7.11(m,2H),7.03-6.91(m,1H),4.11(t,J=4.0Hz,2H),3.45(t,J=4.0Hz,2H). 18 F NMR(377MHz, Methanol-d4)δ-79.02,-139.71. 13 C NMR (100MHz, Methanol-d4) δ167.84, 155.61 (d, J = 214.4Hz), 149.25 (d, J = 10.1Hz), 128.75 ( d, J=4.0Hz), 125.54 (d, J=6.5Hz), 117.85 (d, J=17.1Hz), 116.00 (d, J=1.6Hz), 66.92, 45.57.

[0070] Compound 127 Synthesis of I-1: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.08-6.91(m,3H),6.72-6.85(m,1H),4.01(t,J=5.0Hz,2H),3.55(t,J=5.0Hz,2H). 18 F NMR(377MHz, Methanol-d4)δ-77.12,-136.71. 13C NMR (100MHz, Methanol-d4) δ159.88, 151.22 (d, J = 204.1Hz), 141.28 (d, J = 10.2Hz), 122.25 ( d, J=4.0Hz), 120.71 (d, J=5.9Hz), 111.71 (d, J=17.1Hz), 115.00 (d, J=1.9Hz), 68.61, 40.65.

[0071] Compound 127 Synthesis of I-2: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.13-7.01(m,1H),6.64-6.70(m,1H),6.37-6.21(m,2H),4.04(t,J=5.0Hz,2H),3.52(t,J=5.1Hz,2H). 18 F NMR(377MHz,Methanol-d4)δ-76.03,-112.61. 13 C NMR (100MHz, Methanol-d4) δ161.65 (d, J = 241.0Hz), 159.86 (d, J = 11.1Hz), 157.72, 130.29 (d ,J=11.0Hz),110.05(d,J=2.9Hz),107.51(d,J=21.5Hz),101.78(d,J=25.3Hz),66.11,41266.

[0072] Compound 127 Synthesis of I-5: According to 18 The synthesis method of F-1 is to replace the raw materials. 1 H NMR (400MHz, Methanol-d4) δ7.23-7.11(m,1H),6.71-6.64(m,1H),6.54-6.60(m,2H),4.01(t,J=5.9Hz,2H),3.34(t,J=6.8Hz,2H),2.10-2.00(m,2H). 18 F NMR(377MHz, Methanol-d4)δ-73.84,-111.27. 13C NMR(100MHz, Methanol-d4)δ163.68(d,J=243.5Hz),160.03,160.29(d,J=11.0Hz),130.05(d,J= 10.1Hz), 110.05 (d, J = 2.9Hz), 107.06 (d, J = 21.6Hz), 101.66 (d, J = 25.2Hz), 65.91, 38.02, 28.11.

[0073] Example 2

[0074] Synthesis of F-18 Labeled Precursors of Phenoxyalkylguanidine Derivatives

[0075]

[0076] Synthesis of compound 16:

[0077] Resorcinol (500 mg, 4.55 mmol, 1.0 eq) and 4-chlorophenylboronic acid (783 mg, 5.01 mmol, 1.1 eq) were dissolved in 1,2-dichloroethane (50 mL), copper acetate (910 mg, 5.01 mmol) and triethylamine (947 ul, 6.83 mmol) were added, and the mixture was reacted at room temperature for 24 h. The reaction was monitored by TLC (PE: EA = 10: 1). 1 M citric acid aqueous solution (40 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3), the organic layers were combined, washed with saturated sodium chloride aqueous solution (100 mL × 1), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (PE: EA = 15: 1) to obtain a yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.35-7.27(m,2H),7.21(td,J=8.1,1.3Hz,1H),6.98(dd,J =8.7,1.5Hz,2H),6.60(ddd,J=8.7,6.9,2.3Hz,2H),6.50(q,J=2.0Hz,1H),4.95(br,1H). 13 C NMR (100MHz, Chloroform-d) δ158.34,156.81,155.43,130.59,129.78,128.60,120.49,111.05,110.58,106.09.

[0078] 3-(4-chlorophenoxy)phenol (450mg, 2.05mmol, 1.0eq) was dissolved in acetonitrile (10mL), and then potassium carbonate (508mg, 3.68mmol, 1.8eq), tetrabutylammonium iodide (45mg, 10%), potassium iodide (45mg, 10%) and N-Boc-3-aminopropyl bromide (585mg, 2.46mmol, 1.2eq) were added to the reaction solution, and the temperature was raised to 80°C for overnight reaction. TLC showed that (PE:EA=5:1) the raw materials were basically reacted completely. After the reaction solution was cooled to room temperature, water (10mL) was added, and it was extracted with ethyl acetate (20mL×3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA=5:1) to obtain a milky white solid. 1 H NMR (400MHz, Chloroform-d) δ7.32-7.25(m,2H),7.22(t,J=8.2Hz,1H),6.99-6.91(m,2H),6.65(ddd,J=8.3,2.4,0.9Hz,1H),6.57(ddd,J= 8.2, 2.3, 0.9Hz, 1H), 6.53 (t, J = 2.3Hz, 1H), 4.74 (br, 1H), 3.98 (t, J = 6.0Hz, 2H), 3.31 (q, J = 6.4Hz, 2H), 1.96 (p, J = 6.3Hz, 2H), 1.43 (s, 9H). 13 C NMR(100MHz,Chloroform-d)δ160.21,158.14,156.00,155.65,130.30,129.74 ,128.41,120.30,111.10,109.64,105.41,79.27,65.93,37.99,29.50,28.41.

[0079] The product of the previous step (300 mg, 0.79 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 5 h. TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. The solvent was dried under reduced pressure to obtain a light yellow oil, and the crude product was directly used for the next reaction without purification. The Boc removal product of the previous step (311 mg, 0.79 mmol, 1.0 eq) and N, N'-di-Boc-1H-1-guanidinopyrazole (269 mg, 0.87 mmol, 1.1 eq) were dissolved in acetonitrile (10 mL), potassium carbonate (273 mg, 1.98 mmol, 2.5 eq) was added, and then the reaction was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE:EA=15:1) to obtain compound 16 as a white solid. 1 H NMR(400MHz,Chloroform-d)δ11.50(s,1H),8.64(t,J=5.2Hz,1H),7.29-7.27(m,2H),7.25-7.18(m,1H),6.96-6.89(m,2H),6.73-6.70(m,1H),6 .64(t,J=2.4Hz,1H),6.57(dd,J=8.1,2.3Hz,1H),4.03(t,J=5.7Hz,2H),3.63(q,J=6.2Hz,2H),2.06(p,J=6.0Hz,2H),1.50(s,9H),1.47(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.60,160.15,157.83,156.15,155.90,153.16,130.21,129.6 8,128.16,119.94,111.35,109.65,105.91,83.04,79.27,66.63,39.08,28.55,28.31,28.07.

[0080] Synthesis of compound 12: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.42(s,1H),8.62(t,J=5.7Hz,1H),7.24-7.19(m,2H),7.15-7.10(m,1H),7.08-7.05( m,1H),7.02-6.93(m,2H),6.90-6.84(m,2H),4.11(t,J=5.2Hz,2H),3.71(q,J=5.3Hz,2H),1.50(s,9H),1.46(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.42,156.84,156.33,152.90,150.32,145.31,129.36,12 7.23,125.26,122.08,121.65,118.35,115.35,83.10,79.35,67.55,40.08,28.31,28.01.

[0081] Synthesis of compound 13: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1 H NMR(400MHz,Chloroform-d)δ11.51(s,1H),8.75(t,J=5.5Hz,1H),7.34-7.23(m,3H),7.02-6.95(m,2H),6.75 -6.72(m,1H),6.65-6.58(m,2H),4.09(dd,J=6.6,3.8Hz,2H),3.86(q,J=5.3Hz,2H),1.54(s,9H),1.52(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.49,159.94,158.13,156.37,155.61,153.07,130.33,12 9.74,128.44,120.31,111.43,109.79,105.76,83.22,79.41,66.51,40.10,28.30,28.07.

[0082] Synthesis of compound 14: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.49(s,1H),8.74(t,J=5.6Hz,1H),7.26-7.21(m,2H),6.98-6.90( m,4H),6.90-6.84(m,2H),4.08(t,J=5.2Hz,2H),3.84(q,J=5.3Hz,2H),1.51(s,9H),1.50(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.50,157.09,156.38,155.06,153.09,150.24,12 9.57,127.46,120.79,118.87,115.96,83.21,79.41,66.85,40.17,28.31,28.08.

[0083] Synthesis of compound 15: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1 H NMR(400MHz,Chloroform-d)δ11.46(s,1H),8.29(t,J=5.6Hz,1H),7.25-7.19(m,2H),7.19-7.09(m,1H),7.07-6.91(m,3H ),6.89-6.81(m,2H),4.00(t,J=6.0Hz,2H),3.35(td,J=6.8,5.5Hz,2H),1.91(p,J=6.5Hz,2H),1.49(s,8H),1.48(s,8H). 13 C NMR(100MHz,Chloroform-d)δ163.62,157.10,156.24,153.22,150.71,144.72,129.37,127.0 2,125.47,122.05,121.62,117.81,114.70,83.05,79.19,66.28,37.49,28.81,28.32,28.07.

[0084] Synthesis of compound 16a: The synthesis was carried out according to the synthesis method of compound 16 except that the starting materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.50(s,1H),8.67(t,J=5.2Hz,1H),7.28-7.26(m,2H),6.97-6.88(m,2H),6.58(s,1H),6.4 8-6.35(m,2H),4.01(t,J=5.7Hz,2H),3.63(q,J=6.0Hz,2H),2.28(s,3H),2.04(p,J=6.1Hz,2H),1.50(s,9H),1.48(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.62,159.93,157.64,156.12,155.99,153.15,140.71,129.65,1 28.04,119.94,112.14,110.80,102.73,83.01,79.27,66.68,39.23,28.52,28.32,28.08,21.63.

[0085] Synthesis of compound 17: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1 H NMR (400MHz, Chloroform-d) δ11.52 (s, 1H), 8.67 (t, J = 5.1Hz, 1H), 7.26-7.20 (m, 2H), 6.94 (s, 4H), 6.89-6. 83(m,2H),4.05(t,J=5.8Hz,2H),3.65(td,J=6.5,5.2Hz,2H),2.08(p,J=6.1Hz,2H),1.50(d,J=1.9Hz,18H). 13 C NMR(100MHz,Chloroform-d)δ163.63,157.24,156.15,155.30,153.18,149.87,129.5 4,127.33,120.78,118.74,115.55,83.02,79.27,66.90,39.14,28.63,28.33,28.11.

[0086] Synthesis of compound 18: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.48(s,1H),8.24(t,J=5.4Hz,1H),7.25-7.18(m,2H),7.16-7.11(m,1H),7.05(dd,J=7.9,1.7Hz,1H),6.98 -6.92(m,2H),6.85-6.80(m,2H),3.96(t,J=6.1Hz,2H),3.37-3.32(m,2H),1.73-1.65(m,2H),1.50(s,9H),1.49(s,9H),1.48-1.42(m,2H). 13 CNMR(100MHz,Chloroform-d)δ163.62,157.22,156.16,153.30,150.85,144.46,129.29,126.93, 125.55,122.15,121.35,117.69,114.29,83.06,79.24,68.04,40.35,28.32,28.10,26.42,25.40.

[0087] Synthesis of compound 19: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1 H NMR(400MHz,Chloroform-d)δ11.50(s,1H),8.37(d,J=5.4Hz,1H),7.31-7.25(m,2H),7.24-7.17(m,1H),6.98-6.91(m,2H),6.66 -6.63(m,1H),6.59-6.50(m,2H),3.94(t,J=6.0Hz,2H),3.48(td,J=7.0,5.2Hz,2H),1.88-1.70(m,4H),1.50(s,9H),1.49(s,9H). 13 C NMR(100MHz,Chloroform-d)δ163.63,160.35,158.07,156.21,155.73,153.34,130.25,129.72,1 28.32,120.24,110.99,109.69,105.45,83.13,79.30,67.41,40.47,28.31,28.08,26.52,25.78.

[0088] Synthesis of compound 20: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.51(s,1H),8.38(t,J=5.3Hz,1H),7.26-7.20(m,2H),6.97-6.91(m,2H),6.91-6.83(m, 4H),3.97(t,J=6.0Hz,2H),3.50(td,J=6.9,5.2Hz,2H),1.89-1.82(m,2H),1.81-1.73(m,2H),1.50(s,9H),1.49(s,9H). 13 CNMR(100MHz,Chloroform-d)δ163.64,157.25,156.22,155.51,153.35,149.73,129.53, 127.31,120.84,118.74,115.58,83.13,79.30,67.74,40.47,28.32,28.09,26.60,25.80.

[0089] Synthesis of compound 21: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1 H NMR(400MHz,Chloroform-d)δ11.50(s,1H),8.27(t,J=5.2Hz,1H),7.25-7.19(m,2H),7.16-7.12(m,1H),7.04(dd,J=7.9,1.7Hz,1H),7.00-6. 91(m,2H),6.86-6.80(m,2H),3.93(t,J=6.3Hz,2H),3.33(td,J=7.3,5. 3Hz,2H),1.65(p,J=6.5Hz,2H),1.54-1.46(m,20H),1.32-1.24(m,2H). 13 C NMR(100MHz,Chloroform-d)δ163.67,157.22,156.11,153.34,150.97,144.50,129.28,126.89,125. 51,122.10,121.27,117.72,114.33,83.02,79.20,68.44,40.74,28.71,28.68,28.33,28.10,23.16.

[0090] Synthesis of compound 22: The synthesis was carried out according to the synthesis method of compound 16 except that the raw materials were replaced. 1H NMR(400MHz,Chloroform-d)δ11.22(s,1H),8.64(t,J=5.4Hz,1H),7.36-7.29(m,2H),7.19-7.12(m,1H),7. 02-6.85(m,2H),6.80-6.74(m,2H),4.10(t,J=5.0Hz,2H),3.61(q,J=6.3Hz,2H),1.50(s,9H),1.46(s,9H). 13 C NMR(100MHz,Chloroform-d)δ165.44,157.86,156.63,152.93,151.36,146.31,129.76,12 8.23,126.26,123.08,123.63,119.36,116.35,82.13,79.36,68.55,41.08,29.31,29.14.

[0091] Example 3

[0092] Synthesis of I-131 Labeled Precursors of Phenoxyalkylguanidine Derivatives

[0093]

[0094] Tetra-Boc-bromophenoxyalkylguanidine was synthesized according to the method of compound 1. Tetra-Boc-bromophenoxyalkylguanidine (1.0 eq), tetrakistriphenylphosphine palladium (0.2 eq), and lithium chloride (6.0 eq) were dissolved in toluene, and then hexamethyltin (1.5 eq) was added, and nitrogen was protected and reacted at 100°C for 1.5 h. Cooled, filtered through diatomaceous earth, washed with EA, concentrated, and purified on a silica gel column (DCM:EA=20:1) to obtain a light yellow oil.

[0095] Synthesis of compound 23: 1 H NMR(400MHz,Chloroform-d)δ7.37(dd,J=7.0,1.7Hz,1H),7.31-7.27(m,1H),6.99-6.96(m ,1H),6.90-6.83(m,1H),4.24-4.11(m,4H),1.51(s,18H),1.50(s,18H),0.34-0.20(m,9H). 13C NMR(100MHz,Chloroform-d)δ162.59,157.38,151.11,147.29,143.79,136.50,130.30,130.04, 121.24,109.88,84.15,83.85,82.14,63.06,45.39,28.01,27.97,27.91,-7.25,-9.04,-10.77.

[0096] Synthesis of compound 24: 1 H NMR(400MHz,Chloroform-d)δ7.26-7.21(m,1H),7.08-6.97(m,2H),6.87-6.80(m,1H) ,4.28-4.25(m,2H),4.21-4.18(m,2H),1.49(s,18H),1.45(s,18H),0.34-0.20(m,9H). 13 C NMR(100MHz,Chloroform-d)δ158.11,157.50,151.33,147.30,143.87,143.74,128.96,128.11, 121.83,113.85,83.82,83.70,82.05,63.70,45.68,28.00,27.89,27.81,-7.10,-9.59,-11.83.

[0097] Synthesis of compound 25: 1 H NMR(400MHz,Chloroform-d)δ7.29-7.22(m,1H),7.09-6.97(m,2H),6.86-6.79(m, 1H),4.06-3.97(m,4H),2.21-2.12(m,2H),1.53-1.44(m,36H),0.34-0.20(m,9H). 13 C NMR(100MHz,Chloroform-d)δ158.45,157.68,151.33,147.38,143.72,143.68,128.94,127.97,121.88 ,113.84,83.62,83.55,81.96,65.51,44.59,30.33,28.01,27.93,27.89,27.23,-7.90,-9.56,-11.31.

[0098] Example 4

[0099] F-18 Labeling and Preparation of Phenoxyalkylguanidine

[0100] Synthesis and preparation of F-18 labeled NET-targeted phenoxyalkylguanidine derivatives: Take 0.01 mmol of the precursor, 2 mg of 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CAS NO.1810004-87-5) in a V-shaped reaction bottle, add 0.5 ml of dichloromethane or dichloroethane, and add 18 F-solution, 200-400nm light irradiation and nitrogen blowing for 15 minutes, nitrogen blowing to remove the solvent, add 100μl concentrated hydrochloric acid, react at 100℃ for 10 minutes, add saturated potassium carbonate to adjust the pH to 6-7, and HPLC purification to prepare F-18 labeled phenoxyalkylguanidine derivatives. The F-18 labeling chemical conversion rate of the phenoxyalkylguanidine derivative precursor and the radiochemical purity of the F-18 labeled phenoxyalkylguanidine derivatives are detected by radio HPLC as shown in the following table (nd: not detected):

[0101] serial number Chemical conversion rate Radiochemical purity <![CDATA[LogD 7.4 ]]> <![CDATA[ 18 F-1]]> 83.19％ >96％ -0.21±0.01 <![CDATA[ 18 F-2]]> 75.97％ >96％ -0.39±0.01 <![CDATA[ 18 F-3]]> 17.37％ >96％ -0.18±0.02 <![CDATA[ 18 F-4]]> 93.61％ >96％ 0.16±0.01 <![CDATA[ 18 F-5]]> 77.12％ >96％ 0.01±0.01 <![CDATA[ 18 F-6]]> 84.37％ >96％ 0.17±0.01 <![CDATA[ 18 F-7]]> 77.64％ >96％ 0.53±0.01 <![CDATA[ 18 F-8]]> 29.61％ >96％ 0.34±0.01 <![CDATA[ 18 F-9]]> nd >96％ 0.42±0.02 <![CDATA[ 18 F-10]]> 35.47％ >96％ 0.50±0.02 <![CDATA[ 18 F-11]]> 47.49％ >96％ nd

[0102] Example 5

[0103] I-131 Labeling and Preparation of Phenoxyalkylguanidine

[0104] Synthesis and preparation of I-131 labeled NET-targeting phenoxyalkylguanidine derivatives: In 0.1 mL 131 I - 0.2 ml methanol, 2 mg labeled precursor, 10 μL glacial acetic acid, 10 μL hydrogen peroxide (30% aqueous solution) were added to the aqueous solution, and the reaction was carried out at room temperature for 20 minutes. Then 200 μL trifluoroacetic acid was added and the reaction was carried out at 100°C for 10 minutes. Saturated potassium carbonate was added to adjust the pH to 6-7, and the I-131 labeled phenoxyalkylguanidine derivative was prepared by HPLC purification. The I-131 labeling chemical conversion rate of the phenoxyalkylguanidine derivative precursor and the radiochemical purity of the I-131 labeled phenoxyalkylguanidine derivative were detected by radio HPLC as shown in the following table:

[0105] serial number Chemical conversion rate Radiochemical purity <![CDATA[ 131 I-1]]> 100％ >96％ <![CDATA[ 131 I-1]]> 100％ >96％ <![CDATA[ 131 I-1]]> 71％ >96％

[0106] Example 6

[0107] Cellular Uptake and Efflux of F-18-Labeled Phenoxyalkylguanidine Derivatives

[0108] Human neuroblastoma SK-N-SH cells with good growth and positive expression of NET were obtained, digested with 0.25% trypsin, centrifuged at 1000 r / min for 5 minutes, collected the cells, resuspended in DMEM complete medium, counted, and diluted to a cell concentration of 5.0×10 5 / mL. Add SK-N-SH single cell suspension to 6-well plate, 2 mL per well, and culture in a 37°C, 5% CO2 incubator overnight.

[0109] Cell uptake experiment: discard the culture medium, wash the cells once with PBS, add 2mL DMEM serum-free culture medium containing NET inhibitor desipramine (10mmol / L) to the blocking group, and add 2mL DMEM serum-free culture medium to the non-blocking group, and set up 3 replicates for each group. After completion, place in a 37℃, 5% CO2 incubator for 60 minutes. After the incubation, add 1μCi of freshly prepared F-18-labeled phenoxyalkylguanidine derivatives to each well, place in a 37℃, 5% CO2 incubator for 15min, 30min, 60min and 120min, respectively, collect the supernatant of each well, wash the cells with 1mL PBS and combine with the supernatant, add 1mL sodium hydroxide solution (concentration of 0.1mmol / L) to each well to lyse the cells, collect the cell lysate of each well, add 1mL PBS to each well to wash the cell culture plate and combine with the cell lysate. The CPM value of the supernatant and cell lysate was measured by a radioactive γ counter.

[0110] Cell efflux experiment: discard the culture medium, wash the cells once with PBS, add 2 mL of DMEM serum-free culture medium, and set up 3 replicate wells for each group. After completion, place the cells in a 37°C, 5% CO2 incubator for 60 minutes. After the incubation, add 1 μCi of freshly prepared 18 F-labeled phenoxyalkylguanidine derivatives were placed in a 37°C, 5% CO2 incubator for 60 minutes, the culture medium was removed, the cells were washed 3 times with pre-cooled PBS, 2 mL of DMEM serum-free culture medium was added, and the cells were placed in a 37°C, 5% CO2 incubator for 5 minutes, 15 minutes, 30 minutes and 60 minutes, respectively. The supernatant of each well was collected, the cells were washed with 1 mL of PBS and then combined with the supernatant, 1.0 mL of sodium hydroxide solution (concentration of 0.1 mmol / L) was added to each well to lyse the cells, and the cell lysate of each well was collected, and 1 mL of PBS was added to each well to wash the cell culture plate and then combined with the cell lysate. The CPM values ​​of the supernatant and cell lysate were measured using a radioactive γ counter.

[0111] Cellular Uptake:

[0112] SK-N-SH cell uptake (min) <![CDATA[ 18 F-1uptake%]]> <![CDATA[ 18 F-1uptake%after blocking]]> 15 35.59±1.30 0.46±0.04 30 51.08±0.44 0.44±0.01 60 60.60±1.85 0.58±0.03 120 64.86±0.07 0.92±0.07

[0113] Cell outflow:

[0114] SK-N-SH cell out (min) <![CDATA[ 18 F-1out%]]> 5 7.28±0.72 15 9.14±0.74 30 14.26±0.25 60 22.52±0.37

[0115] Example 7

[0116] Tumor imaging

[0117] F-18 labeled NET-targeting phenoxyalkylguanidine derivatives were used for PET-CT tumor imaging in rats bearing PC12 adrenal pheochromocytoma: 50-100 μCi of F-18 labeled NET-targeting phenoxyalkylguanidine derivatives were injected into the tail vein, and PET-CT imaging was performed 30 minutes, 60 minutes, and 90 minutes after administration. 18 F-OFBG (o-fluorobenzylguanidine), 18 F-MFBG (meta-fluorobenzylguanidine), 18 The SUVmax values ​​and their ratios of F-PFBG (p-fluorobenzylguanidine) in tumor, muscle, liver and lung at 60 minutes are as follows:

[0118]

[0119] Example 8

[0120] Myocardial sympathetic nerve imaging

[0121] F-18 labeled NET targeting phenoxyalkylguanidine derivatives were used for myocardial sympathetic nerve imaging in SD rats: 50-100 μCi of F-18 labeled NET targeting phenoxyalkylguanidine derivatives were injected into the tail vein, and PET-CT imaging was performed 60 minutes after administration. 18 F-OFBG (o-fluorobenzylguanidine), 18 F-MFBG (meta-fluorobenzylguanidine), 18 The absorption values ​​and ratios of F-PFBG (p-fluorobenzylguanidine) in the heart and liver at 60 minutes are as follows:

[0122] serial number Heart SUVmax Liver SUVmax Lung SUVmax Heart / Liver Heart / Lungs <![CDATA[ 18 F-1]]> 8.15 2.02 1.26 4.04 6.46 <![CDATA[ 18 F-2]]> 6.64 3.37 1.02 1.97 6.51 <![CDATA[ 18 F-3]]> 8.06 3.43 1.10 2.35 7.34 <![CDATA[ 18 F-4]]> 4.01 1.48 2.04 2.72 1.97 <![CDATA[ 18 F-5]]> 5.23 2.10 0.91 2.49 5.75 <![CDATA[ 18 F-6]]> 5.49 2.26 1.59 2.42 3.46 <![CDATA[ 18 F-7]]> 7.75 1.08 0.53 7.19 14.61 <![CDATA[ 18 F-8]]> 5.30 2.00 0.59 2.66 8.99 <![CDATA[ 18 F-9]]> 7.39 1.40 0.76 5.27 9.67 <![CDATA[ 18 F-OFBG]]> 3.02 4.91 0.49 0.61 6.13 <![CDATA[ 18 F-MFBG]]> 4.77 3.91 0.59 1.22 8.09 <![CDATA[ 18 F-PFBG]]> 5.66 1.97 0.64 2.87 8.84

[0123] Example 9

[0124] Distribution in the body

[0125] PC12 tumor-bearing mice were injected with 50-100 μCi of F-18-labeled phenoxyalkylguanidine derivatives via the tail vein and killed at the designated time (5 min, 15 min, 30 min, 60 min, 120 min, 240 min, n ≥ 4). Organs were weighed and the radioactivity intensity was measured using a γ counter. 18 The distribution of F-1 is shown in the following table (%ID / g):

[0126] 5min 15min 30min 60min 120min 240min Blood 8.26 5.81 3.97 2.63 1.33 0.99 Heart 121.3 127.11 107.92 94.08 95.5 94.59 Lung 160.88 74.35 48.41 27.65 21.07 17.33 Liver 13.21 9.27 9.18 7.54 5.31 5.37 Spleen 11.16 12.78 10.37 10.35 9.6 10.31 Adrenal glands 75.79 64.99 56.29 53.58 39.32 46.14 Kidney 23.57 18.39 14.25 10.9 9.06 8.69 Pancreas 51.65 52.93 40.48 31.63 26.41 25.98 Stomach 18.72 18.45 16.85 15.85 15.06 17.96 Intestine 45.56 38.91 28.45 25.81 21.09 19.26 Muscle 12.17 14.95 10.26 10.3 9.06 7.69 Bone 10.46 11.03 11.05 12.43 9.62 6.85 Brain 0.72 0.51 0.43 0.3 0.24 0.15 Salivary glands 47.41 42.74 30.36 40.44 36.55 50.98 Tumor 196.08 215.29 231.12 192.4 247.41 225.53 Brown fat 103.89 195.68 140.85 161.03 158.93 87.39

[0127] In summary, the F-18 or I-131 labeled phenoxyalkylguanidine derivatives provided by the present invention can be used as a NET-targeted radioactive diagnostic or therapeutic drug with higher affinity and better targeting, and can be used in nuclear medicine for myocardial sympathetic nerve imaging and diagnosis or treatment of NET-positive tumors.

[0128] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

Claims

1. A phenoxyalkylguanidine derivative, characterized in that: Its structure is shown in formula (I): Among them, R1 is 19 F. 18 F or 131 I; R2 is hydrogen, hydroxyl, fluorine, chlorine, bromine, C1-C6 alkoxy or C1-C6 substituted alkoxy; L is a linker, C2-C 10 Alkyl, C2-C 10 Substituted alkyl, C 3- C 10 Cycloalkyl or C 3- C 10 Substituted cycloalkyl.

2. The phenoxyalkylguanidine derivative according to claim 1, characterized in that The structure of formula (I) is selected from any one of the following compounds:

3. A method for preparing an F-18 labeled phenoxyalkylguanidine derivative, characterized in that: The F-18 labeled precursor is used for photooxidation-reduction catalysis, and the protecting group is removed after the labeling reaction, and the product is separated and purified; the structure of the F-18 labeled precursor is shown in formula (II): Wherein, R29 is hydrogen or fluorine, chlorine, bromine, aldehyde, cyano, aryl, alkyl or -COR35 which may be substituted at any position; R35 is alkoxy or substituted amino; R30, R31, R32, R33 are hydrogen or a Boc protecting group; The specific steps are as follows:

4. The method for preparing the F-18 labeled phenoxyalkylguanidine derivative according to claim 3, characterized in that: The photocatalyst used for the photocatalytic labeling reaction comprises 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate and riboflavin tetraacetate; and the solvent is dichloromethane or dichloroethane.

5. An F-18 labeled phenoxyalkylguanidine derivative prepared by the method according to any one of claims 3 to 4.

6. A method for preparing an I-131 labeled phenoxyalkylguanidine derivative, characterized in that: The I-131-labeled precursor is subjected to a labeling reaction, and then the protecting group is removed, separated and purified to obtain the product; the structure of the I-131-labeled precursor is shown in formula (III): Wherein, R30, R31, R32, and R33 are Boc protecting groups, and R34 is trimethyltin or tributyltin; The specific steps are as follows:

7. An I-131 labeled phenoxyalkylguanidine derivative prepared by the method according to claim 6.

8. A pharmaceutical composition, characterized in that Containing an effective dose of the phenoxyalkylguanidine derivative according to claim 1, the F-18 labeled phenoxyalkylguanidine derivative according to claim 5 or the I-131 labeled phenoxyalkylguanidine derivative according to claim 7 and a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

9. Use of the phenoxyalkylguanidine derivatives according to claim 1, the F-18-labeled phenoxyalkylguanidine derivatives according to claim 5, or the I-131-labeled phenoxyalkylguanidine derivatives according to claim 7, and drug combinations thereof in the preparation of products for the diagnosis and treatment of NET-positive tumors and / or NET-positive tumor metastases.

10. Use of the phenoxyalkylguanidine derivative according to claim 1, the F-18 labeled phenoxyalkylguanidine derivative according to claim 5, or the I-131 labeled phenoxyalkylguanidine derivative according to claim 7 in the preparation of a product for imaging myocardial sympathetic nerves and NET-positive tumors.

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