Molecular image probe targeting poly ADP ribose polymerase, and preparation method and use therefor

Abstract

Provided are a molecular image probe targeting poly ADP ribose polymerase, and a preparation method and use therefor. The molecular image probe is represented by formula Ia or Ib. The compound can be applied to PARP-targeted positron emission, single-photon emission or nuclear magnetic resonance imaging probes, and has a great application prospect in imaging treatment of diseases such as tumors and PARP expression abnormalities.

Description

A molecular imaging probe targeting poly (ADP-ribose) polymerase, preparation method and application thereof Technical Field

[0001] The present invention relates to radiopharmaceutical chemistry, and in particular to a class of compounds used as molecular imaging probes targeting poly (ADP-ribose) polymerase (PARP), and a preparation method and application thereof. Background Art

[0002] First discovered over 50 years ago, poly(ADP-ribose) polymerase (PARP) is a key enzyme involved in the repair of single-strand DNA damage (SSBs). PARP1 is the first member of the poly(ADP-ribose) polymerase superfamily, which consists of proteins with homology to PARP1. The family now has 17 members, four of which—PARP1, PARP2, PARP5A, and PARP5B—catalyze the formation of PAR chains. PARP1 is the most numerous enzyme in the PARP family and plays a crucial role in the repair of single-strand DNA damage. PARP1 recognizes SSBs through its three zinc fingers. Binding of the PARP1 zinc fingers to DNA induces a conformational change, activating PARP1 and cleaving NAD+ into nicotinamide and ADP-ribose moieties. The ADP-ribose moiety is covalently attached to PARP1 or other nuclear proteins, and additional ADP-ribose moieties are then added to it, generating long or branched PAR chains. These negatively charged polymers recruit the DNA repair enzyme XRCC1 to the site of damage for repair.

[0003] In recent years, several PARP inhibitors, such as olaparib, rucaparib, and niraparib, have been clinically approved as anticancer drugs. Some of these inhibitors have been radiolabeled for non-invasive imaging of PARP expression in several types of tumors. For example, 18F-BO is a 18F-labeled 18F-binding oligonucleotide (Olaparib) that is structurally modified with Olaparib as a targeting group (References: Keliher, EJ; Reiner, T.; Turetsky, A.; Hilderbrand, SA; Weissleder, R. High-Yielding, Two-Step 18F Labeling Strategy for 18F-PARP1 Inhibitors. ChemMedChem). 2011, 6(3), 424–427. https: / / doi.org / 10.1002 / cmdc.201000426). 18F-FTT is obtained by structural modification of rucaparib with 18F labeling and has entered the clinical trial stage (references: Michel, LS; Dyroff, S.; Brooks, FJ; Spayd, KJ; Lim, S.; Engle, JT; Phillips, S.; Tan, B.; Wang-Gillam, A.; Bognar, C.; Chu, W.; Zhou, D.; Mach, RH; Laforest, R.; Chen, DL. PET of Poly(ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies. Radiology 2017, 282(2), 453–463. https: / / doi.org / 10.1148 / radiol.2016161929.), [64Cu]Cu-DOTA-PARP is obtained by modifying olaparib with DOTA group and labeling it with 64Cu (reference: Huang, T. Initial Evaluation of Cu-64 Labeled PARPi-DOTAPET Imaging in Mice with Mesothelioma. 2017, 5.).

[0004] However, the above probes are all based on the structural modification of targeting groups with large lipid-water distribution coefficients, resulting in high uptake in the liver and gallbladder, affecting the imaging effect of the abdomen. For example, in HCC1937 tumor-bearing mice, the liver uptake of two probes in the clinical trial stage, 18F-FTT and 18F-PARPi, was close to 20%ID / g after intravenous injection for 1.5 hours, and the tumor uptake was only about 2%ID / g and 6%ID / g, respectively. The liver uptake of the modified 18FFPyPARP was also close to 20%ID / g, while the tumor uptake was only about 2%ID / g. (Reference: Two experts and a newbie: [18F]PARPi vs [18F]FTT vs [18F]FPyPARP—a comparison of PARP imaging agents. European Journal of Nuclear Medicine and Molecular Imaging 2021, 49(3), 834-846). Moreover, 18F labeling is very difficult and complicated to operate. Therefore, we searched for a targeting group quinazoline-2,4-dione derivative with a low lipid-water distribution coefficient, modified its structure, and chelated it with metals to further reduce the lipid-water distribution coefficient and reduce nonspecific uptake by the liver and gallbladder. This is meaningful for imaging treatment of diseases such as tumors that are related to abnormal PARP expression. Summary of the Invention

[0005] The purpose of the present invention is to provide a class of molecular imaging probes targeting poly (ADP-ribose) polymerase (PARP).

[0006] Another object of the present invention is to provide a method for preparing the molecular imaging probe targeting poly (ADP-ribose) polymerase (PARP).

[0007] Another object of the present invention is to provide the application of the molecular imaging probe targeting poly (ADP-ribose) polymerase (PARP).

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] According to one aspect of the present invention, there is provided a compound of formula Ia or Ib:

[0010] Among them, Rx is

[0011] R5 is a group derived from a chelating agent that chelates with an element,

[0012] The element is selected from elements that generate nuclear magnetic signals and elements that generate radioactive signals,

[0013] In Formula Ia,

[0014] R1 is R 1a 、R 1a -C(=O)N(R4)R3-、R 1a -N(R4)-C(=O)R3-,R 1a Selected from: -C1-C20 alkylene, -((CH2) a -O) b -(CH2) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocyclylene; R 1a may be optionally substituted by a substituent selected from the group consisting of halogen, hydroxy, wherein

[0015] R3 is selected from: direct bond, -C1-C20 alkylene, -((CH2) a -O) b -(CH2) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocyclylene,

[0016] R4 is selected from: H, -C1-C20 alkyl, -((CH2) a -O) b -(CH2) d CH3, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl;

[0017] R2 is selected from: H, -C1-C20 alkyl, -((CH2) a -O) b -(CH2) c CH3, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl, or

[0018] In R1 is R 1a -C(=O)N(R4)R3-、R 1a -N(R4)-C(=O)R3-, R2 and R4 together with the atoms to which they are attached form a four- to seven-membered heterocyclic ring;

[0019] In Formula Ib,

[0020] R6 and R7 are each independently the same as defined for R1, or are a direct bond;

[0021] R2 is selected from: H, -C1-C20 alkyl, -((CH2) a -O) b -(CH2) c CH3, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl,

[0022] Subscripts a, b, and c are each independently an integer from 1 to 5;

[0023] Preferably, R1 is R 1a , or R 1a -C(=O)N(R4)R3-,R 1a Selected from: -C1-C20 alkylene, and -((CH2) a -O) b -(CH2) c -;R 1a may be optionally substituted by a substituent selected from the group consisting of halogen, hydroxy, wherein

[0024] R3 is selected from: a direct bond and -C1-C20 alkylene,

[0025] R4 is selected from: H and -C1-C20 alkyl;

[0026] Subscripts a, b, and c are each independently an integer from 1 to 5;

[0027] R2 is selected from: H and -C1-C20 alkyl, or

[0028] In R1 is R 1a -C(=O)N(R4)R3-, R2 and R4 together with the atoms to which they are attached form a piperazine ring;

[0029] In Formula Ib,

[0030] R6 and R7 are each independently the same as defined for R1;

[0031] R2 is selected from the group consisting of: H and -C1-C20 alkyl.

[0032] According to one embodiment of the present invention, in R5, the chelating agent is selected from tetraazacyclododecane tetraacetic acid (DOTA), triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-1-pentanedioic acid-4,7-diacetic acid (NODAGA), 1,4,7,10-tetraazacyclododecane-1-pentanedioic acid-4,7,10-triacetic acid (DOTAGA), 2,2',2",2"-(5 2 ,13 2 -Dihydroxy-5-5 , 13 5 any one of dimethyl-3,7,11,15-tetraaza-1,9(2,6)-dipyridine-5,13(1,3)-dibenzocyclohexanedione-3,7,1,11,15-tetrayl)tetraacetic acid (Dar), dimethyltriaminepentaacetic acid (DTPA), 32-amino-5,16,27-trihydroxy-4,12,15,23,26-pentacarbonyl-5,11,16,22,27-pentaazadotriacontanoic acid (DFO), 2-(6-hydrazinopyridin-3-yl)acetic acid (HYNIC) and mercaptoacetyl triglycine (MAG3),

[0033] In R5, the element generating nuclear magnetic signals is selected from Gd, Fe, Eu, Mn, Cu, Si and Nd, and the element generating radioactive signals is selected from 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re、 186 Re、 213 Bi, 44 Sc, 47 Sc, 212 Pb and 203 Pb.

[0034] According to one embodiment of the present invention,

[0035] Wherein R5 is selected from the following structures

[0036] According to one embodiment of the present invention, the compound of formula Ia or Ib is selected from the following compounds:

[0037] The present invention further provides a method for preparing the compound of formula Ia or Ib, the preparation route of which is as follows:

[0038] Method 1: Preparation of compound of formula Ia

[0039] The method comprises the following steps:

[0040] (a) Compound 1 undergoes nitrogen acylation reaction with HOOC-R1-NR2Boc to obtain compound 2;

[0041] (b) removing the N-Boc protecting group from compound 2 to expose the amino group, evaporating the solvent under reduced pressure, and then reacting the compound with a bifunctional chelating agent to produce compound 3;

[0042] (c) Compound 3 and a metal selected from the group consisting of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re、 186 Re、 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 Compound Ia is obtained by reacting a compound of the element Pb, or

[0043] Method 2: Preparation of compound of formula Ib

[0044] (a') Compound 1 and formula The compound undergoes nitrogen acylation reaction to obtain compound 2';

[0045] (b') removing the N-Boc protecting group from compound 2' to expose the amino group, evaporating the solvent under reduced pressure, and then reacting the compound 2' with a bifunctional chelating agent to give compound 3';

[0046] (c') Compound 3' and a metal selected from the group consisting of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re、 186 Re、 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 The compound of the element Pb reacts to obtain compound Ib,

[0047] In the reaction schemes of the above methods 1 and 2, the definitions of the substituents are the same as those above.

[0048] In one embodiment, the method comprises the steps of:

[0049] (1) Compound 1, HOOC-R1-NR2Boc (e.g., 5-((tert-butoxycarbonyl)amino)pentanoic acid, 5-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-oxopentanoic acid)) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate are added to N,N-dimethylformamide, and N,N-diisopropylethylamine is added. The mixture is reacted at room temperature for 30 minutes to 2 hours. After the reaction is completed, 8-15 times the volume of the solvent is added to dilute the mixture with saturated ammonium chloride aqueous solution, and the mixture is extracted with EA three times. The EA phases are combined, washed with water, and concentrated and purified to obtain Compound 2;

[0050] (2) Compound 2 was added to a mixed solvent of DCM and trifluoroacetic acid in a volume ratio of 1:2-3 and reacted for 60 minutes. After the reaction, the solvent was removed under reduced pressure, N,N-dimethylformamide was added, N,N-diisopropylethylamine was added, and an NHS active ester of a bifunctional chelating agent (for example: 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) was added and reacted at room temperature for 12-48 hours. The solvent was removed under reduced pressure and purified to obtain compound 3;

[0051] (3) dissolving compound 3 in a buffer solution of suitable pH (e.g., acetic acid-sodium acetate buffer solution of pH=5), adding a 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re、 186 Re、 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 Compounds of Pb elements (such as 68 GaCl3, 64 Cu(AcO)2, europium trifluoromethanesulfonate) at 60-100°C for 10 min-48 h, and purify to obtain compound Ia, or

[0052] The method comprises the following steps:

[0053] (1') Compound 1, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added to N,N-dimethylformamide, and N,N-diisopropylethylamine was added. The reaction was carried out at room temperature for 30 minutes to 2 hours. After the reaction, 8-15 times the volume of the solvent was added to dilute the mixture with saturated ammonium chloride aqueous solution. The mixture was extracted with EA three times. The EA phases were combined, washed with water, and concentrated and purified to obtain compound 2'.

[0054] (2') Compound 2' was added to a mixed solvent of DCM and trifluoroacetic acid in a volume ratio of 1:2-3 and reacted for 60 minutes. After the reaction, the solvent was removed under reduced pressure, N,N-dimethylformamide was added, N,N-diisopropylethylamine was added, and an NHS active ester of a bifunctional chelating agent (for example: 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) was added and reacted at room temperature for 12-48 hours. The solvent was removed under reduced pressure and purified to obtain compound 3';

[0055] (3') Compound 3' is dissolved in a buffer solution of suitable pH (e.g., acetic acid-sodium acetate buffer solution of pH=5), and a solution containing a mixture of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re、 186 Re、 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 Compounds of Pb elements (such as 68 GaCl3, 64 Cu(AcO)2, europium trifluoromethanesulfonate) at 60-100°C for 10 min-48 h, and compound Ib was obtained after purification.

[0056] According to another aspect of the present invention, the present invention also provides the use of the compound of Formula Ia or Ib as a PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probe, particularly in diseases with abnormal PARP expression, and particularly in the preparation of tumor PET imaging agents, tumor SPECT imaging agents or tumor MRI imaging agents. Beneficial effects

[0057] The present application synthesizes a class of novel structural compounds that can act as PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probes and have great application prospects in the imaging treatment of diseases such as tumors that are associated with abnormal PARP expression. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIG1 is a micro-PET / CT imaging diagram of the tumor in A549 tumor-bearing mice of M6 prepared in Example 6, where the circle indicates the location of the tumor.

[0059] FIG2 is a micro-PET / CT imaging diagram of the tumor in A549 tumor-bearing mice of M7 prepared in Example 7, where the circle indicates the location of the tumor. DETAILED DESCRIPTION

[0060] Unless otherwise specified, the raw materials, reagents, experimental animals, etc. used in this application are conventional raw materials, reagents, experimental animals in the field and are commercially available. The animal experiments comply with the ethical requirements for experimental animals, and the equipment and methods used are conventional equipment and methods in the field.

[0061] Example 1: Preparation of M1

[0062] Step 1: Synthesis of Intermediate 1 from Example 1

[0063] 50 mg of 1-((5-fluoro-4-(piperazine-1-carbonyl)pyridin-2-yl)methyl)quinazoline-2,4(1H,3H)-dione, 50 mg of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid, and 100 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added to N,N-dimethylformamide, and 80 μL of N,N-diisopropylethylamine were added. The mixture was reacted at room temperature for 60 minutes. After the reaction, 10 times the solvent volume of saturated ammonium chloride aqueous solution was added for dilution. The mixture was extracted with EA three times. The EA phases were combined, washed with water, concentrated, and purified by column chromatography to obtain 65 mg of a white solid with a yield of 75%. 1H NMR (400 MHz, chloroform-d) δ9.62 (d, J = 36.0 Hz, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 7.9, 1.7 Hz, 1H), 7.71-7.59 (m, 1H), 7.44 (dd, J = 6.6, 4.8 Hz, 1H), 7.36 (t, J = 9.3 Hz, 1H), 7.26 (d, J = 7.6 Hz ,1H),5.45(s,2H),3.90-3.68(m,3H),3.59(tt,J=9.9,4.9Hz,5H),3.46(s,4H),3.41(dd,J= 6.7, 3.6Hz, 2H), 3.28 (d, J = 23.9Hz, 2H), 2.57-2.38 (m, 4H), 2.07-1.87 (m, 2H), 1.47 (s, 9H).

[0064] Step 2: Synthesis of Intermediate 2 from Example 1

[0065] The intermediate 1 (20 mg) from the previous step was added to 5 mL of DCM, and 10 mL of trifluoroacetic acid was added. The reaction was carried out for 60 minutes, and the solvent was dried by rotary evaporation. 2 mL of N,N-dimethylformamide was added, 100 microliters of DIPEA was added, and 40 mg of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid was added. The reaction was carried out for 24 hours, and the solvent was dried by rotary evaporation. The product was purified by preparative liquid chromatography to give 21 mg of a white solid with a yield of 73%. 1H NMR (500 MHz, D2O) δ 8.40 (d, J = 4.3 Hz, 1H), 7.97 (dt, J = 7.9, 1.7 Hz, 1H), 7.58 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.28-7.19 (m, 1H), 7.08 (dd, J = 8.5, 1.9 Hz, 1H), 5.37 (s, 2H), 4.37-2.73 (m, 40H), 2.46-2.28 (m, 4H), 1.84-1.61 (m, 2H). LRMS (ESI) m / z: [M+H]+ calcd: C44H59FN11O12: 952.43, found: 952.91.

[0066] Step 3: Synthesis of Product M1 from Example 1

[0067] Take 40 μL of sodium acetate solution (1.5 M) and add it to a glass reaction bottle, then add 10 μg of intermediate 2, and then add 5 mCi 68 GaCl3 (~2 mL) was added to make the final pH of the reaction solution between 4-5, and the reaction solution was heated in a 95°C metal bath for 10 min. After the reaction was completed, it was cooled to room temperature to obtain M1.

[0068] Example 2: Preparation of M2

[0069] Step 1: Synthesis of Intermediate 1 from Example 2

[0070] The method was the same as step 1 of Example 1, except that 5-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-oxopentanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 63 mg of a white solid. 1H NMR (400MHz, chloroform-d) δ9.46 (d, J=76.8Hz, 1H), 8.50 (s, 1H), 8.21 (dd, J=7.8, 1.6H z,1H),7.65(q,J=7.7Hz,1H),7.50-7.32(m,2H),7.30(s,1H),6.50(s,1H),5.45 (s,2H),5.16(s,1H),3.91-3.46(m,6H),3.44-3.14(m,6H),2.44(dt,J=25.2,7. 2Hz, 2H), 2.29 (q, J=6.1, 5.4Hz, 2H), 1.96 (dt, J=12.9, 6.8Hz, 2H), 1.44 (s, 9H).

[0071] Step 2: Synthesis of Intermediate 2 from Example 2

[0072] The method was the same as that in step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 20 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.41 (d, J = 4.6 Hz, 1H), 8.00 (dt, J = 7.9, 2.1 Hz, 1H), 7.59 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.33 (dd, J = 5.0, 3.3 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.49- 5.35 (m, 2H), 4.13-2.68 (m, 36H), 2.34 (dt, J = 36.1, 7.5 Hz, 2H), 2.18 (td, J = 7.5, 4.6 Hz, 2H), 1.73 (dp, J = 14.9, 7.6 Hz, 2H). LRMS (ESI) m / z: [M+H]+ calculated for C42H57FN11O12: 926.41, found: 926.81.

[0073] Step 3: Synthesis of Example 2 Product M2

[0074] The method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M2.

[0075] Example 3: Preparation of M3

[0076] Step 1: Synthesis of Intermediate 1 of Example 3

[0077] The method was the same as that in Step 1 of Example 1, except that (tert-butyloxycarbonyl)glycine was used instead of 5-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 53 mg of a white solid. 1H NMR (400 MHz, chloroform-d) δ 9.48 (d, J = 22.3 Hz, 1H), 8.51 (s, 1H), 8.22 (dd, J = 7.8, 1.6 Hz, 1H), 7.64 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 5.52 (dd, J = 10 .9,5.0Hz,1H),5.46(s,2H),4.01(dd,J=24.5,4.6Hz,2H),3.79(s,3H),3.64(s,1H),3.53( t,J=5.3Hz,1H),3.43(t,J=5.0Hz,1H),3.31(dt,J=10.6,4.9Hz,2H),1.46(d,J=3.3Hz,9H).

[0078] Step 2: Synthesis of Intermediate 2 from Example 3

[0079] The method was the same as that in Step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 22 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.43 (d, J = 4.6 Hz, 1H), 7.99 (ddd, J = 8.0, 3.8, 1.5 Hz, 1H), 7.60 (ddt, J = 8.8, 7.4, 2.2 Hz, 1H), 7.41-7.21 (m, 2H), 7.10 (t, J = 8.7 Hz, 1H), 5.55-5.24 (m, 2H), 4.23-2.66 (m, 34H). LRMS (ESI) m / z: [M+H]+ calcd: C37H48FN10O11: 827.34, found: 827.79.

[0080] Step 3: Synthesis of Example 3 Product M3

[0081] The method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M3.

[0082] Example 4: Preparation of M4

[0083] Step 1: Synthesis of Intermediate 1 of Example 4

[0084] The method was the same as that in Step 1 of Example 1, except that 3-((tert-butoxycarbonyl)amino)propionic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 54 mg of a white solid. 1H NMR (600 MHz, chloroform-d) δ 9.41 (d, J = 21.0 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 3.9 Hz, 1H), 7.36 (dd, J = 8.5, 5.7 Hz, 1H), 5.46 (s, 2H), 5.29 (q, J = 6.2 Hz ,1H),3.76(dt,J=33.6,9.6Hz,3H),3.63(d,J=5.5Hz,1H),3.56(t,J=5.3Hz,1H),3.45(dq,J=18. 5,5.6Hz,3H),3.29(dt,J=21.9,5.3Hz,2H),2.55(dt,J=37.6,5.8Hz,2H),1.44(d,J=5.8Hz,9H).

[0085] Step 2: Synthesis of Intermediate 2 from Example 4

[0086] The method was the same as that in Step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 20 mg of a white solid. 1H NMR (600 MHz, D2O) δ 8.36 (s, 1H), 7.82 (ddd, J = 7.6, 5.4, 1.6 Hz, 1H), 7.57-7.43 (m, 1H), 7.26 (d, J = 4.9 Hz, 1H), 7.14 (td, J = 7.5, 4.9 Hz, 1H), 6.99 (t, J = 8.2 Hz, 1H), 5.24 (s, 2H), 4.36-2.63 (m, 34H), 2.61-2.41 (m, 2H). LRMS (ESI) m / z: [M+H]+ calcd: C38H50FN10O11: 841.36, found: 841.85.

[0087] Step 3: Synthesis of Example 4 Product M4

[0088] The method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M4.

[0089] Example 5: Preparation of M5

[0090] Step 1: Synthesis of Intermediate 1 from Example 5

[0091] The method was the same as that in Step 1 of Example 1, except that 4-((tert-butoxycarbonyl)amino)butanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 54 mg of a white solid. 1H NMR (400 MHz, chloroform-d) δ 9.80 (d, J = 20.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.44 (dd, J = 5.1, 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 4.2 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 5.46 (s, 2 H),4.90-4.76(m,1H),3.88-3.70(m,3H),3.59(dt,J=18.2,5.3Hz,2H),3.47(dd,J=6.8,3.5Hz,1H),3.28(dt, J=10.0,4.8Hz,2H),3.22-3.07(m,2H),2.39(dt,J=23.4,7.2Hz,2H),1.90-1.76(m,2H),1.43(d,J=6.6Hz,9H).

[0092] Step 2: Synthesis of Intermediate 2 from Example 5

[0093] The method was the same as that in step 2 of Example 2, except that the intermediate 1 from the previous step was used to obtain 19 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.39 (s, 1H), 7.91 (ddd, J = 7.9, 3.3, 1.6 Hz, 1H), 7.55 (ddt, J = 8.4, 7.1, 1.3 Hz, 1H), 7.30 (dd, J = 15.8, 5.0 Hz, 1H), 7.26-7.13 (m, 1H), 7.04 (dd, J = 8.5, 2.7 Hz, 1H) z, 1H), 5.32 (s, 2H), 4.19-2.82 (m, 34H), 2.35 (dt, J = 35.8, 7.7 Hz, 2H), 1.65 (dp, J = 14.3, 7.2 Hz, 2H). LRMS (ESI) m / z: [M+K+Na-H]+ calculated for C39H50FKN10NaO11: 915.31, found: 915.96.

[0094] Step 3: Synthesis of Example 5 Product M5

[0095] The method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M5.

[0096] Example 6: Preparation of M6

[0097] Step 1: Synthesis of Intermediate 1 from Example 6

[0098] The method was the same as that in step 1 of Example 1, except that 5-((tert-butoxycarbonyl)amino)pentanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid. 1H NMR (400 MHz, chloroform-d) δ 9.82 (d, J = 21.6 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.62 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.43 (d, J = 4.7 Hz, 1H), 7.35 (dd, J = 8.5, 3.9 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 5.46 (s, 2H), 4.7 3(s,1H),3.75(d,J=15.9Hz,3H),3.58(dd,J=12.3,7.0Hz,2H),3.48(t,J=5.1Hz,1H),3.35-3.20(m,2H),3.14( t,J=7.0Hz,2H),2.37(dt,J=23.1,7.4Hz,2H),1.67(h,J=6.9Hz,2H),1.61-1.49(m,2H),1.43(d,J=7.6Hz,9H).

[0099] Step 2: Synthesis of Intermediate 2 from Example 6

[0100] The method was the same as step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 19 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.41 (d, J = 3.0 Hz, 1H), 8.01-7.91 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.31 (t, J = 4.9 Hz, 1H), 7.24 (td, J = 7.6, 2.6 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.46-5.27 (m, 2H), 4.12-2.89 (m, 34H), 2.34 (dt, J = 37.1, 7.0 Hz, 2H), 1.45 (s, 4H). LRMS (ESI) m / z: [M+K]+ calcd: C40H53FKN10O11: 907.35, found: 907.83.

[0101] Step 3: Synthesis of Example 6 Product M6

[0102] The method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M6.

[0103] Example 7: Preparation of M7

[0104] Step 1: Synthesis of Intermediate 1 of Example 7

[0105] The method was the same as that in Step 1 of Example 1, except that 6-((tert-butoxycarbonyl)amino)hexanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid. 1H NMR (500 MHz, chloroform-d) δ 9.26 (d, J = 29.1 Hz, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.20 (dd, J = 7.9, 1.6 Hz, 1H), 7.61 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.40 (d, J = 4.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 5.43 (s, 2H), 4.60 (s, 1H), 3.76 (s, 3H), 3. 57(dt,J=17.4,5.1Hz,2H),3.45(t,J=5.2Hz,1H),3.26(dd,J=22.7,5.9Hz,2H),3.10(p,J=7.1Hz,2H),2.32(dt,J= 29.0,7.5Hz,2H),1.64(h,J=7.9Hz,2H),1.49(d,J=8.2Hz,2H),1.42(d,J=7.0Hz,9H),1.35(td,J=13.5,7.0Hz,2H).

[0106] Step 2: Synthesis of Intermediate 2 from Example 7

[0107] The method was the same as that in Step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 18 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.39 (d, J = 6.1 Hz, 1H), 7.90 (ddd, J = 7.9, 4.9, 1.6 Hz, 1H), 7.55 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.30 (dd, J = 5.1, 1.8 Hz, 1H), 7.20 (td, J = 7.2, 1.8 Hz, 1H), 7.04 (dd, J = 8. 6, 5.5 Hz, 1H), 5.32 (s, 2H), 4.16-2.81 (m, 34H), 2.29 (dt, J = 37.7, 7.5 Hz, 2H), 1.54-1.33 (m, 4H), 1.30-1.14 (m, 2H). LRMS (ESI) m / z: [M+K+H]2+ calculated for C41H56FKN10O11: 461.19, found: 461.51.

[0108] Step 3: Synthesis of Example 7 Product M7

[0109] The method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M7.

[0110] Example 8: Preparation of M8

[0111] Step 1: Synthesis of Intermediate 1 from Example 8

[0112] The method was the same as that in Step 1 of Example 1, except that 3-(2-((tert-butoxycarbonyl)amino)ethoxy)propanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 10.08 (d, J = 19.9 Hz, 1H), 8.49 (s, 1H), 8.19 (dd, J = 7.8, 1.6 Hz, 1H), 7.60 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.43 (dd, J = 5.0, 1.9 Hz, 1H), 7.33 (dd, J = 8.7, 3.4 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H). z,1H),5.45(s,2H),5.07(t,J=5.7Hz,1H),3.83-3.69(m,5H),3.61(p,J=5.4,4.9Hz,2H),3.51(d q,J=8.6,4.1,3.1Hz,3H),3.37-3.15(m,4H),2.62(dt,J=24.0,6.2Hz,2H),1.42(d,J=5.4Hz,9H).

[0113] Step 2: Synthesis of Intermediate 2 from Example 8

[0114] The method was the same as step 2 of Example 1, except that the intermediate 1 from the previous step was used to obtain 18 mg of a white solid. 1H NMR (500 MHz, D2O) δ 8.40 (s, 1H), 8.15-7.89 (m, 1H), 7.58 (ddt, J = 9.1, 7.3, 1.8 Hz, 1H), 7.31 (dd, J = 9.0, 4.9 Hz, 1H), 7.24 (ddt, J = 8.0, 5.5, 2.6 Hz, 1H), 7.07 (dd, J = 8.7, 3.4 Hz, 1H), 5.37 (s, 2H), 4.22-2.73 (m, 38H), 2.60 (dt, J = 39.8, 6.0 Hz, 2H). LRMS (ESI) m / z: [M+H]+ calcd: C40H54FN10O12: 885.39, found: 885.90.

[0115] Step 3: Synthesis of Example 8 Product M8

[0116] The method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M8.

[0117] Example 9: Preparation of M9

[0118] Step 1: Synthesis of Intermediate 1 from Example 9

[0119] 50 mg of 1-((5-fluoro-4-(piperazine-1-carbonyl)pyridin-2-yl)methyl)quinazoline-2,4(1H,3H)-dione, 16 mg of (tert-butyloxycarbonyl)glutamic acid, and 100 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added to N,N-dimethylformamide, and 80 microliters of N,N-diisopropylethylamine were added. The reaction was carried out at room temperature for 60 minutes. After the reaction, 10 times the solvent volume of saturated ammonium chloride aqueous solution was added for dilution, and EA was extracted three times. The EA phases were combined, washed with water, and concentrated and purified by column chromatography to obtain 50 mg of a white solid with a yield of 78%. 1H NMR (500MHz, chloroform-d) δ10.38-9.28(m,2H),8.60-8.43(m,2H),8.21(t,J=8.3Hz,2H),7.65(p,J=7.2Hz,2H),7.39(ddt,J=32.9,14.4,9.6Hz,4H ),7.30(s,2H),5.71-5.36(m,5H),4.67(d,J=57.8Hz,1H),4.08-3.12(m,16H),2.74-2.22(m,2H),2.13(s,1H),1.42(dd,J=13.1,7.9Hz,9H).

[0120] Step 2: Synthesis of Intermediate 2 from Example 9

[0121] The intermediate 1 (20 mg) from the previous step was added to 5 mL of DCM, and 10 mL of trifluoroacetic acid was added. The reaction was carried out for 60 minutes, and the solvent was dried by rotary evaporation. 2 mL of N,N-dimethylformamide was added, 100 microliters of DIPEA was added, and 40 mg of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid was added. The reaction was carried out for 24 hours, and the solvent was dried by rotary evaporation. The product was purified by preparative liquid phase to obtain 15 mg of a white solid with a yield of 58%. 1H NMR (500 MHz, D2O) δ 8.56-8.24 (m, 2H), 7.99-7.65 (m, 2H), 7.51 (dt, J = 14.0, 7.7 Hz, 2H), 7.39-6.86 (m, 6H), 5.28 (s, 4H), 4.26-2.65 (m, 41H), 2.38 (d, J = 41.5 Hz, 2H), 1.79 (d, J = 66.5 Hz, 2H). LRMS (ESI) m / z: [M+H]+ calculated for C59H68F2N15O15: 1264.50, found: 1265.11.

[0122] Step 3: Synthesis of Example 9 Product M9

[0123] Take 40 μL of sodium acetate solution (1.5 M) and add it to a glass reaction bottle, then add 10 μg of intermediate 2, and then add 5 mCi 68 GaCl3 (~2 mL) was heated in a 95°C metal bath for 10 min and cooled to room temperature after the reaction was completed to obtain M9.

[0124] Example 10: Preparation of M10

[0125] Step 1: Synthesis of Intermediate 1 from Example 10

[0126] The method was the same as step 1 of Example 1, except that 12-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-12-oxododecanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 60 mg of a white solid.

[0127] Step 2: Synthesis of Intermediate 2 from Example 10

[0128] The procedure was the same as in Example 1, Step 2, except that Intermediate 1 from the previous step was used to obtain 16 mg of a colorless semisolid. LRMS (ESI) m / z: [M+H]+ calculated for C49H71FN11O12: 1024.53, found: 1025.00.

[0129] Step 3: Synthesis of Example 10 Product M10

[0130] The method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M10.

[0131] Test Example 1: Determination of the Lipid-Water Distribution Coefficient LogD7.4 of M6

[0132] About 30 μCi of the M6 ​​probe was placed in a centrifuge tube containing equal volumes of PBS buffer and n-octanol. After vortexing for 15 minutes, the tube was allowed to stand for 5 minutes. The upper n-octanol phase and the lower aqueous phase were centrifuged separately. Then, equal volumes of the n-octanol phase and the aqueous phase were taken and the ratio of the probes in the two phases was measured using a gamma counter. The LogD7.4 of M6 was obtained to be -3.623±0.196, which has a very low lipid-water distribution coefficient compared to the currently developed PARP-targeted PET probes.

[0133] Experimental Example 2: Application of M6 in micro-PET / CT imaging of tumor-bearing mice

[0134] Three commercially available SPF-grade Balb / c nude mice were inoculated with A549 cells (human non-small cell lung cancer cells) in the right forelimb axilla. When the tumor diameter reached approximately 7 mm, the mice were injected via the tail vein with a dose of 100-150 μCi of the M6 ​​probe prepared in Example 6. The mice were anesthetized with a 2.0% isoflurane-oxygen mixture. PET / CT scanning (Siemens Inveon microPET) was performed simultaneously with the injection, and images were collected for 1 hour. The results are shown in Figure 1. The circled area represents the tumor location, and it can be clearly seen that the tumor site has a high enrichment of radioactive signal. The images show good imaging of the tumor, and the signal in the liver is less than 1% ID / g, which is better than that of previous probes.

[0135] Experimental Example 3: Application of M7 in micro-PET / CT imaging of tumor-bearing mice

[0136] Three commercially available SPF-grade Balb / c nude mice were inoculated with A549 cells (human non-small cell lung cancer cells) in the left forelimb axilla. When the tumor diameter reached approximately 7 mm, the mice were injected via the tail vein with a dose of 100-150 μCi of the M7 probe prepared in Example 7. The mice were anesthetized with a 2.0% isoflurane-oxygen mixture. PET / CT scanning (Siemens Inveon microPET) was performed simultaneously with the injection, and images were collected for 1 hour. The results are shown in Figure 2. The circled area represents the tumor location, and it can be clearly seen that the tumor site has a high enrichment of radioactive signal. The images show good imaging of the tumor, and the signal in the liver is less than 2% ID / g, which is better than that of previous probes.

[0137] In summary, the probe synthesized in the present application has an imaging effect on diseases related to abnormal PARP expression (such as tumors) and can be developed into a PET imaging agent for diseases related to abnormal PARP expression.

Claims

1. A compound of formula Ia or Ib: in, Rx is R5 is a group derived from a chelating agent that chelates with an element, The element is selected from elements that generate nuclear magnetic signals and elements that generate radioactive signals, In Formula Ia, R1 is R 1a , R 1a -C(=O)N(R4)R3-、R 1a -N(R4)-C(=O)R3-,R 1a Selected from: -C1-C20 alkylene, -((CH2) a -O) b -(CH2) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocyclylene; R 1a may be optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, wherein R3 is selected from: direct bond, -C1-C20 alkylene, -((CH2) a -O) b -(CH2) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocyclylene, R4 is selected from: H, -C1-C20 alkyl, -((CH2) a -O) b -(CH2) d CH3, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl; subscripts a, b, c are each independently an integer of 1 to 5; R2 is selected from: H, -C1-C20 alkyl, -((CH2) a -O) b -(CH2) d CH3, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl, or In R1 is R 1a -C(=O)N(R4)R3-、R 1a -N(R4)-C(=O)R3-, R2 and R4 together with the atoms to which they are attached form a four-membered to seven-membered heterocyclic ring; In Formula Ib, R6 and R7 are each independently the same as defined in R1, or are a direct bond; R2 is selected from: H, -C1-C20 alkyl, -C1-C20 ether, -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl.

2. The compound according to claim 1, wherein R1 is R 1a , or R 1a -C(=O)N(R4)R3-、R 1a Selected from: -C1-C20 alkylene, and -((CH2) a -O) b -(CH2) c -; R 1a may be optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, wherein R3 is selected from: a direct bond, and -C1-C20 alkylene, R4 is selected from: H, and -C1-C20 alkyl; The subscripts a, b, and c are each independently an integer from 1 to 5; R2 is selected from: H, and -C1-C20 alkyl, or In R1 is R 1a -C(=O)N(R4)R3-, R2 and R4 together with the atoms to which they are attached form a piperazine ring; In Formula Ib, R6 and R7 are each independently the same as defined for R1; R2 is selected from: H, and -C1-C20 alkyl, R5 and Rx are as defined in claim 1.

3. The compound according to claim 1 or 2, In R5, the chelating agent is selected from tetraazacyclododecane tetraacetic acid, triazacyclononane triacetic acid, 1,4,7-triazacyclononane-1-pentanedioic acid-4,7-diacetic acid, 1,4,7,10-tetraazacyclododecane-1-pentanedioic acid-4,7,10-triacetic acid, 2,2',2",2"-(5 2 ,13 2 -Dihydroxy-5- 5 , 13 5 any one of dimethyl-3,7,11,15-tetraaza-1,9(2,6)-bipyridine-5,13(1,3)-dibenzocyclohexanedione-3,7,1,11,15-tetrayl)tetraacetic acid (Dar), dimethyltriaminepentaacetic acid (DTPA), 32-amino-5,16,27-trihydroxy-4,12,15,23,26-pentacarbonyl-5,11,16,22,27-pentaazatriacontanoic acid (DFO), 2-(6-hydrazinopyridin-3-yl)acetic acid (HYNIC) and mercaptoacetyl triglycine (MAG3), In R5, the element generating nuclear magnetic signal is selected from Gd, Fe, Eu, Mn, Cu, Si and Nd, and the element generating radioactive signal is selected from 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb and 203 Pb.

4. The compound according to claim 1 or 2, Wherein R5 is selected from the following structures:

5. The compound according to claim 1 or 2, wherein The compound of formula Ia or Ib is selected from the following compounds: as well as 6. The method for preparing the compound of formula Ia or Ib according to claim 1, which comprises method 1 or method 2: Method 1: Preparation of Compounds of Formula Ia The method comprises the following steps: (a) Compound 1 undergoes nitrogen acylation reaction with HOOC-R1-NR2Boc to obtain compound 2; (b) removing the N-Boc protecting group from compound 2 to expose the amino group, evaporating the solvent under reduced pressure, and then reacting the compound 2 with a bifunctional chelating agent to give compound 3; (c) Compound 3 and a metal selected from the group consisting of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 The compound of the element Pb is reacted to obtain compound Ia, or Method 2: Preparation of Compounds of Formula Ib (a') Compound 1 and formula The compound undergoes nitrogen acylation reaction to obtain compound 2'; (b') removing the N-Boc protecting group from compound 2' to expose the amino group, evaporating the solvent under reduced pressure, and then reacting the compound 2' with a bifunctional chelating agent to give compound 3'; (c') Compound 3' and a metal selected from the group consisting of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 The compound of the element Pb reacts to obtain compound Ib, In the reaction routes of the above methods 1 and 2, the definition of each substituent is the same as that in claim 1, and "Chelator" refers to a chelating agent.

7. The method according to claim 6, comprising the steps of: (1) Compound 1, HOOC-R1-NR2Boc and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate are added to N,N-dimethylformamide, and N,N-diisopropylethylamine is added. The mixture is reacted at room temperature for 30 minutes to 2 hours. After the reaction is completed, 8-15 times the volume of a saturated ammonium chloride aqueous solution is added to dilute the mixture, and EA is extracted three times. The EA phases are combined, washed with water, and concentrated and purified to obtain compound 2; (2) Compound 2 was added to a mixed solvent of DCM and trifluoroacetic acid in a volume ratio of 1:2-3 and reacted for 60 minutes. After the reaction, the solvent was removed under reduced pressure, N,N-dimethylformamide was added, N,N-diisopropylethylamine was added, and NHS active ester of a bifunctional chelating agent was added to react at room temperature for 12-48 hours. The solvent was removed under reduced pressure and purified to obtain compound 3; (3) dissolving compound 3 in a buffer solution with a pH of 4-6, adding a 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 The compound of the element Pb is reacted at 60-100°C for 10 min-48 h, and purified to obtain compound Ia, or The method comprises the following steps: (1') Compound 1, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added to N,N-dimethylformamide, and N,N-diisopropylethylamine was added. The reaction was carried out at room temperature for 30 minutes to 2 hours. After the reaction, 8-15 times the volume of the solvent was added to dilute with saturated ammonium chloride aqueous solution, and EA was extracted three times. The EA phases were combined, washed with water, and concentrated and purified to obtain compound 2'; (2') Compound 2' was added to a mixed solvent of DCM and trifluoroacetic acid in a volume ratio of 1:2-3, and reacted for 60 minutes. After the reaction, the solvent was removed under reduced pressure, N,N-dimethylformamide was added, N,N-diisopropylethylamine was added, and NHS active ester of a bifunctional chelating agent was added to react at room temperature for 12-48 hours, and the solvent was removed under reduced pressure, and purified to obtain compound 3'; (3') dissolving compound 3' in a buffer solution with a pH of 4-6, adding a 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y. 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 The compound of the Pb element is reacted at 60-100° C. for 10 min-48 h and purified to obtain compound Ib.

8. Use of the compound of formula Ia or Ib according to claim 1 or 2 as a PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probe.

9. The use according to claim 8, wherein the use is the use of the compound of formula Ia or Ib in the preparation of a tumor PET imaging agent, a tumor SPECT imaging agent or a tumor MRI imaging agent.

Images