Molecular imaging probe targeting poly ADP ribose polymerase, preparation method and application thereof

Abstract

The invention discloses a molecular imaging probe targeting poly ADP ribose polymerase as well as a preparation method and application of the molecular imaging probe. The molecular imaging probe is represented by the following formula Ia or Ib. The compound disclosed by the invention can be used as a PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probe, and has a great application prospect in imaging treatment of PARP expression abnormity related diseases such as tumors. # imgabs0 #

Description

Technical Field

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

[0002] Poly(ADP-ribose) polymerase (PARP) was first discovered more than fifty years ago and is an important enzyme involved in repairing single-strand damaged DNA (SSB). PARP1 is the first member of the poly(ADP-ribose) polymerase superfamily, which consists of proteins homologous to PARP1. There are now 17 members in this family, and 4 members - PARP1, PARP2, PARP5A, and PARP5B - can catalyze the formation of PAR chains. PARP1 is the most abundant enzyme in the PARP family and plays the most important role in DNA single-strand damage repair. PARP1 recognizes SSB through its three zinc finger structures. The binding of the PARP1 zinc finger structure to DNA causes a conformational change, activating PARP1, which cleaves NAD+ into nicotinamide and an ADP-ribose moiety. The ADP-ribose moiety is covalently linked to PARP1 or other nuclear proteins, and then other ADP-ribose groups are added to it, generating long or branched PAR chains. These negatively charged polymers recruit the DNA repair enzyme XRCC1 to the damage site for repair.

[0003] In recent years, some 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 was obtained by structurally modifying olaparib as the targeting group and labeling it with 18F (Reference: Keliher, E.J.; Reiner, T.; Turetsky, A.; Hilderbrand, S.A.; 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 was obtained by structurally modifying rucaparib and labeling it with 18F and has entered the clinical trial stage (Reference: Michel, L.S.; Dyroff, S.; Brooks, F.J.; Spayd, K.J.; Lim, S.; Engle, J.T.; Phillips, S.; Tan, B.; Wang-Gillam, A.; Bognar, C.; Chu, W.; Zhou, D.; Mach, R.H.; Laforest, R.; Chen, D.L. 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.), and [64Cu]Cu-DOTA-PARP was obtained by modifying olaparib with the DOTA group and labeling it with 64Cu (Reference: Huang, T. Initial Evaluation of Cu-64 Labeled PARPi-DOTA PET Imaging in Mice with Mesothelioma. 2017, 5.).

[0004] However, the above probes are all structurally modified based on targeting groups with relatively large partition coefficients of lipid and water, resulting in high uptake in the liver and gallbladder, which affects the imaging effect of the abdomen. For example, in HCC1937 tumor-bearing mice, the liver uptake of two probes, 18F-FTT and 18F-PARPi, at the clinical trial stage, was close to 20% ID / g 1.5 hours after intravenous injection, 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, and 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, the 18F labeling is very difficult and the operation is complex. Therefore, we searched for a targeting group, quinazoline-2,4-dione derivative, with a relatively low partition coefficient of lipid and water, carried out structural modification on this basis, and chelated it with a metal to further reduce the partition coefficient of lipid and water and reduce the non-specific uptake of the liver and gallbladder, which is meaningful for the imaging and treatment of diseases related to abnormal PARP expression such as tumors. Summary of the Invention

[0005] The object 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 preparation method of the above-mentioned molecular imaging probes targeting poly (ADP-ribose) polymerase (PARP).

[0007] Another object of the present invention is to provide an application of the above-mentioned molecular imaging probes 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, a compound of formula Ia or Ib is provided:

[0010]

[0011] Wherein, Rx is

[0012] R 5 is a group derived from a chelating agent chelated with an element,

[0013] The element is selected from elements that generate nuclear magnetic signals and elements that generate radioactive signals.

[0014] In formula Ia,

[0015] R 1 is R 1a 、R 1a -C(=O)N(R 4 )R 3 -、R 1a -N(R 4 )-C(=O)R 3 -,R 1a is selected from: -C1-C20

[0016] alkylene, -((CH 2 ) a -O) b -(CH 2 ) c -、-C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocycloalkylene; R 1a may optionally be substituted with substituents selected from the following: halogen, hydroxyl, where

[0017] R 3 is selected from: direct bond, -C1-C20 alkylene, -((CH 2 ) a -O) b -(CH 2 ) c -、-C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocycloalkylene,

[0018] R 4 is selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) d CH 3 、-C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocycloalkyl;

[0019] R 2 is selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) cCH 3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclic group, or

[0020] When R 1 is R 1a -C(=O)N(R 4 )R 3 -, R 1a -N(R 4 )-C(=O)R 3 -, R 2 and R 4 together with the atoms to which they are attached form a four- to seven-membered heterocycle;

[0021] In formula Ib,

[0022] R 6 , R 7 are each independently the same as the definition of R 1 , or a direct bond;

[0023] R 2 is selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) c CH 3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclic group,

[0024] The subscripts a, b, c are each independently an integer from 1 to 5;

[0025] Preferably, R 1 is R 1a , or R 1a -C(=O)N(R 4 )R 3 -, R 1a is selected from: -C1-C20 alkylene, and -((CH 2 ) a -O) b -(CH 2 ) c -; R 1a is optionally substituted with substituents selected from the following: halogen, hydroxyl, wherein,

[0026] R 3 is selected from: a direct bond and -C1-C20 alkylene,

[0027] R4 Selected from: H and -C1-C20 alkyl;

[0028] The subscripts a, b, and c are each independently an integer from 1 to 5;

[0029] R 2 Selected from: H and -C1-C20 alkyl, or

[0030] In R 1 being R 1a -C(=O)N(R 4 )R 3 - when, R 2 and R 4 together with the atoms to which they are attached jointly form a piperazine ring;

[0031] In formula Ib,

[0032] R 6 , R 7 each independently has the same definition as R 1 ;

[0033] R 2 Selected from: H and -C1-C20 alkyl.

[0034] According to an embodiment of the present invention, in R 5 , the chelating agent is selected from any one of 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 -dimethyl-3,7,11,15-tetraaza-1,9(2,6)-dipyridine-5,13(1,3)-dibenzo cyclohexanedione-3,7,1,11,15-tetrayl)tetraacetic acid (Dar), dimethyltriamine pentaacetic acid (DTPA), 32-amino-5,16,27-trihydroxy-4,12,15,23,26-pentacarbonyl-5,11,16,22,27-pentaaza dotriacontane-1-acid (DFO), 2-(6-hydrazinopyridin-3-yl)acetic acid (HYNIC), and mercaptoacetyltriglycine (MAG3),

[0035] In R 5 , the element that generates the nuclear magnetic signal is selected from Gd, Fe, Eu, Mn, Cu, Si, and Nd, and the element that generates the 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.

[0036] According to an embodiment of the present invention, wherein,

[0037] wherein R 5 is selected from the following structures

[0038]

[0039] According to an embodiment of the present invention, wherein the compound of formula Ia or Ib is selected from the following compounds:

[0040]

[0041]

[0042]

[0043] The present invention further provides a method for preparing the compound of formula Ia or Ib, and the preparation route is as follows:

[0044] Method 1: Preparation of the compound of formula Ia

[0045]

[0046] The method includes the following steps:

[0047] (a) Compound 1 reacts with HOOC-R 1 -NR 2 Boc to undergo a nitrogen acylation reaction to obtain compound 2;

[0048] (b) The N-Boc protecting group of compound 2 is removed to expose the amino group. After removing the solvent by evaporation under reduced pressure, it reacts with a bifunctional chelating agent reagent to undergo a nitrogen acylation reaction to obtain compound 3;

[0049] (c) Compound 3 reacts with a compound containing a metal selected from 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 Ia is obtained by reacting with a compound of the element Pb, or

[0050] Method 2: Preparation of Compound Ib

[0051]

[0052] (a’) Compound 1 reacts with a compound of the formula to undergo a nitrenylation reaction to obtain Compound 2’;

[0053] (b’) The N-Boc protecting group of Compound 2’ is removed to expose the amino group. After removing the solvent by evaporation under reduced pressure, it reacts with a bifunctional chelating agent reagent to undergo a nitrenylation reaction to obtain Compound 3’;

[0054] (c’) Compound 3’ reacts with a compound of an element selected from 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 to obtain Compound Ib,

[0055] In the reaction routes of the above Methods 1 and 2, the definitions of each substituent are the same as those defined previously.

[0056] In one embodiment, the method comprises the following steps:

[0057] (1) Compound 1, HOOC-R 1 -NR 2Boc (such as 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, N,N-diisopropylethylamine is added, and the reaction is carried out at room temperature for 30 minutes to 2 hours. After the reaction is completed, the reaction mixture is diluted with 8-15 times the volume of saturated ammonium chloride aqueous solution, extracted three times with EA, the EA phases are combined, washed with water, concentrated and purified to obtain Compound 2;

[0058] (2) Compound 2 is added to a mixed solvent of DCM and trifluoroacetic acid with a volume ratio of 1:2 - 3 and reacted for 60 minutes. After the reaction is completed, the solvent is removed under reduced pressure, N,N-dimethylformamide is added, N,N-diisopropylethylamine is added, and the NHS active ester of the bifunctional chelating agent (such as: 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) is reacted at room temperature for 12 - 48 hours, the solvent is removed under reduced pressure, and purified to obtain Compound 3;

[0059] (3) Compound 3 is dissolved in a buffer solution with a suitable pH (such as acetic acid-sodium acetate buffer solution with pH = 5), and a compound containing an element selected from 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 Pb (such as 68 GaCl 3 , 64 Cu(AcO) 2 , europium trifluoromethanesulfonate) is reacted at 60 - 100 °C for 10 min - 48 h, and purified to obtain Compound Ia, or

[0060] The method includes the following steps:

[0061] (1’) Compound 1, 2-(7-Azabenzotriazol-1-yl)-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 was completed, the reaction mixture was diluted with 8 - 15 times the volume of saturated ammonium chloride aqueous solution, extracted three times with EA, the EA phases were combined, washed with water, concentrated and purified to obtain compound 2';

[0062] (2') Compound 2' was added to a mixed solvent of DCM and trifluoroacetic acid with a volume ratio of 1:2 - 3 and reacted for 60 minutes. After the reaction was completed, the solvent was removed under reduced pressure. N,N-dimethylformamide was added, N,N-diisopropylethylamine was added, and the NHS active ester of the 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. The reaction was carried out at room temperature for 12 - 48 hours, and the solvent was removed under reduced pressure and purified to obtain compound 3';

[0063] (3') Compound 3' was dissolved in a buffer solution with an appropriate pH (for example, acetic acid - sodium acetate buffer solution with pH = 5), and a compound containing an element selected from 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 Pb (for example 68 GaCl 3 , 64 Cu(AcO) 2 , europium trifluoromethanesulfonate) was reacted at 60 - 100 °C for 10 min - 48 h and purified to obtain compound Ib.

[0064] 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, especially in the application of diseases with abnormal PARP expression levels, especially in the preparation of tumor PET imaging agents, in the preparation of tumor SPECT imaging agents or in the preparation of tumor MRI imaging agents.

[0065] Beneficial effects

[0066] A novel class of compounds with unique structures has been synthesized in this application. These compounds can serve as positron emission, single photon emission, or nuclear magnetic resonance imaging probes targeting PARP, and have great application prospects in the imaging and treatment of diseases related to abnormal PARP expression, such as tumors. Brief description of the drawings

[0067] Figure 1 Micro-PET / CT imaging effect diagram of tumor in A549 tumor-bearing mice for M6 prepared in Example 6. The position of the tumor is within the circle.

[0068] Figure 2 Micro-PET / CT imaging effect diagram of tumor in A549 tumor-bearing mice for M7 prepared in Example 7. The position of the tumor is within the circle. Detailed implementation manners

[0069] Unless otherwise specified, the raw materials, reagents, experimental animals, etc. used in this application are all conventional raw materials, reagents, and experimental animals in the art and are commercially available. Animal experiments comply with the ethical requirements of experimental animals. The equipment and methods used are all conventional equipment and methods in the art.

[0070] Example 1: Preparation of M1

[0071] Step 1: Synthesis of Intermediate 1 of Example 1

[0072]

[0073] 50 mg of 1-((5-fluoro-4-(piperazine-1-carbonyl)pyridin-2-yl)methyl)quinazoline-2,4(1H,3H)-dione and 50 mg of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid, 100 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added to N,N-dimethylformamide, 80 μL of N,N-diisopropylethylamine was added, and the reaction was carried out at room temperature for 60 minutes. After the reaction was completed, it was diluted with 10 times the volume of saturated ammonium chloride aqueous solution, extracted three times with EA, the EA phases were combined, washed with water, concentrated and purified by column chromatography to obtain 65 mg of white solid, with a yield of 75%. 1H NMR (400 MHz, chloroform-d) δ 9.62 (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, 4.9 Hz, 5H), 3.46 (s, 4H), 3.41 (dd, J = 6.7, 3.6 Hz, 2H), 3.28 (d, J = 23.9 Hz, 2H), 2.57 - 2.38 (m, 4H), 2.07 - 1.87 (m, 2H), 1.47 (s, 9H).

[0074] Step 2: Synthesis of Intermediate 2 of Example 1

[0075]

[0076] The intermediate 1 (20 mg) from the previous step was added to 5 mL of DCM, 10 mL of trifluoroacetic acid was added, and the reaction was carried out for 60 minutes. The solvent was evaporated to dryness, 2 mL of N,N-dimethylformamide was added, 100 μL of DIPEA was added, 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, and the reaction was carried out for 24 h. The solvent was evaporated to dryness, and purified by preparative liquid chromatography to obtain 21 mg of white solid, with a yield of 73%. 1H NMR (500 MHz, D 2O) 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]+ calculated for C44H59FN11O12: 952.43, found: 952.91.

[0077] Step 3: Synthesis of the product M1 of Example 1

[0078] Add 40 μL of sodium acetate solution (1.5 M) to a glass reaction flask, then add 10 μg of Intermediate 2, and then add 5 mCi 68 GaCl 3 (~2 mL) to make the final pH of the reaction solution between 4 - 5, heat in a metal bath at 95 °C for 10 min, and after the reaction is completed, cool to room temperature to obtain M1.

[0079] Example 2: Preparation of M2

[0080] Step 1: Synthesis of Intermediate 1 of Example 2

[0081]

[0082] The method is the same as Step 1 of Example 1, except that 5 - ((2 - ((tert - butoxycarbonyl)amino)ethyl)amino) - 5 - oxopentanoic acid is used instead of 5 - (4 - (tert - butoxycarbonyl)piperazin - 1 - yl) - 5 - oxopentanoic acid, and 63 mg of white solid is obtained. 1H NMR (400 MHz, chloroform - d) δ 9.46 (d, J = 76.8 Hz, 1H), 8.50 (s, 1H), 8.21 (dd, J = 7.8, 1.6 Hz, 1H), 7.65 (q, J = 7.7 Hz, 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, 7.2 Hz, 2H), 2.29 (q, J = 6.1, 5.4 Hz, 2H), 1.96 (dt, J = 12.9, 6.8 Hz, 2H), 1.44 (s, 9H).

[0083] Step 2: Synthesis of Intermediate 2 of Example 2

[0084]

[0085] The method is the same as step 2 of Example 1, except that the intermediate 1 from the previous step is used to obtain 20 mg of a white solid. 1H NMR (500 MHz, D 2 O) 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: C42H57FN11O12: 926.41, found: 926.81.

[0086] Step 3: Synthesize the product M2 of Example 2

[0087] 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.

[0088] Example 3: Preparation of M3

[0089] Step 1: Synthesize the intermediate 1 of Example 3

[0090]

[0091] The method was the same as Step 1 of Example 1, except that (tert-butoxycarbonyl)glycine was used instead of 5-(4-(tert-butoxycarbonyl)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, 5.0 Hz, 1H), 5.46 (s, 2H), 4.01 (dd, J = 24.5, 4.6 Hz, 2H), 3.79 (s, 3H), 3.64 (s, 1H), 3.53 (t, J = 5.3 Hz, 1H), 3.43 (t, J = 5.0 Hz, 1H), 3.31 (dt, J = 10.6, 4.9 Hz, 2H), 1.46 (d, J = 3.3 Hz, 9H).

[0092] Step 2: Synthesis of Intermediate 2 of Example 3

[0093]

[0094] The method was the same as 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, D 2 O) 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]+ calculated: C37H48FN10O11: 827.34, found: 827.79.

[0095] Step 3: Synthesis of Product M3 of Example 3

[0096] The method was the same as Step 3 of Example 1, except that the intermediate 2 from the previous step was used to prepare M3.

[0097] Example 4: Preparation of M4

[0098] Step 1: Synthesis of Intermediate 1 of Example 4

[0099]

[0100] The method was the same as Step 1 of Example 1, except that 3-((tert-butoxycarbonyl)amino)propanoic 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, 9.6 Hz, 3H), 3.63 (d, J = 5.5 Hz, 1H), 3.56 (t, J = 5.3 Hz, 1H), 3.45 (dq, J = 18.5, 5.6 Hz, 3H), 3.29 (dt, J = 21.9, 5.3 Hz, 2H), 2.55 (dt, J = 37.6, 5.8 Hz, 2H), 1.44 (d, J = 5.8 Hz, 9H).

[0101] Step 2: Synthesis of Intermediate 2 of Example 4

[0102]

[0103] The method was the same as 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, D 2 O) 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]+ calculated: C38H50FN10O11: 841.36, found: 841.85.

[0104] Step 3: Synthesis of Product M4 of Example 4

[0105] The method was the same as Step 3 of Example 1, except that the intermediate 2 from the previous step was used to prepare M4.

[0106] Example 5: Preparation of M5

[0107] Step 1: Synthesis of Intermediate 1 of Example 5

[0108]

[0109] The method is the same as step 1 of Example 1, except that 4-((tert-butoxycarbonyl)amino)butyric acid is 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, 2H), 4.90 - 4.76 (m, 1H), 3.88 - 3.70 (m, 3H), 3.59 (dt, J = 18.2, 5.3 Hz, 2H), 3.47 (dd, J = 6.8, 3.5 Hz, 1H), 3.28 (dt, J = 10.0, 4.8 Hz, 2H), 3.22 - 3.07 (m, 2H), 2.39 (dt, J = 23.4, 7.2 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.43 (d, J = 6.6 Hz, 9H).

[0110] Step 2: Synthesis of Intermediate 2 of Example 5

[0111]

[0112] The method is the same as step 2 of Example 2, except that the intermediate 1 from the previous step is used to obtain 19 mg of a white solid. 1H NMR (500 MHz, D 2 O) 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), 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: C39H50FKN10NaO11: 915.31, found: 915.96.

[0113] Step 3: Synthesis of Product M5 of Example 5

[0114] The method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M5.

[0115] Example 6: Preparation of M6

[0116] Step 1: Synthesis of Intermediate 1 of Example 6

[0117]

[0118] The method is the same as step 1 of Example 1, except that 5-((tert-butoxycarbonyl)amino)pentanoic acid is 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), 4.73 (s, 1H), 3.75 (d, J = 15.9 Hz, 3H), 3.58 (dd, J = 12.3, 7.0 Hz, 2H), 3.48 (t, J = 5.1 Hz, 1H), 3.35 - 3.20 (m, 2H), 3.14 (t, J = 7.0 Hz, 2H), 2.37 (dt, J = 23.1, 7.4 Hz, 2H), 1.67 (h, J = 6.9 Hz, 2H), 1.61 - 1.49 (m, 2H), 1.43 (d, J = 7.6 Hz, 9H).

[0119] Step 2: Synthesis of Intermediate 2 of Example 6

[0120]

[0121] The method is the same as step 2 of Example 1, except that the intermediate 1 from the previous step is used to obtain 19 mg of a white solid. 1H NMR (500 MHz, D 2O) 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]+ calculated for C40H53FKN10O11: 907.35, found: 907.83.

[0122] Step 3: Synthesis of the product M6 of Example 6

[0123] The method was the same as Step 3 of Example 1, except that the intermediate 2 from the previous step was used to obtain M6.

[0124] Example 7: Preparation of M7

[0125] Step 1: Synthesis of Intermediate 1 of Example 7

[0126]

[0127] The method was the same as 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, 5.1 Hz, 2H), 3.45 (t, J = 5.2 Hz, 1H), 3.26 (dd, J = 22.7, 5.9 Hz, 2H), 3.10 (p, J = 7.1 Hz, 2H), 2.32 (dt, J = 29.0, 7.5 Hz, 2H), 1.64 (h, J = 7.9 Hz, 2H), 1.49 (d, J = 8.2 Hz, 2H), 1.42 (d, J = 7.0 Hz, 9H), 1.35 (td, J = 13.5, 7.0 Hz, 2H).

[0128] Step 2: Synthesis of Intermediate 2 of Example 7

[0129]

[0130] The method was the same as Step 2 of Example 1, except that the intermediate 1 from the previous step was used, and 18 mg of white solid was obtained. 1H NMR (500 MHz, D 2 O) 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: C41H56FKN10O11: 461.19, found: 461.51.

[0131] Step 3: Synthesis of the product M7 of Example 7

[0132] The method was the same as Step 3 of Example 1, except that the intermediate 2 from the previous step was used to prepare M7.

[0133] Example 8: Preparation of M8

[0134] Step 1: Synthesis of the intermediate 1 of Example 8

[0135]

[0136] The method was the same as 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), 5.45 (s, 2H), 5.07 (t, J = 5.7 Hz, 1H), 3.83 - 3.69 (m, 5H), 3.61 (p, J = 5.4, 4.9 Hz, 2H), 3.51 (dq, J = 8.6, 4.1, 3.1 Hz, 3H), 3.37 - 3.15 (m, 4H), 2.62 (dt, J = 24.0, 6.2 Hz, 2H), 1.42 (d, J = 5.4 Hz, 9H).

[0137] Step 2: Synthesis of Intermediate 2 of Example 8

[0138]

[0139] 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, D 2 O) 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]+ calculated: C40H54FN10O12: 885.39, found: 885.90.

[0140] Step 3: Synthesis of Product M8 of Example 8

[0141] The method was the same as Step 3 of Example 1, except that the intermediate 2 from the previous step was used to prepare M8.

[0142] Example 9: Preparation of M9

[0143] Step 1: Synthesis of Intermediate 1 of Example 9

[0144]

[0145] 50 mg of 1-((5-fluoro-4-(piperazine-1-carbonyl)pyridin-2-yl)methyl)quinazoline-2,4(1H,3H)-dione, 16 mg of (tert-butoxycarbonyl)glutamic acid, and 100 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added to N,N-dimethylformamide. 80 μL of N,N-diisopropylethylamine was added, and the reaction was carried out at room temperature for 60 minutes. After the reaction was completed, it was diluted with 10 times the volume of saturated ammonium chloride aqueous solution, extracted three times with EA, the EA phases were combined, washed with water, concentrated, and purified by column chromatography to obtain 50 mg of a white solid with a yield of 78%. 1H NMR (500 MHz, chloroform-d) δ 10.38 - 9.28 (m, 2H), 8.60 - 8.43 (m, 2H), 8.21 (t, J = 8.3 Hz, 2H), 7.65 (p, J = 7.2 Hz, 2H), 7.39 (ddt, J = 32.9, 14.4, 9.6 Hz, 4H), 7.30 (s, 2H), 5.71 - 5.36 (m, 5H), 4.67 (d, J = 57.8 Hz, 1H), 4.08 - 3.12 (m, 16H), 2.74 - 2.22 (m, 2H), 2.13 (s, 1H), 1.42 (dd, J = 13.1, 7.9 Hz, 9H).

[0146] Step 2: Synthesis of Intermediate 2 of Example 9

[0147]

[0148] The intermediate 1 (20 mg) from the previous step was added to 5 mL of DCM, 10 mL of trifluoroacetic acid was added, and the reaction was carried out for 60 minutes. The solvent was evaporated to dryness, 2 mL of N,N-dimethylformamide was added, 100 μL 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 h, the solvent was evaporated to dryness, and purified by preparative liquid phase to obtain 15 mg of a white solid with a yield of 58%. 1H NMR (500 MHz, D 2O) 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.

[0149] Step 3: Synthesis of the product M9 of Example 9

[0150] Add 40 μL of sodium acetate solution (1.5 M) to a glass reaction flask, then add 10 μg of Intermediate 2, and then add 5 mCi 68 GaCl 3 (~2 mL) and heat in a metal bath at 95 °C for 10 min. After the reaction is completed, cool to room temperature to obtain M9.

[0151] Example 10: Preparation of M10

[0152] Step 1: Synthesis of Intermediate 1 of Example 10

[0153]

[0154] The method is the same as Step 1 of Example 1, except that 12 - ((2 - ((tert - butoxycarbonyl)amino)ethyl)amino) - 12 - oxododecanoic acid is used instead of 5 - (4 - (tert - butoxycarbonyl)piperazin - 1 - yl) - 5 - oxopentanoic acid, to obtain 60 mg of a white solid.

[0155] Step 2: Synthesis of Intermediate 2 of Example 10

[0156]

[0157] The method is the same as Step 2 of Example 1, except that the intermediate 1 from the previous step is used, to obtain 16 mg of a colorless semi - solid. LRMS(ESI) m / z: [M+H]+ calculated for C49H71FN11O12: 1024.53, found: 1025.00.

[0158] Step 3: Synthesis of the product M10 of Example 10

[0159] The method is the same as Step 3 of Example 1, except that the intermediate 2 from the previous step is used, to obtain M10.

[0160] Test Example 1: Determination of the LogD7.4 of the lipid - water partition coefficient of M6

[0161] Approximately 30 μCi of M6 probe was placed in a centrifuge tube containing an equal volume of PBS buffer and n-octanol. After vortexing for 15 minutes, it 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 measured with a γ counter to obtain the ratio of the probe in the two phases. The LogD7.4 of M6 was -3.623 ± 0.196, which had a very low lipid-water distribution coefficient compared to the existing PARP-targeted PET probes developed.

[0162] Experimental Example 2: Application of M6 in micro-PET / CT imaging of tumor-bearing mice

[0163] Three commercially available SPF-grade Balb / c nude mice were taken and inoculated with A549 cells (human non-small cell lung cancer cells) under the right forelimb axilla. When the tumor diameter was about 7 mm, the M6 probe prepared in Example 6 with a dose of 100 - 150 μCi was injected via the tail vein respectively. The mice were maintained in an anesthetized state with a 2.0% mixture of isoflurane-oxygen. PET / CT scanning (Siemens Inveon microPET) was started synchronously with the injection, and 1 h imaging pictures were collected. The results are shown in Figure 1 , and the position circled is the location of the tumor. It can be clearly seen that there is a high enrichment of radioactive signal in the tumor site. From the images, the tumor has a good imaging effect, and the signal in the liver is less than 1% ID / g, which is better than previous probes.

[0164] Experimental Example 3: Application of M7 in micro-PET / CT imaging of tumor-bearing mice

[0165] Three commercially available SPF-grade Balb / c nude mice were taken and inoculated with A549 cells (human non-small cell lung cancer cells) under the left forelimb axilla. When the tumor diameter was about 7 mm, the M7 probe prepared in Example 7 with a dose of 100 - 150 μCi was injected via the tail vein respectively. The mice were maintained in an anesthetized state with a 2.0% mixture of isoflurane-oxygen. PET / CT scanning (Siemens Inveon microPET) was started synchronously with the injection, and 1 h imaging pictures were collected. The results are shown in Figure 2 , and the position circled is the location of the tumor. It can be clearly seen that there is a high enrichment of radioactive signal in the tumor site. From the images, the tumor has a good imaging effect, and the signal in the liver is less than 2% ID / g, which is better than previous probes.

[0166] In summary, the probe synthesized in this application has an imaging effect on diseases (such as tumors) related to abnormal PARP expression 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: Wherein, Rx is R 5 is a group derived from a chelating agent chelated with an element, The element is selected from elements that generate nuclear magnetic signals and elements that generate radioactive signals, In formula Ia, R 1 is R 1a 、R 1a -C(=O)N(R 4 )R 3 -、R 1a -N(R 4 )-C(=O)R 3 -,R 1a selected from: -C1-C20 Alkylene, -((CH 2 ) a -O) b -(CH 2 ) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocycloalkylene; R 1a is optionally substituted with substituents selected from the following: halogen, hydroxyl, wherein, R 3 Selected from: a direct bond, -C1-C20 alkylene, -((CH 2 ) a -O) b -(CH 2 ) c -, -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, -C3-20 heterocycloalkylene, R 4 Selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) d CH 3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclic group; The subscripts a, b, c are each independently an integer from 1 to 5; R 2 Selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) d CH 3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclic group, or At R 1 is R 1a -C(=O)N(R 4 )R 3 -, R 1a -N(R 4 )-C(=O)R 3 - when, R 2 and R 4 together with the atoms to which they are attached jointly form a four- to seven-membered heterocycle; In formula Ib, R 6 、R 7 Each independently has the same definition as R 1 or is a direct bond; R 2 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 heterocyclic group.

2. The compound according to claim 1, wherein R 1 is R 1a 、or R 1a -C(=O)N(R 4 )R 3 -、R 1a selected from: -C1-C20 alkylene, and -((CH 2 ) a -O) b -(CH 2 ) c -; R 1a is optionally substituted with substituents selected from the following: halogen, hydroxy, Wherein, R 3 Selected from: a direct bond, and a C1-C20 alkylene group R 4 Selected from: H, and -C1-C20 alkyl; The subscripts a, b, c are each independently an integer from 1 to 5; R 2 selected from: H, and -C1-C20 alkyl, or At R 1 is R 1a -C(=O)N(R 4 )R 3 - when, R 2 and R 4 together with the atoms to which they are attached jointly form a piperazine ring; In formula Ib, R 6 and R 7 are each independently the same as the definition of R 1 ; R 2 Selected from: H, and -C1-C20 alkyl, R 5 The definitions of R and Rx are the same as those in claim 1.

3. The compound according to claim 1 or 2, In R 5 , the chelating agent is selected from any one of cyclen tetraacetic acid, trineopentylenetetramine 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 -dimethyl-3,7,11,15-tetraaza-1,9(2,6)-dipyridyl-5,13(1,3)-dibenzo-cyclohexadione-3,7,1,11,15-tetrayl)tetraacetic acid (Dar), dimethyltriamine pentaacetic acid (DTPA), 32-amino-5,16,27-trihydroxy-4,12,15,23,26-pentacarbonyl-5,11,16,22,27-pentaaza-dotriacontan-1-oic acid (DFO), 2-(6-hydrazinopyridin-3-yl)acetic acid (HYNIC) and mercaptoacetyltriglycine (MAG3). In R 5 the element generating the nuclear magnetic signal is selected from Gd, Fe, Eu, Mn, Cu, Si, and Nd, and the element generating the 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 R 5 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: and 6. A method for preparing the compound of formula Ia or Ib according to claim 1, the method comprising Method 1 or Method 2: Method 1: Preparation of the compound of formula Ia The method comprises the following steps: (a) Compound 1 reacts with HOOC-R 1 -NR 2 to undergo N-acylation reaction with Boc to obtain Compound 2; (b) Remove the N-Boc protecting group from Compound 2 to expose the amino group, evaporate the solvent under reduced pressure, and then carry out a nitrogen acylation reaction with a bifunctional chelating agent reagent to obtain Compound 3; (c) Compound 3 reacts with a compound of an element selected from 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 Pb to obtain Compound Ia, or Method 2: Preparation of the compound of formula Ib (a’) Compound 1 undergoes a nitrilation reaction with a compound of the formula to obtain Compound 2’; (b’) Remove the N-Boc protecting group from Compound 2’ to expose the amino group, evaporate the solvent under reduced pressure, and then carry out a nitrogen acylation reaction with a bifunctional chelating agent reagent to obtain Compound 3’; (c’) Compound 3’ reacts with a compound of an element selected from 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 to obtain Compound Ib. In the reaction routes of the above Method 1 and Method 2, the definitions of each substituent are the same as those in claim 1, and "Chelator" refers to a chelating agent.

7. The method according to claim 6, the method comprising the following steps: (1) Add compound 1, HOOC-R 1 -NR 2 Boc and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate into N,N-dimethylformamide, add N,N-diisopropylethylamine, react at room temperature for 30 minutes to 2 hours. After the reaction, dilute with 8-15 times the solvent volume of saturated ammonium chloride aqueous solution, extract three times with EA, combine the EA phases, wash with water, concentrate and purify to obtain compound 2; (2) Add Compound 2 to a mixed solvent of DCM and trifluoroacetic acid with a volume ratio of 1:2 - 3 and react for 60 minutes. After the reaction is completed, remove the solvent under reduced pressure, add N,N-dimethylformamide, add N,N-diisopropylethylamine, add the NHS active ester of the bifunctional chelating agent and react at room temperature for 12 - 48 hours, remove the solvent under reduced pressure, and purify to obtain Compound 3; (3) Dissolve compound 3 in a buffer solution with a pH of 4 - 6, add a compound containing an element selected from 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 Pb and react at 60 - 100 °C for 10 min - 48 h, and purify to obtain compound Ia, or The method comprises the following steps: (1’) Add Compound 1, and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to N,N-dimethylformamide, add N,N-diisopropylethylamine, react at room temperature for 30 minutes to 2 hours. After the reaction is completed, dilute with 8 - 15 times the solvent volume of saturated ammonium chloride aqueous solution, extract three times with EA, combine the EA phases, wash with water, and concentrate and purify to obtain Compound 2’; (2’) Add Compound 2’ to a mixed solvent of DCM and trifluoroacetic acid with a volume ratio of 1:2 - 3 and react for 60 minutes. After the reaction is completed, remove the solvent under reduced pressure, add N,N-dimethylformamide, add N,N-diisopropylethylamine, add the NHS active ester of the bifunctional chelating agent and react at room temperature for 12 - 48 hours, remove the solvent under reduced pressure, and purify to obtain Compound 3’; (3’) Dissolve compound 3’ in a buffer solution with a pH of 4 - 6, add a compound containing an element selected from 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 Pb, and react at 60 - 100 °C for 10 min - 48 h, then purify 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, in the preparation of a tumor SPECT imaging agent or in the preparation of a tumor MRI imaging agent.

Images