PSMA diagnosis and treatment compound assembled by connection of tetrazine-trans-cyclooctene

Abstract

The present disclosure relates to ureido ligands targeting PSMA comprising a moiety targeting PSMA, a linker, and a pyridazine moiety. The disclosed PSMA-targeted ureido ligands are suitable for use as radiopharmaceuticals, as imaging agents (e.g., diagnostic agents), or for the treatment of prostate cancer, or as diagnostic agents.

Description

Technical Field

[0001] This invention relates to urea-ligands assembled via tetrazine linkage and their use in radiotherapy and imaging, wherein the urea-ligands target prostate-specific membrane antigens. Background Technology

[0002] Prostate cancer (PC) is one of the most frequently diagnosed cancers in men. Further complications arising from PC (such as bone metastases) can occur in a significant number of patients, resulting in a one-year survival rate of only 40%. Complicating matters further, some of these patients do not respond to conventional hormone therapy, thus developing what is known as castration-resistant prostate cancer (CRPC). Currently, treatment options for CRPC patients are limited. Potent and selective radiopharmaceuticals may represent an important diagnostic and treatment option for this disease. Recently, prostate-specific membrane antigen (PSMA) has emerged as a promising target due to its overexpression in PC cells compared to healthy tissue (8 to 12 times higher). However, some developed and marketed radiopharmaceuticals targeting PSMA have shown limited response and adverse side effects in patients, such as nephrotoxicity and salivary gland accumulation. .

[0003] The most advanced PSMA-targeted radiotherapy currently available is based on 177 Lu-PSMA-617 (Pluvicto) demonstrated a good molecular response in clinical evaluations, clearing a significant amount of metastases and significantly reducing PSA concentrations to normal levels (below 4.0 ng / mL). However, it is noteworthy that 30% of patients were β-based. - -Therapeutic treatment of emitters (e.g.) 177 Lu-PSMA-617 did not respond, therefore an alternative strategy is needed. .

[0004] Alpha-emitting radionuclides have recently become more common than beta-emitting radionuclides. - - A more efficient alternative to emitters, because they are able to deliver a greater amount of energy to cancer cells. This approach is currently being explored for PSMA-based therapies. For example, actinium-225 (… 225 Ac) has been extensively studied, but it is not an ideal therapeutic radionuclide because it decays through a chain of four active alpha daughter radionuclides, with a total half-life of 10 days. This means it can cause widespread damage to healthy tissues, thereby increasing the toxic effects on patients and limiting the use of these radiopharmaceuticals.

[0005] Astatine-211 ( 211 At) is characterized by its short half-life of 7.2 hours and the fact that its decay does not produce any long-lived alpha emitters, representing 225 An effective alternative to Ac. Compared to... 225 Compared to PSMA derivatives of Ac, both of these properties can significantly reduce cytotoxicity in patients. .

[0006] Radiolabeled drugs targeting PSMA have been developed and have shown good, specific tumor uptake, but these compounds are impaired due to accumulation in the kidneys and salivary glands when no blocking agent is administered. Furthermore, the synthesis and radiolabeling procedures are based on standard methods, which are not always easy to implement in radiopharmacy, hospitals, and clinics.

[0007] Click chemistry has shown great potential in the synthesis of radiopharmaceuticals for imaging and therapy. In particular, the inverse electron-demanding Diels-Alder cycloaddition reaction (IEDDA) between tetrazine and dienophile exhibits the fastest reaction kinetics in click chemistry and has been used in the radiosynthesis of various labeled radiopharmaceuticals. The main limitation of this reaction is the formation of multiple isomers after the click. This problem has recently been solved by synthesizing a novel trans-cyclooctene (IsoF-TCO), which, when combined with an oxidation step, leads to the formation of a single isomer product (PCT / EP2023 / 055930).

[0008] This paper demonstrates that compounds targeting PSMA, containing a urea-based moiety, a linker, an IsoF-TCO, and a radiolabeled tetrazine, can be synthesized to obtain PSMA-targeting compounds with specific pharmacokinetic properties. Furthermore, the modularity of this method allows for rapid and efficient modification of radiopharmaceuticals, enabling quick optimization of certain properties, such as renal excretion and hepatic accumulation.

[0009] As also shown in this paper, it was surprisingly found that by adding increasing numbers of polar amino acids (D-glutamic acid and D-arginine) to the linker between the PSMA-binding moiety and the pyridazine moiety, the excretion of ureidoligands targeting PSMA could be controlled by shifting excretion from the liver to the kidneys and bladder. In particular, this effect was more pronounced with 2 to 6 amino acids.

[0010] Furthermore, the use of different radiolabeled tetrazines provided in this paper allows for the synthesis of therapeutic PSMA compounds starting from the same urea-based ligand precursors that target PSMA.

[0011] Finally, the radiolabeled compounds presented in this paper showed surprisingly higher tumor accumulation compared to PSMA-617, while retaining the same affinity for the target. Summary of the Invention

[0012] This invention provides novel urea-based ligands for targeting PSMA having the following general formula (I) and pharmaceutically acceptable salts thereof:

[0013]

[0014] In the formula:

[0015] A can be a carboxylic acid, sulfonic acid, phosphonic acid, tetrazolium, or isoxazole independently;

[0016] o is an integer selected from 1 to 4;

[0017] m is an integer selected from 0 to 10;

[0018] R1 is either -CH-CH2-Z or -CH-CH2-Y;

[0019] Z is selected from the following:

[0020]

[0021] Y is selected from the following:

[0022]

[0023] In the formula,

[0024] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0025] Q2 is O, S, or NH;

[0026] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0027] The condition is that when R2 = -CH-CH2-Y, then R1 must be -CH-CH2-Z;

[0028] R2 is either -CH-CH2-Y or -CH2-T-;

[0029] Wherein, T is an aromatic monocyclic or polycyclic system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

[0030] Y is selected from the following:

[0031]

[0032] In the formula,

[0033] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0034] Q2 is O, S, or NH;

[0035] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0036] The condition is that when R1 = -CH-CH2-Y, then R2 must be -CH2-T;

[0037] L represents the portion containing groups selected from the following:

[0038] -CO(CH2) n NH-, -CO(CH2CH2O) n NH-, -M-, -CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-, -MnCO(CH2CH2O) n NH-, -LysG-, -LysJ-, -LysGCO(CH2CH2O) n NH-, -LysJCO(CH2) n NH-, -LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O) n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJMn CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-, -CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l LysJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-,

[0039] Where n and l are integers independently selected from 0 to 10;

[0040] M is selected from one or more natural amino acids, one or more sugars, and combinations of one or more natural amino acids and one or more sugars;

[0041] Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains.

[0042] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0043] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0044] R4 is selected from the following pyridazines:

[0045]

[0046] R5 and R6 are identical or differ only in the isotope number of the labeling agent, and are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0047] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0048] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15O、 16 O、 17 O、 18 O、 43 Scr、 44 Scr、 45 Scr、 45 To, 46 To, 47 To, 48 To, 49 To, 50 To, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 My, 113 My, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 King、 186 King、 188 King、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 The、 139 The、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt;

[0049] E and D are independently selected from: -CH and -N-;

[0050] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0051] X is G or J.

[0052] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0053] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0054] R4 is selected from the following pyridazines:

[0055]

[0056] R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0057] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0058] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48You、 49 You、 50 You、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 doesn't, 115 doesn't, 175 Lu、 177 Lu、 185 Re, 186 Re, 188 Re, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213 Wind、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Scr、 47 Scr、 84 Sr、 86 Sr、 87Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr 52 Cr 53 Cr 54 Cr 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt;

[0059] E and D are independently selected from: -CH and -N-;

[0060] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u-OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-C10)cycloalkyl, (C3-C10)heteroalkyl, (C3-C10)cycloalkyl, (C3-C10)heteroalkyl, (C3-C10)heteroalkyl, (C3-C10)cycloalkyl, (C3-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-C10)cycloalkyl, (C3-C10)heteroalkylene, (C2-C10)heteroalkylene ... Cycloalkyl, (C3-C10)cycloalkylene, (C3-C10) heterocycloalkylene, (C1-C10) haloalkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenoxy, (C3-C10) alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6) alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0061] R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent;

[0062] Formula (I) contains at least one radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine, and astatine.

[0063] At least one of L and X contains J.

[0064] This disclosure also provides (Me)3Sn, (Me)3Si, B(OH)2 and B(OR9)2 precursors that can be used to provide ligands for targeting PSMA according to formula (I).

[0065] Depending on the specific radionuclide contained in the compound, compounds of formula (I) can be used for treatment and imaging. Therefore, this disclosure relates to pharmaceutical preparations containing compounds of formula (I), the use of compounds of formula (I) as pharmaceuticals, the use of compounds of formula (I) for treating prostate cancer, the use of compounds of formula (I) as radiopharmaceuticals, the use of compounds of formula (I) as imaging agents, and the use of compounds of formula (I) as diagnostic agents. Attached Figure Description

[0066] Figure 1 The diagram shows the synthetic routes for compounds 15 and 16.

[0067] Figure 2 The diagram shows the synthetic routes for compounds 20 and 21.

[0068] Figure 3 The diagram shows the synthetic routes for compounds 24, 25, and 26.

[0069] Figure 4 The diagram shows the synthetic routes for compounds 29, 30, and 31.

[0070] Figure 5 The diagram shows the synthetic routes for compounds 34, 35, and 36.

[0071] Figure 6 The diagram shows the synthetic routes for compounds 39, 40, and 41.

[0072] Figure 7 The diagram shows the synthetic routes for compounds 44 and 45.

[0073] Figure 8 The diagram shows the synthetic routes for compounds 48 and 49.

[0074] Figure 9 The diagram shows the synthetic routes for compounds 52 and 53.

[0075] Figure 10A , Figure 10B , Figure 10C The diagram shows the synthetic routes for compounds 63 and 64.

[0076] Figure 11 The diagram shows the synthetic routes for compounds 68 and 69.

[0077] Figure 12A , Figure 12B The diagram shows the synthetic routes for compounds 76 and 77.

[0078] Figure 13A , Figure 13B The diagram shows the synthetic routes for compounds 82 and 83.

[0079] Figure 14A , Figure 14B This shows a schematic diagram of the synthetic route for compound 88.

[0080] Figure 15: Assembled via tetrazine-trans-cyclooctene linkage [ 18 F]-PSMA derivatives[ 18 The overall synthesis route of F]25.

[0081] Figure 16 :[ 18 Semi-preparative HPLC chromatogram of F]25 (UV=top, radioactivity=bottom).

[0082] Figure 17 : Assembled via tetrazine-trans-cyclooctene linkage [ 211 At]-PSMA derivatives[ 211 The overall synthesis route of At]31.

[0083] Figure 18 :[ 211 Semi-preparative HPLC chromatogram of At]31 (UV=right, radioactivity=left).

[0084] Figure 19 :[ 211 Stability of At]31 in EtOH + 5% ascorbic acid (hours).

[0085] Figure 20 : Obtained in healthy rats [ 18 Activity / time curves of F-PSMA derivatives for selected organs.

[0086] Figure 21 : Obtained in healthy rats [ 68 Activity / time curves of Ga]-PSMA derivatives for selected organs.

[0087] Figure 22 : Obtained in tumor-bearing (PC3-PIP) mice [ 18 F]25 Activity / time curves for selected organs.

[0088] Figure 23 : Obtained in tumor-bearing (LnCAP) mice [ 18 F]25 and [ 18 F]30 refers to the accumulation of tumors in selected organs and tumors.

[0089] Figure 24 In tumor-bearing mice [ 211 Distribution of At]31 in vitro. Detailed Implementation

[0090] The PSMA-targeting urea-based ligand of the present invention is suitable for use as a radiopharmaceutical, either as an imaging agent (e.g., a diagnostic agent) or for the treatment of prostate cancer, and can also be used as a therapeutic agent. The PSMA-targeting urea-based ligand of the present invention utilizes a urea-binding motif (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid. This motif specifically interacts with the PSMA antigen-binding pocket.

[0091] The compounds disclosed in this invention have superior internalization compared to existing molecules (e.g., PSMA-617) while retaining the same affinity for the target.

[0092] The urea-based ligands targeting PSMA and their pharmaceutically acceptable salts of the present invention have the following general formula (I):

[0093]

[0094] In the formula:

[0095] A can be a carboxylic acid, sulfonic acid, phosphonic acid, tetrazolium, or isoxazole independently;

[0096] o is an integer selected from 1 to 4;

[0097] m is an integer selected from 0 to 10;

[0098] R1 is either -CH-CH2-Z or -CH-CH2-Y;

[0099] Z is selected from the following:

[0100]

[0101] Y is selected from the following:

[0102]

[0103] In the formula,

[0104] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0105] Q2 is O, S, or NH;

[0106] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0107] The condition is that when R2 = -CH-CH2-Y, then R1 must be -CH-CH2-Z;

[0108] R2 is either -CH-CH2-Y or -CH2-T-;

[0109] Wherein, T is an aromatic monocyclic or polycyclic system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

[0110] Y is selected from the following:

[0111]

[0112] In the formula,

[0113] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0114] Q2 is O, S, or NH;

[0115] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0116] The condition is that when R1 = -CH-CH2-Y, then R2 must be -CH2-T;

[0117] L represents the portion containing groups selected from the following:

[0118] -CO(CH2) n NH-, -CO(CH2CH2O) n NH-, -M-, -CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-, -MnCO(CH2CH2O) n NH-, -LysG-, -LysJ-, -LysGCO(CH2CH2O) n NH-, -LysJCO(CH2) n NH-, -LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O)n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJM n CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-, -CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l LysJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-,

[0119] Where n and l are integers independently selected from 0 to 10;

[0120] M is selected from one or more natural amino acids, one or more sugars, and combinations of one or more natural amino acids and one or more sugars;

[0121] Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains.

[0122] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0123] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0124] R4 is selected from the following pyridazines:

[0125]

[0126] R5 and R6 are identical or differ only in the isotopic mass number of the labeling agent, and are independently selected. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0127] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0128] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19F、 123 I、 124 I、 125 I、 127 I、 131 I、 211 Available、 15 O、 16 O、 17 O、 18 O、 43 Scr、 44 Scr、 45 Scr、 45 To, 46 To, 47 To, 48 To, 49 To, 50 To, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 My, 113 My, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 King、 186 King、 188 King、 201 Tl、 203 Tl、 205 Tl、206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 The、 139 The、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt;

[0129] E and D are independently selected from: -CH and -N-;

[0130] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0131] X is G or J.

[0132] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0133] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0134] R4 is selected from the following pyridazines:

[0135]

[0136] R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0137] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0138] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、45 Scr、 45 To, 46 To, 47 To, 48 To, 49 To, 50 To, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 My, 113 My, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 King、 186 King、 188 King、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213 Wind、 31 P、 32 P、 33 P、 32 S、 35 S、45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 The、 139 The、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt;

[0139] E:-CH-N-;

[0140] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0141] R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent;

[0142] Formula (I) contains at least one radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine, and astatine.

[0143] At least one of L and X contains J.

[0144] In a preferred embodiment, the PSMA-targeting urea ligand and its pharmaceutically acceptable salt of the present invention have the following general formula (I):

[0145]

[0146] In the formula:

[0147] A can be a carboxylic acid, sulfonic acid, phosphonic acid, tetrazolium, or isoxazole independently;

[0148] o is an integer selected from 1 to 4;

[0149] m is an integer selected from 0 to 10;

[0150] R1 is either -CH-CH2-Z or -CH-CH2-Y;

[0151] Z is selected from the following:

[0152]

[0153] Y is selected from the following:

[0154]

[0155] In the formula,

[0156] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0157] Q2 is O, S, or NH;

[0158] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0159] The condition is that when R2 = -CH-CH2-Y, then R1 must be -CH-CH2-Z;

[0160] R2 is either -CH-CH2-Y or -CH2-T-;

[0161] Wherein, T is an aromatic monocyclic or polycyclic system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

[0162] Y is selected from the following:

[0163]

[0164] In the formula,

[0165] Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl;

[0166] Q2 is O, S, or NH;

[0167] Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine.

[0168] The condition is that when R1 = -CH-CH2-Y, then R2 must be -CH2-T;

[0169] L represents the portion containing groups selected from the following:

[0170] -CO(CH2) n NH-, -CO(CH2CH2O) n NH-, -M-, -CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-, -MnCO(CH2CH2O) n NH-, -LysG-, -LysJ-, -LysGCO(CH2CH2O) n NH-, -LysJCO(CH2) n NH-, -LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O) n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJM n CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-, -CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHMl LysJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l LysJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-,

[0171] Where n and l are integers independently selected from 0 to 10;

[0172] M is a natural amino acid;

[0173] Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains.

[0174] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0175] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0176] R4 is selected from the following pyridazines:

[0177]

[0178] R5 and R6 are identical or differ only in the isotopic mass number of the labeling agent, and are independently selected. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b-WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0179] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0180] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr 52 Cr 53 Cr 54 Cr 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt;

[0181] E and D are independently selected from: -CH and -N-;

[0182] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u-OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0183] X is G or J.

[0184] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0185] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0186] R4 is selected from the following pyridazines:

[0187]

[0188] R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b-WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0189] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0190] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr 52 Cr 53 Cr 54 Cr 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt;

[0191] E and D are independently selected from: -CH and -N-;

[0192] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u-OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0193] R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent;

[0194] Formula (I) contains at least one radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine, and astatine.

[0195] At least one of L and X contains J.

[0196] Therefore, compounds of formula (I) always contain at least one pyridazine. The pyridazine is part of either the L or X moiety, or both the L and X moiety contain a pyridazine. The pyridazine is represented as R4 in formula (I) and is contained in J, where J is -CO(CH2). p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5. The pyridazine R4 may or may not be connected to a chelating agent.

[0197] As described above, formula (I) further comprises at least one radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine, and astatine. When pyridazine is included in J(i) or J(ii) (i.e., when pyridazine is not linked to a chelating agent), these radioactive isotopes may be located on pyridazine R4. These radioactive isotopes may also be located on R1 or R2, but not on both R1 and R2 simultaneously.

[0198] Radioactive isotopes of fluorine, iodine, bromine, and astatine include: 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 76 Br、 77 Br、 79 Br、 80m Br、 81 Br and 211 At.

[0199] In a preferred embodiment, the radionuclide is selected from... 18 F, 125 I, 123 I, 131 I, 124 I, 211 At、 77 Br and 80m Br.

[0200] In a preferred embodiment, at least one radionuclide contained in formula (I) is located on R7.

[0201] In a preferred embodiment, formula (I) includes at least one radionuclide. 18 F and located on R7.

[0202] In one embodiment, formula (I) includes a radioactive isotope located on R1, the radioactive isotope being selected from radioactive isotopes of fluorine, iodine, bromine, and astatine.

[0203] In another embodiment, formula (I) includes a radioactive isotope located on R2, the radioactive isotope being selected from radioactive isotopes of fluorine, iodine, bromine, and astatine.

[0204] In another embodiment, formula (I) includes a radioactive isotope located on R4, the radioactive isotope being selected from radioactive isotopes of fluorine, iodine, bromine, and astatine, wherein R4 is included in a portion L.

[0205] In another embodiment, formula (I) includes a radioactive isotope located on R4, the radioactive isotope being selected from radioactive isotopes of fluorine, iodine, bromine, and astatine, wherein R4 is included in part X.

[0206] In one embodiment, formula (I) comprises two radioactive isotopes located on R1 and R4, the radioactive isotopes being selected from radioactive isotopes of fluorine, iodine, bromine and astatine, wherein R4 is included in a portion of L.

[0207] In one embodiment, formula (I) comprises two radioactive isotopes located on R1 and R4, the radioactive isotopes being selected from radioactive isotopes of fluorine, iodine, bromine and astatine, wherein R4 is included in part X.

[0208] In one embodiment, formula (I) comprises two radioactive isotopes located on R2 and R4, the radioactive isotopes being selected from radioactive isotopes of fluorine, iodine, bromine and astatine, wherein R4 is included in part L.

[0209] In one embodiment, formula (I) comprises two radioactive isotopes located on R2 and R4, the radioactive isotopes being selected from radioactive isotopes of fluorine, iodine, bromine and astatine, wherein R4 is included in part X.

[0210] In a preferred embodiment, formula (I) includes a radioactive isotope located on R4, the radioactive isotope being selected from radioactive isotopes of fluorine, iodine, bromine, and astatine, wherein R4 is contained in a portion of X or a portion of L.

[0211] In another preferred embodiment, formula (I) comprises two radioactive isotopes located on R4, the radioactive isotopes being selected from radioactive isotopes of fluorine, iodine, bromine and astatine, wherein R4 is contained in portions L and X.

[0212] In a preferred embodiment, the portion L in formula (I) is selected from the following:

[0213] -CO(CH2) n NH-、-CO(CH2CH2O) n NH-、-M-、-CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-、-MnCO(CH2CH2O) n NH-、-LysG-、-LysJ-、-LysGCO(CH2CH2O) n NH-、-LysJCO(CH2) n NH-、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O) n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJM n CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-、-CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l CourtJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM lLysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l LysJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-;

[0214] Where n and l are integers independently selected from 0 to 10;

[0215] M is selected from one or more natural amino acids, one or more sugars, and combinations of one or more natural amino acids and one or more sugars;

[0216] Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains.

[0217] G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative.

[0218] J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5.

[0219] R4 is selected from the following pyridazines:

[0220]

[0221] R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotopic labeling agent of the aromatic ring, or (ii) connected to the isotopic labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O)h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25;

[0222] When R7 is (i) or (ii), the isotope labeling agent is selected from the following:

[0223] 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、71 Though, 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 THE, 89 THE, 90 THE, 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 See, 113 See, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re, 186 Re, 188 Re, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213 Wind、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Scr、 47 Scr、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Of, 158 Of, 160 Of, 161 Of, 162 Of, 163 Of, 164 Of, 165 Of, 227 Th、 232 Th、51 Cr 52 Cr 53 Cr 54 Cr 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt;

[0224] E and D are independently selected from: -CH and -N-;

[0225] R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u-OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino;

[0226] R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent.

[0227] Formula (I) includes a portion M, which is one or more naturally occurring amino acids, one or more sugars, or a combination of one or more naturally occurring amino acids and one or more sugars. Twenty amino acids are naturally occurring in humans. Except for glycine, all of these amino acids are chiral amino acids, and these chiral amino acids generally have an L-configuration. However, the D-configuration is sometimes also present in humans, particularly in association with certain diseases; therefore, the D-configuration of an amino acid is also included in the term "natural amino acid" referring to the portion M of Formula (I).

[0228] Compounds according to formula (I) may contain one or two chelating agents and may not contain any.

[0229] When both L and X contain J(i) or J(ii), the compound according to formula (I) does not contain a chelating agent.

[0230] Therefore, when L is a portion containing J, formula (I) does not contain a chelating agent, wherein J is (i) an isotopic labeling agent directly attached to the aromatic ring, or (ii) an isotopic labeling agent attached to the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, and the isotopic labeling agent is selected from the following: 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、80m Br、 81 Br、 72 As、 75 As、 86 THE, 89 THE, 90 THE, 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 See, 113 See, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re, 186 Re, 188 Re, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213 Wind、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Scr、 47 Scr、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Of, 158 Of, 160 Of, 161 Of, 162 Of, 163 Of, 164 Of, 165 Of, 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt; where X is a portion containing J, wherein J is (i) an isotopic labeling agent directly connected to the aromatic ring, or (ii) an isotopic labeling agent connected to the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, and the isotopic labeling agent is selected from the following: 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I,127 I、 131 I、 211 Available、 15 O、 16 O、 17 O、 18 O、 43 Scr、 44 Scr、 45 Scr、 45 To, 46 To, 47 To, 48 To, 49 To, 50 To, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 My, 113 My, 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 King、 186 King、 188 King、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 The、 139 The、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196Pt, 198 Pt.

[0231] When L is the portion containing chelating agent G and X is the portion containing J(i) or J(ii), the compound according to formula (I) contains only one chelating agent. Furthermore, when X is the portion containing G and L is the portion containing J(i) or J(ii), the compound according to formula (I) contains only one chelating agent.

[0232] Therefore, in one embodiment, L is the portion containing chelating agent G, and X is the portion containing J, wherein J is (i) an isotope labeling agent directly connected to the aromatic ring, or (ii) an isotope labeling agent connected to the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, and the isotopic labeling agent is selected from the following: 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr 52 Cr 53 Cr 54 Cr 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt.

[0233] In one embodiment, X is the portion containing chelating agent G, and L is the portion containing J, wherein J is (i) an isotope labeling agent directly attached to the aromatic ring, or (ii) an isotope labeling agent attached to the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) hb and h are independent integers selected from 1 to 25, and the isotopic labeling agent is selected from the following: 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 13 N、 14 N、 15 N、 18 F, 19 F, 123 I, 124 I, 125 I, 127 I, 131 I, 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb, 152 Tb, 159 Tb,161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt.

[0234] When L is the portion containing chelating agent G and X is the portion containing J(iii), the compound according to formula (I) contains two chelating agents. Furthermore, when X is the portion containing G and L is the portion containing J(iii), the compound according to formula (I) contains two chelating agents.

[0235] Therefore, in one embodiment, L is the portion containing chelating agent G, and X is the portion containing J, wherein J is (iii) an isotopic labeling agent chelated by a chelating agent connected to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are integers independently selected from 1 to 25.

[0236] In one embodiment, X is the portion containing chelating agent G, and L is the portion containing J, wherein J is (iii) an isotopic labeling agent chelated by the chelating agent, the chelating agent being linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O)q r and q are integers independently selected from 1 to 25.

[0237] In one embodiment, L is a portion containing J, where J is (iii) an isotopic labeling agent chelated by a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25; X is a portion containing J, where J is (iii) an isotopic labeling agent chelated by a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are integers independently selected from 1 to 25.

[0238] In those embodiments of formula (I) that include two chelating agents, the chelating agents may be the same or different.

[0239] Regardless of whether formula (I) contains one or two chelating agents, the following chelating agents are preferred and can be selected independently:

[0240] 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-Tetraacetic acid (DOTA)

[0241] N,N'-Bis(2-hydroxy-5-(carboxyethyl)benzyl)ethylenediamine-N,N'-diacetic acid (HBED-CC)

[0242] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0243] 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)glutaric acid (NODAGA)

[0244] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA)

[0245] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0246] 1,4,7-Triazacyclononane-1-methyl(2-carboxyethyl)phosphonic acid-4,7-bis(methyl(2-hydroxymethyl)phosphonic acid (NOPO),

[0247] 3,6,9,15-Tetraazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA)

[0248] N'-(5-acetylhydroxyoximepentyl)-N-(5-(4-(5-aminopentyl)(hydroxy)amino-4-oxobutyryl)amino)pentyl-N-hydroxysuccinamide (DFO)

[0249] Diethylenetriaminepentaacetic acid (DTPA)

[0250] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0251] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (OXO-Do3A)

[0252] p-Benzyl-DTPA isothiocyanate (SCN-BZ-DTPA)

[0253] 1-(benzyl p-isothiocyanate)-3-methyl-DTPA (1B3M)

[0254] 2-(benzyl p-isothiocyanate)-4-methyl-DTPA (1M3B)

[0255] 1-(2)-Methyl-4-benzyl-DTPA (MX-DTPA), wherein the chelating agent may contain a metal; and

[0256] Their pharmaceutically acceptable salts.

[0257] The purpose of including more than one chelating agent in formula (I) is to optimize the polarity of formula (I) or for the technical features provided by the metal bound by the chelating agent.

[0258] Therefore, in some embodiments, one or more chelating agents do not contain any metal.

[0259] In other embodiments, one or more chelating agents comprise a metal. If two metal-containing chelating agents are present in formula (I), the metal contained in these chelating agents may be the same metal, or the metals may be selected independently.

[0260] In a preferred embodiment, the chelating agent comprises a metal selected from the following: 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb, 152 Tb, 159 Tb, 161 Tb, 111 In、 113 In、 114 mIn, 115 mIn, 175 Lu、 177 Lu、 185 Re、 186 Re、 188 Re、 201 Tl、 203 Tl、 205 Tl、 206 Pb, 207 Pb, 208 Pb, 212 Pb, 209 Bi、 212 Bi、 213 Bi、 45 Sc、 47 Sc、 227 Th、 232 Th、 94 Tc, 99m Tc, 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 193 mPt, 195 mPt, 192 Pt, 194 Pt, 195 Pt, 196 Pt, 198 Pt, 225 Ac.

[0261] These metals are known to be chelateable, and their use in treatment, imaging, and / or diagnosis is widely known.

[0262] The radionuclide (Hal) is located on either the R1 group or the R2 group in formula (I). The radionuclide is selected from the halogen family. This family includes radionuclides of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At).

[0263] In a preferred embodiment, the ligand targeting PSMA according to formula (I) is one of the following compounds:

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] In the formula, F is 18 F or 19 F;

[0303] I am 125 I, 123 I, 127 I, 131 I or 124 I;

[0304] Hal is 18 F, 19 F, 18 F, 125 I, 123 I,127 I, 131 I, 124 I, 211 At、 77 Br、 79 Br or 80m Br.

[0305] The ligands targeting PSMA according to formula (I) can be prepared by suitable methods known in the art.

[0306] In one embodiment, the halogenated radionuclide is selected from radioactive isotopes of fluorine, iodine, bromine, or astatine.

[0307] In a preferred embodiment, the halogenated radionuclide is one of the following radionuclides: 18 F, 19 F, 18 F, 125 I, 123 I, 127 I, 131 I, 124 I, 211 At、 77 Br、 79 Br or 80m Brr.

[0308] The present invention also provides (Me)3Sn, (Me)3Si, B(OH)2 and B(OR9)2 precursors, which can be used to provide ligands for targeting PSMA according to formula (I).

[0309] These precursors include (Me)3Sn, (Me)3Si, B(OH)2, and B(OR9)2 with and without chelating agents, and have the following structures:

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] Wherein, R9 is -Si(CH3)3, -Si(CH2CH2CH2CH3)3, -Sn(CH3)3, -Sn(CH2CH2CH2CH3)3, -B(OH)2 or .

[0326] The PSMA-targeting ligands of Formula (I) can be used for radiotherapy, as imaging agents (e.g., diagnostic agents), or both, i.e., as therapeutic agents.

[0327] Tests showed that the internalization of PSMA-targeting ligands using formula (I) was superior to existing alpha-radionium-based probes.

[0328] Formula (I) can be suitably included in pharmaceutical formulations, such as liquid pharmaceutical formulations for injection. Therefore, in one aspect, the present invention relates to a pharmaceutical formulation comprising a ureidyl ligand targeting PSMA according to Formula (I).

[0329] The PSMA-targeting urea ligand of formula (I) is suitable for use as a drug. Therefore, in one aspect, the present invention relates to the use of the PSMA-targeting urea ligand of formula (I) as a drug.

[0330] The specific use of Formula (I) as a drug depends on a specific radioisotope and optionally on a chelating metal. The potential uses of the various isotopes and optional metals that can be included in Formula (I) in therapeutic, diagnostic, imaging, and therapeutic applications are well known, and depend on the radiation provided by the specific isotope and metal. Therefore, urea-based ligands targeting PSMA according to Formula (I) can be modified to suit a chosen specific use based on the selection of the radioisotope and optionally the chelating metal.

[0331] In particular, the PSMA-targeting urea ligand according to formula (I) is suitable for treating prostate cancer and other PSMA-expressing cancers or metastases. Therefore, in one aspect, the present invention relates to PSMA-targeting urea ligands according to formula (I) for use with isotopes (e.g., 177 Lu、 225Ac、 211 At、 131 I and 212 Pb is used to treat prostate cancer or other cancers or metastases that express PSMA.

[0332] Since PSMA is not only associated with prostate cancer, the PSMA-targeting urea ligand of formula (I) is itself suitable for use as a radiopharmaceutical. Therefore, in one aspect, the present invention relates to the PSMA-targeting urea ligand of formula (I) for use with isotopes (e.g., 177 Lu、 225 Ac、 211 At、 131 I, 212 Pb, 67 Cu is used as a radiopharmaceutical.

[0333] Furthermore, the urea-based ligand for PSMA targeting according to formula (I) is suitable for use as an imaging agent. Therefore, in one aspect, the present invention relates to the urea-based ligand for PSMA targeting according to formula (I) for use with isotopes (e.g., 18 F, 68 Ga、 64 Cu、 203 The use of Pb as an imaging agent.

[0334] Furthermore, the urea-based ligands targeting PSMA according to formula (I) are suitable for use as therapeutic agents (i.e., agents that are both therapeutic and diagnostic). This could be, for example, when the chelating agent contains a metal suitable for imaging, and R4 and / or R1 or R2 contains a radionuclide suitable for therapeutic use. Alternatively, when the chelating agent contains a metal suitable for therapeutic use, and R4 and / or R1 or R2 contains a radionuclide suitable for imaging. Therefore, in one aspect, the present invention relates to urea-based ligands targeting PSMA according to formula (I) for use with, for example, therapeutic agents. 8 F / 211 At、 123 I / 131 I, 64 / Cu / 67 Cu、 68 Ga / 177 Lu 68 Ga / 225 Ac、 203 Pb / 212 Use of Pb as a diagnostic and therapeutic agent. Example

[0335] Example 1: Synthesis of a universal reagent

[0336] 3-(4-(2-fluoroethoxy)phenyl)-1,2,4,5-tetraazine (Compound 1)

[0337]

[0338] The compound was synthesized according to the method previously described in the literature, yielding 0.36 g (37%) of the target compound as a red oil. R f = 0.33 (heptane / EtOAc 80 / 20); 1 H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H),8.53 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 4.89 - 4.78 (m, 1H), 4.74 -4.62 (m, 1H), 4.43 - 4.29 (m, 1H), 4.27 - 4.16 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 166.06, 162.56, 157.40, 130.26, 124.56, 115.38, 81.63 (d, J = 171.5Hz), 67.29 (d, J = 20.6 Hz).

[0339] 2-(4-(1,2,4,5-tetraazine-3-yl)phenoxy)ethyl 4-nitrobenzenesulfonate (compound 2)

[0340]

[0341] The compound was synthesized according to the method described in the literature, yielding 0.12 g (65%) of the target product as a red solid. R f = 0.41 (heptane / EtOAc 50 / 50); 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.97 -8.31 (m, 5H), 8.33 - 7.87 (m, 2H), 7.11 (d, J = 8.9 Hz, 2H), 4.97 - 4.50 (m,2H), 4.48 - 4.06 (m, 2H); 13 C NMR (101 MHz, DMSO) δ 165.57, 161.88, 158.28, 154.85, 147.71, 130.25, 127.38, 125.26, 123.79, 116.05, 75.01, 67.33.

[0342] 3-(4-Iodophenyl)-1,2,4,5-Tetraazine (Compound 3)

[0343]

[0344] The compound was synthesized according to the method previously described in the literature. 4-Iodobenzonitrile (0.92 g, 4.0 mmol), CH₂Cl₂ (0.26 mL, 4.0 mmol), sulfur (0.26 g, 1.0 mmol), and ethanol (4.0 mL) were mixed together in a microwave-safe reaction flask. Hydrazine hydrate (1.55 mL, 32.00 mmol) was added dropwise with stirring. The container was sealed, and the reaction mixture was heated to 50 °C and maintained for 24 hours. The reaction was diluted with 3 mL of CH₂Cl₂, and sodium nitrite (2.76 g, 40.00 mmol) dissolved in 30 mL of H₂O was added dropwise to the mixture while cooling. Then, excess acetic acid (14 mL) was slowly added, during which time the solution turned bright red. The reaction mixture was extracted with CH₂Cl₂ (3 × 30 mL). The organic phase was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by rapid chromatography (n-heptane / EtOAc 95 / 5) to give 0.36 g (29%) of the target compound (a mixture of rotational isomers) as a red oil. The crude product was purified by rapid chromatography (n-heptane / EtOAc 90 / 10) to give 0.30 mg (27%) of a pink solid. Rf = 0.37 (n-heptane: 10% EtOAC); 1 H NMR (400 MHz, chloroform-) d )δ 10.24 (s, 1H), 8.39 - 8.32 (m, 2H), 8.02 - 7.95 (m, 2H).; 13 C NMR (101 MHz, CDCl3) δ 166.36, 158.10, 138.90, 131.24, 129.75, 101.22.

[0345] 3-(4-Trimethyltin)-6-methyl-1,2,4,5-Tetraazine (Compound 4)

[0346]

[0347] The compound was synthesized according to the previously described method. Pd(PPh3)4 (19.4 mg, 10%) and hexamethyldistin (87 µL, 0.42 mmol, 2.5 equivalence) were added sequentially to a microwave-safe vial equipped with a stir bar. The vial was then sealed and purged with N2. Compound 3 (0.05 g, 0.17 mmol) dissolved in dry THF (2.5 mL) was added via syringe, and the reaction was stirred in the microwave at 65 °C for 2 h. The reaction was allowed to cool to room temperature, the seal was opened, and the reaction was quenched with a saturated aqueous solution of KF (1 mL). The solution was extracted with CH2Cl2, washed with brine (2 × 5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The tetraazine was then purified by rapid chromatography (90 / 10 n-heptane / EtOAc) to give 0.27 g (61%) of pink solid. Rf = 0.43 (n-heptane: 20% EtOAc). 1 H NMR (400 MHz, chloroform-) d ) δ 10.20 (s, 1H), 8.58 - 8.54 (m, 2H), 7.84 -7.67 (m, 2H), 0.37 (s, 9H).; 13 C NMR (101 MHz, chloroform-) d ) δ 167.00, 157.96,150.34, 136.90, 130.29, 127.35, -9.33.; HPLC-MS [M+H] + m / z calculation [C 11 H 15 SnN4] + 323.04; Actual measurement: 323.38.

[0348] 2,5-Dioxopyrrolidine-1-yl(E)-2-(1,3-dioxo-1,3,6,7,10,11-hexahydro-2H-cyclooctyl[b]) Synthesis of pyrrolo[3,4-g]quinoxalo-2-yl)acetate (compound 5)

[0349]

[0350] The compound was synthesized according to the previously reported method, yielding 0.056 g (72%) of the target compound as a yellow solid (PCT / EP2023 / 055930). f =0.41 (n-heptane / EtOAc 50 / 50); 1 H NMR (400 MHz, CDCl3) δ 8.56- 8.47 (m, 2H), 6.10 (td, J= 12.1, 5.9 Hz, 1H), 5.25 - 5.07 (m, 1H), 4.87 (s,2H), 3.40 - 3.30 (m, 2H), 3.30 - 3.21 (m, 1H), 3.15 - 3.04 (m, 1H), 2.92 -2.68 (m, 6H), 2.45 (q, J = 11.9 Hz, 1H), 2.33 (dt, J = 12.1, 6.1 Hz, 1H); 13 C NMR(101 MHz, CDCl3) δ 168.16, 165.58, 163.15, 161.67, 161.31, 143.40, 143.24,136.54, 132.67, 130.16, 130.00, 126.26, 126.07, 46.74, 41.81, 37.05, 34.19,28.26, 25.55.

[0351] Example 2: PSMA-NH-T4CO (compound 15, Figure 1 Synthesis of )

[0352] Figure 1 A schematic diagram of the synthetic route for compound 16 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-ix): i) 2CT-resin, DIPEA, CH2Cl2, room temperature, 12 hours; ii) triphosgene, DIPEA, CH2Cl2, 0 °C, 20 minutes; iii) DCM, 0 °C to room temperature, 12 hours; iv) Pd(PPh3)4, morpholine, CH2Cl2, room temperature, 4 hours; v) a) Fmoc-L-NaI-OH, HATU, DIPEA, DMF, room temperature, 2 hours; b) 50% piperidine in DMF, room temperature, 20 minutes; vi) N-Fmoc-tranexamic acid, HATU, DIPEA, DMF, room temperature, 2 hours; b) 50% piperidine in DMF, room temperature, 20 minutes; vii) trifluoroacetic acid, TIPS, H2O, room temperature, 2 hours; viii) compound 5,4-methylmorpholine, DMF, room temperature, 6 hours; ix) Compound 1, ACN, H2O, TFA, room temperature, 5 hours.

[0353] PSMA-NH 2 Synthesis of (Compound 14, Scheme 1)

[0354]

[0355] The resin-bonded and tert-butyl-protected binding motif (11) is synthesized according to the previously described method. 5 4 equivalents of Fmoc-L-2-Nal-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin (0.22 mmol). After 2 minutes, the solution was added to the resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product (12) was reacted with 4 equivalents of trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (N-Fmoc-tranexamic acid), wherein the N-Fmoc-tranexamic acid was activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA. The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give compound 13. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.110 g of target compound 14. 1 H NMR (600 MHz, DMSO) δ 12.74 - 12.36 (m, 2H), 12.14 (s, 1H), 7.98 - 7.93 (m, 2H), 7.86 (dd, J = 7.7, 1.6 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.69(d, J = 1.7 Hz, 1H), 7.60 (s, 3H), 7.49 - 7.43 (m, 2H), 7.40 (dd, J = 8.4, 1.7Hz, 1H), 6.34 - 6.25 (m, 2H), 4.55 (td, J = 9.0, 5.1 Hz, 1H), 4.11 (td, J = 8.3, 5.2 Hz, 1H), 4.03 (td, J = 8.2, 5.2 Hz, 1H), 3.12 (dd, J = 13.7, 5.0 Hz, 1H), 3.06 (dq, J = 13.0, 6.6 Hz, 1H), 2.99 (dq, J = 13.0, 6.7 Hz, 1H), 2.93 (dd, J=13.7, 9.5 Hz, 1H), 2.66 - 2.59 (m, 3H), 2.31 - 2.18 (m, 2H), 2.09 (ddt, J =12.0, 7.5, 3.6 Hz, 1H), 1.93 (dddd, J = 14.1, 9.3, 6.7, 5.2 Hz, 1H), 1.77 -1.56 (m, 5H), 1.55 - 1.19 (m, 9H), 1.05 (qd, J = 13.0, 3.5 Hz, 1H), 0.93 - 0.81(m, 2H); ESI-MS [M+H] + = 656.3.

[0356] PSMA-NH-T4CO (compound 15, Figure 1 Synthesis of )

[0357]

[0358] Under argon atmosphere, 4-methylmorpholine (0.03 mL, 0.27 mmol) was added to an anhydrous DMF (3 mL) solution of compound 14 (0.03 g, 0.046 mmol) and compound 5 (0.02 g, 0.046 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.03 g (64% yield) of the target compound as a white solid. ESI-MS [M+H] + = 976.4.

[0359] Example 3: PSMA-NH-T4CO-FTz (compound 16, Figure 1 Synthesis of )

[0360]

[0361] Compound 1 (0.001 g, 0.0051 mmol) was added to a solution of compound 15 (0.005 g, 0.0051 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.003 g (50%) of the target compound as a white solid. ESI-MS [M+H] + = 1165.3.

[0362] Example 4: PSMA-AA-NH-T4CO (compound 20, Figure 2 Synthesis of )

[0363] Figure 2 A schematic diagram of the synthetic route for compound 21 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-v): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1, ACN, H2O, TFA, room temperature, 5 h.

[0364] PSMA-AA-NH 2 (Compound 19, Figure 2 Synthesis of )

[0365]

[0366] Four equivalents of Fmoc-D-Glu-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 13 (0.22 mmol). After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product (17) was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give compound 18. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.09 g of target compound 19. ESI-MS [M+H] + = 941.3.

[0367] PSMA-AA-NH-T4CO (compound 20, Figure 2 Synthesis of )

[0368]

[0369] Under argon atmosphere, 4-methylmorpholine (0.03 mL, 0.27 mmol) was added to an anhydrous DMF (3 mL) solution of compound 19 (0.035 g, 0.030 mmol) and compound 5 (0.013 g, 0.030 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.011 g (28%) of the target compound as a white solid. ESI-MS [M+H] + = 1261.1.

[0370] Example 5: PSMA-NH-AA-T4CO-FTz (21, Figure 2 Synthesis of )

[0371]

[0372] Compound 1 (0.0008 g, 0.0036 mmol) was added to a solution of compound 20 (0.005 g, 0.0036 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (38%) of the target compound as a white solid. ESI-MS [M+H] + = 1450.6.

[0373] Example 6: PSMA-AAAA-NH-T4CO (compound 24, Figure 3 Synthesis of )

[0374] Figure 3 A schematic diagram of the synthetic routes for compounds 25 and 26 is shown. Gray dots in the intermediate structures represent resins. In compound 25, R = OCH2CH2F. In compound 26, R = I. The following reagents and conditions were used in steps i)-v): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1 or Compound 3, ACN, H2O, TFA, room temperature, 5 h.

[0375] PSMA-AAAA-NH 2 (Compound 23, Figure 3 Synthesis of )

[0376]

[0377] 4 equivalents of Fmoc-D-Glu-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 18 (0.22 mmol). After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). Deprotection of the Fmoc group with a mixture of DMF and piperidine (1:1) yielded compound 22. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.07 g of target compound 23. ESI-MS [M+H] + = 1226.8.

[0378] PSMA-AAAA-NH-T4CO (compound 24, Figure 3 Synthesis of )

[0379]

[0380] Under argon atmosphere, 4-methylmorpholine (0.016 mL, 0.15 mmol) was added to an anhydrous DMF (3 mL) solution of compound 23 (0.026 g, 0.016 mmol) and compound 5 (0.007 g, 0.016 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.015 g (51%) of the target compound as a white solid. ESI-MS [M+H] + = 1546.3.

[0381] Example 7: PSMA-NH-AAAA-T4CO-FTz (compound 25, Figure 3 Synthesis of )

[0382]

[0383] Compound 1 (0.0005 g, 0.0023 mmol) was added to a solution of compound 24 (0.00 g, 0.0023 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (45%) of the target compound as a white solid. ESI-MS [M+H] + = 1736.6.

[0384] Example 8: PSMA-NH-AAAA-T4CO-ITz (compound 26, Figure 3 Synthesis of )

[0385]

[0386] Compound 3 (0.0005 g, 0.0023 mmol) was added to a solution of compound 24 (0.004 g, 0.0023 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (44%) of the target compound as a white solid. ESI-MS [M+H] + = 1799.6.

[0387] Example 9: PSMA-AAAAAA-NH-T4CO (compound 29, Figure 4 Synthesis of )

[0388] Figure 4 A schematic diagram of the synthetic routes for compounds 30 and 31 is shown. The gray dots in the intermediate structures represent resins. In compound 30, R = OCH2CH2F. In compound 31, R = I. The following reagents and conditions were used in steps i)-v): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1 or Compound 3, ACN, H2O, TFA, room temperature, 5 h.

[0389] PSMA-AAAAAA-NH 2 (Compound 28, Figure 4 Synthesis of )

[0390]

[0391] Four equivalents of Fmoc-D-Glu-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 22 (0.22 mmol). After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). Deprotection of the Fmoc group with a mixture of DMF and piperidine (1:1) yielded compound 27. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.11 g of target compound 28. ESI-MS [M+H] + = 1226.8.

[0392] PSMA-AAAAAA-NH-T4CO (compound 29, Figure 4 Synthesis of )

[0393]

[0394] Under argon atmosphere, 4-methylmorpholine (0.074 mL, 0.67 mmol) was added to an anhydrous DMF (6 mL) solution of compound 28 (0.11 g, 0.056 mmol) and compound 5 (0.024 g, 0.056 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.040 g (33%) of the target compound as a white solid. ESI-MS [M+H] + = 1831.7.

[0395] Example 10: PSMA-NH-AAAAAA-T4CO-FTz (compound 30, Figure 4 Synthesis of )

[0396]

[0397] Compound 1 (0.0005 g, 0.0023 mmol) was added to a solution of compound 29 (0.005 g, 0.0023 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.004 g (73%) of the target compound as a white solid. ESI-MS [M+H] + = 1010.9.

[0398] Example 11: PSMA-NH-AAAAAA-T4CO-ITz (compound 31, Figure 4 Synthesis of )

[0399]

[0400] Compound 3 (0.001 g, 0.0046 mmol) was added to a solution of compound 29 (0.01 g, 0.0046 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.006 g (54%) of the target compound as a white solid. ESI-MS [M+2H] + = 1042.9.

[0401] Example 12: PSMA-AAAAAAAAA-NH-T4CO (compound 34, Figure 5 Synthesis of )

[0402] Figure 5 A schematic diagram of the synthetic routes for compounds 35 and 36 is shown. The gray dots in the intermediate structures represent resins. In compound 35, R = OCH2CH2F. In compound 36, R = I. The following reagents and conditions were used in steps i)-iv): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1 or Compound 3, ACN, H2O, TFA, room temperature, 5 h.

[0403] PSMA-AAAAAAAAA-NH 2(Compound 33, Figure 5 Synthesis of )

[0404]

[0405] 4 equivalents of Fmoc-D-Glu-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 27 (0.21 mmol). After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The resulting product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). Deprotection of the Fmoc group with a mixture of DMF and piperidine (1:1) gave compound 32. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.12 g of target compound 33. ESI-MS [M+H] + = 1796.9.

[0406] PSMA-AAAAAAAAA-NH-T4CO (compound 34, Figure 5 Synthesis of )

[0407]

[0408] Under argon atmosphere, 4-methylmorpholine (0.076 mL, 0.69 mmol) was added to an anhydrous DMF (6 mL) solution of compound 33 (0.11 g, 0.046 mmol) and compound 5 (0.021 g, 0.046 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.025 g (21%) of the target compound as a white solid. ESI-MS [M+2H] + = 1058.9.

[0409] Example 13: PSMA-NH-AAAAAAAAA-T4CO-FTz (compound 35, Figure 5 Synthesis of )

[0410]

[0411] Compound 1 (0.0005 g, 0.002 mmol) was added to a solution of compound 34 (0.005 g, 0.002 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.004 g (73%) of the target compound as a white solid. ESI-MS [M+2H] + = 1153.9.

[0412] Example 14: PSMA-NH-AAAAAAAAA-T4CO-ITz (compound 36, Figure 5 Synthesis of )

[0413]

[0414] Compound 3 (0.001 g, 0.0046 mmol) was added to a solution of compound 34 (0.01 g, 0.0046 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.006 g (54%) of the target compound as a white solid. ESI-MS [M+2H] + = 1186.2.

[0415] Example 15: PSMA-3Arg-NH-T4CO (compound 39, Figure 6 Synthesis of )

[0416] Figure 6 A schematic diagram of the synthetic routes for compounds 40 and 41 is shown. The gray dots in the intermediate structures represent resins. In compound 40, R = OCH2CH2F. In compound 41, R = I. The following reagents and conditions were used in steps i)-iv): i) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) TFA, TIPS, H2O, room temperature, 2 h; iii) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; iv) Compound 1 or Compound 3, ACN, H2O, TFA, room temperature, 5 h.

[0417] PSMA-3Arg-NH 2 (Compound 38, Figure 6 Synthesis of )

[0418]

[0419] Four equivalents of Fmoc-D-Arg(Pbf)-OH were activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA relative to the resin and compound 13 (0.22 mmol). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give the deprotected intermediate. This process was repeated three times to give compound 37. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.12 g of target compound 38. ESI-MS [M+H] + = 1125.0.

[0420] PSMA-3Arg-NH-T4CO (compound 39, Figure 6 Synthesis of )

[0421]

[0422] Under argon atmosphere, 4-methylmorpholine (0.044 mL, 0.40 mmol) was added to an anhydrous DMF (5 mL) solution of compound 38 (0.07 g, 0.044 mmol) and compound 5 (0.019 g, 0.044 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.042 g (53%) of the target compound as a white solid. ESI-MS [M+H] + = 1444.6.

[0423] Example 16: PSMA-3Arg-NH-T4CO-FTz (compound 40, Figure 6 Synthesis of )

[0424]

[0425] Compound 1 (0.0005 g, 0.0023 mmol) was added to a solution of compound 39 (0.02 g, 0.0011 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.0015 g (67%) of the target compound as a white solid. ESI-MS [M+2H] + = 817.4.

[0426] Example 17: PSMA-3Arg-NH-T4CO-ITz (compound 41, Figure 6 Synthesis of )

[0427]

[0428] Compound 3 (0.0024 g, 0.0084 mmol) was added to a solution of compound 39 (0.015 g, 0.0084 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.006 g (42%) of the target compound as a white solid. ESI-MS [M+2H] + = 849.4.

[0429] Example 18: PSMA-3AGlu-NH-T4CO (Compound 44, Figure 7 Synthesis of )

[0430] Figure 7 A schematic diagram of the synthetic route for compound 45 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-iv): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) TFA, TIPS, H2O, room temperature, 2 h; iii) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; iv) Compound 1, ACN, H2O, TFA, room temperature, 5 h.

[0431] PSMA-3AGlu-NH 2 (Compound 43, Figure 7 Synthesis of )

[0432]

[0433] Four equivalents of Fmoc-D-Glu-OH were activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA relative to the resin and compound 13 (0.32 mmol). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give the deprotected intermediate. This process was repeated three times to give compound 42. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.11 g of target compound 43. ESI-MS [M+H] + = 1043.4.

[0434] PSMA-3 glu-NH-T4CO (compound 44, Figure 7 Synthesis of )

[0435]

[0436] Under argon atmosphere, 4-methylmorpholine (0.051 mL, 0.46 mmol) was added to an anhydrous DMF (5 mL) solution of compound 43 (0.054 g, 0.046 mmol) and compound 5 (0.020 g, 0.046 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.024 g (38%) of the target compound as a white solid. ESI-MS [MH] - = 1361.4.

[0437] Example 19: PSMA-3 glu-NH-T4CO-FTz (compound 45, Figure 7 Synthesis of )

[0438]

[0439] Compound 1 (0.0008 g, 0.0037 mmol) was added to a solution of compound 44 (0.005 g, 0.0037 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.004 g (70%) of the target compound as a white solid. ESI-MS [M+2H] + = 817.4.

[0440] Example 20: PSMA-Lys-DOTA-NH-T4CO (Compound 48, Figure 8 Synthesis of )

[0441] Figure 8 A schematic diagram of the synthetic routes for compounds 49 and 50 is shown. The gray dots in the intermediate structures represent resins. In compound 49, R = OCH2CH2F. In compound 50, R = I. The following reagents and conditions were used in steps i)-iv): i) a) Fmoc-tBuDOTA-L-Lys-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) TFA, TIPS, H2O, room temperature, 2 h; iii) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; iv) Compound 1 or Compound 3, ACN, H2O, TFA, room temperature, 5 h.

[0442]

[0443] 1.4 equivalents of Fmoc-tBuDOTA-L-Lys-OH were activated with 1.2 equivalents of HATU and 4.2 equivalents of DIPEA relative to the resin and compound 13 (0.32 mmol). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give the deprotected intermediate 46. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.04 g of target compound 47. ESI-MS [M+H] + =1170.5.

[0444] PSMA-Lys-DOTA-NH-T4CO (compound 48, Figure 8 Synthesis of )

[0445]

[0446] Under argon atmosphere, 4-methylmorpholine (0.041 mL, 0.37 mmol) was added to an anhydrous DMF (5 mL) solution of compound 47 (0.04 g, 0.034 mmol) and compound 5 (0.015 g, 0.034 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.025 g (49% yield) of the target compound as a white solid. ESI-MS [MH] - =1490.7.

[0447] Example 21: PSMA-Lys-DOTA-NH-T4CO-FTz (compound 49, Figure 8 Synthesis of )

[0448]

[0449] Compound 1 (0.0005 g, 0.002 mmol) was added to a solution of compound 48 (0.003 g, 0.002 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (59%) of the target compound as a white solid. ESI-MS [M+H] + = 1680.7.

[0450] Example 22: PSMA-Lys-DOTA-NH-T4CO-ITz (Compound 50, Figure 8Synthesis of )

[0451]

[0452] Compound 3 (0.0009 g, 0.003 mmol) was added to a solution of compound 48 (0.005 g, 0.003 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (59%) of the target compound as a white solid. ESI-MS [M+H] + = 1774.5.

[0453] Example 23: PSMA-Lys-DOTA-AA-NH-T4CO (Compound 52, Figure 9 Synthesis of )

[0454] Figure 9 A schematic diagram of the synthetic route for compound 54 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-v): i) a) Fmoc-D-Glu-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1, ACN, H2O, TFA, room temperature, 5 h.

[0455] PSMA-Lys-DOTA-AA-NH2 (compound 52, Figure 9 Synthesis of )

[0456]

[0457] Four equivalents of Fmoc-D-Glu-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 46 (0.16 mmol). After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The resulting product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). Deprotection of the Fmoc group with a mixture of DMF and piperidine (1:1) gave compound 51. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.03 g of target compound 52. ESI-MS [M+H] + = 1455.6.

[0458] PSMA-Lys-DOTA-AA-NH-T4CO (compound 53, Figure 9 Synthesis of )

[0459]

[0460] Under argon atmosphere, 4-methylmorpholine (0.027 mL, 0.25 mmol) was added to an anhydrous DMF (5 mL) solution of compound 52 (0.035 g, 0.021 mmol) and compound 5 (0.009 g, 0.021 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.016 g (43%) of the target compound as a white solid. ESI-MS [MH] - = 1775.9.

[0461] Example 24: PSMA-Lys-DOTA-AA-NH-T4CO-FTz (compound 54, Figure 9 Synthesis of )

[0462]

[0463] Compound 1 (0.0009 g, 0.003 mmol) was added to a solution of compound 53 (0.005 g, 0.003 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.004 g (72%) of the target compound as a white solid. ESI-MS [M+H] + = 1965.8.

[0464] Example 25: PSMA-3-I-AAAA-NH-T4CO (Compound 62, Figure 10B Synthesis of )

[0465] Figure 10A , Figure 10B and Figure 10C A schematic diagram of the synthetic routes for compounds 63 and 64 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-x): i) a) Fmoc-Phe(3-I)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) Fmoc-(4-Amb)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) a) Fmoc-D-Glu(OtBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iv) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; v) a) Fmoc-D-Glu(OtBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; vi) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; vii) TFA, TIPS, H2O, room temperature, 2 h; viiii) Compound 5,4-methylmorpholine, DMF, room temperature, 12 h; ix) Compound 1, ACN, H2O, TFA, room temperature, 12 h; x) I-Tz-DOTA, ACN, H2O, TFA, room temperature, 12 h.

[0466] PSMA-3-I-AAAA-NH 2 (Compound 61, Figure 10B Synthesis of )

[0467]

[0468] The resin-bonded and tert-butyl-protected binding motif (11) was synthesized according to the previously described method. 4 equivalents of Fmoc-L-3-I-Phe-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin (0.22 mmol). After 2 minutes, the solution was added to the resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product (12) was reacted with 4 equivalents of trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (N-Fmoc-tranexamic acid), wherein the N-Fmoc-tranexamic acid was activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA. The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give compound 56. 4 equivalents of Fmoc-D-Glu(OtBu)-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the intermediate (0.22 mmol). After 2 min, the solution was added to the resin-fixed peptide and shaken for 1 h. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). The coupling reactions with Fmoc-D-Glu(OtBu)-OH and Fmoc-D-Arg(Pbf)-OH were repeated, and the Fmoc group was finally deprotected with a mixture of DMF and piperidine (1:1) to give compound 60. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.09 g of target compound 61. ESI-MS [M+H] + =1302.5.

[0469] PSMA-3-I-AAAA-NH-T4CO (compound 62, Figure 10B Synthesis of )

[0470]

[0471] Under argon atmosphere, 4-methylmorpholine (0.036 mL, 0.33 mmol) was added to an anhydrous DMF (3 mL) solution of compound 61 (0.05 g, 0.031 mmol) and compound 5 (0.015 g, 0.036 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.021 g (37% yield) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 811.6.

[0472] Example 26: PSMA-3-I-NH-AAAA-T4CO-FTz (compound 63, Figure 10C Synthesis of )

[0473]

[0474] Compound 1 (0.0006 g, 0.0027 mmol) was added to a solution of compound 62 (0.005 g, 0.0027 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.001 g (23%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 906.6.

[0475] Example 27: PSMA-3-I-NH-AAAA-T4CO-ITz-DOTA (Compound 64, Figure 10C Synthesis of )

[0476]

[0477] I-Tz-DOTA (0.001 g, 0.0027 mmol) was added to a solution of compound 62 (0.005 g, 0.0027 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (32%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1146.4.

[0478] Example 28: PSMA-3-I-AAAAAA-NH-T4CO (Compound 67, Figure 11 Synthesis of )

[0479] Figure 11 A schematic diagram of the synthetic routes for compounds 68 and 69 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-vi): i) a) Fmoc-D-Glu(OtBu)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5,4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1, H2O, TFA, room temperature, 5 h; vi) I-Tz-DOTA, H2O, TFA, room temperature, 5 h.

[0480] PSMA-3-I-AAAAAA-NH 2 (Compound 66, Figure 11 Synthesis of )

[0481]

[0482] 4 equivalents of Fmoc-D-Glu(OtBu)-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the resin and compound 60 (0.22 mmol). After 2 min, the solution was added to the resin-fixed glutamic acid-urea-lysine and shaken for 1 h. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give compound 65. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.12 g of target compound 66. ESI-MS [M+2H] 2+ = 794.5.

[0483] PSMA-3-I-AAAAAA-NH-T4CO (compound 67, Figure 11 Synthesis of )

[0484]

[0485] Under argon atmosphere, 4-methylmorpholine (0.064 mL, 0.58 mmol) was added to an anhydrous DMF (6 mL) solution of compound 66 (0.11 g, 0.053 mmol) and compound 5 (0.023 g, 0.053 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.061 g (51% yield) of the target compound as a white solid. ESI-MS [M+3H] 3+ = 954.0.

[0486] Example 29: PSMA-3-I-NH-AAAAAA-T4CO-FTz (Compound 68, Figure 11 Synthesis of )

[0487]

[0488] Compound 1 (0.0002 g, 0.0008 mmol) was added to a solution of compound 67 (0.002 g, 0.0008 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.001 g (64%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1049.0.

[0489] Example 30: PSMA-3-I-NH-AAAAAA-T4CO-ITz-DOTA (Compound 69, Figure 11 Synthesis of )

[0490]

[0491] I-Tz-DOTA (0.005 g, 0.0053 mmol) was added to a solution of compound 67 (0.012 g, 0.0053 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.007 g (49%) of the target compound as a white solid. ESI-MS [M+3H] 3+ = 859.6.

[0492] Example 31: PSMA-3-I-SSAA-NH-T4CO (Compound 75, Figure 12A Synthesis of )

[0493] Figure 12A and Figure 12B A schematic diagram of the synthetic routes for compounds 76 and 77 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-viii): i) a) Fmoc-D-Ser(tBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Ser(tBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) a) Fmoc-D-Glu(OtBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iv) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; v) TFA, TIPS, H2O, room temperature, 2 hours; vi) Compound 5, 4-methylmorpholine, DMF, room temperature, 6 hours; vii) Compound 1, H2O, TFA, room temperature, 5 hours; viii) I-Tz-DOTA, H2O, TFA, room temperature, 5 hours.

[0494] PSMA-3-I-AAAA-NH 2 (Compound 74, Figure 12A Synthesis of )

[0495]

[0496] Relative to compound 56 (0.22 mmol), 4 equivalents of Fmoc-D-Ser(tBu)-OH were activated in DMF using 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA. After 2 minutes, the solution was added to the resin-fixed peptide and shaken for 1 hour. The Fmoc-protecting group was deprotected with a mixture of DMF and piperidine (1:1). The coupling with Fmoc-D-Ser(tBu)-OH and the corresponding deprotection reaction were repeated once. Then, 71 was reacted with 4 equivalents of Fmoc-D-Glu(OtBu)-OH, which was activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA. After 2 minutes, the solution was added to the resin-fixed peptide and shaken for 1 hour. The Fmoc-protecting group was removed with a mixture of DMF and piperidine (1:1). The product was then reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). Finally, the Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give compound 73. The latter was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.09 g of target compound 74. ESI-MS [M+H] + =1191.4.

[0497] PSMA-3-I-AAAAAA-NH-T4CO (compound 75, Figure 12A Synthesis of )

[0498]

[0499] Under argon atmosphere, 4-methylmorpholine (0.042 mL, 0.38 mmol) was added to an anhydrous DMF (6 mL) solution of compound 74 (0.061 g, 0.042 mmol) and compound 5 (0.022 g, 0.051 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.035 g (53% yield) of the target compound as a white solid. ESI-MS [M+2H] 2+ =756.2.

[0500] Example 32: PSMA-3-I-NH-SSAA-T4CO-FTz (Compound 76, Figure 12BSynthesis of )

[0501]

[0502] Compound 1 (0.0001 g, 0.0049 mmol) was added to a solution of compound 75 (0.008 g, 0.0049 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.005 g (63% yield) of the target compound as a white solid. ESI-MS [M+H] + = 1701.4.

[0503] Example 33: PSMA-3-I-NH-SSAA-T4CO-ITz-DOTA (Compound 77, Figure 12B Synthesis of )

[0504]

[0505] I-Tz-DOTA (0.002 g, 0.003 mmol) was added to a solution of compound 75 (0.005 g, 0.003 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.005 g (83% yield) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1090.5.

[0506] Example 34: PSMA-3-I-SSSS-NH-T4CO (Compound 81, Figure 13A Synthesis of )

[0507] Figure 13A and Figure 13BA schematic diagram of the synthetic routes for compounds 82 and 83 is shown. Gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-vi): i) a) Fmoc-D-Ser(tBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Ser(tBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) TFA, TIPS, H2O, room temperature, 2 h; iv) Compound 5,4-methylmorpholine, DMF, room temperature, 6 h; v) Compound 1, H2O, TFA, room temperature, 5 h; vi) I-Tz-DOTA, H2O, TFA, room temperature, 5 h.

[0508] PSMA-3-I-SSSS-NH 2 (Compound 80, Figure 13A Synthesis of )

[0509]

[0510] 4 equivalents of Fmoc-D-Ser(tBu)-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to compound 72 (0.22 mmol). After 2 min, the solution was added to the resin-fixed peptide and shaken for 1 h. The Fmoc-protecting group was deprotected with a mixture of DMF and piperidine (1:1). The coupling reaction with Fmoc-D-Ser(tBu)-OH and the corresponding deprotection reaction were repeated once. The peptide was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.08 g of target compound 80. ESI-MS [M+H] + = 1080.3.

[0511] PSMA-3-I-SSSS-NH-T4CO (compound 81, Figure 13A Synthesis of )

[0512]

[0513] Under argon atmosphere, 4-methylmorpholine (0.025 mL, 0.22 mmol) was added to an anhydrous DMF (6 mL) solution of compound 80 (0.03 g, 0.025 mmol) and compound 5 (0.013 g, 0.030 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.012 g (34%) of the target compound as a white solid. ESI-MS [M+H] + = 1399.5.

[0514] Example 35: PSMA-3-I-NH-SSSS-T4CO-FTz (Compound 82, Figure 13A Synthesis of )

[0515]

[0516] Compound 1 (0.0001 g, 0.0049 mmol) was added to a solution of compound 81 (0.004 g, 0.0029 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.002 g (42%) of the target compound as a white solid. ESI-MS [M+H] + = 1590.4.

[0517] Example 36: PSMA-3-I-SSSS-NH-T4CO-ITz-DOTA (Compound 83, Figures 13A-13B Synthesis of )

[0518]

[0519] I-Tz-DOTA (0.003 g, 0.0039 mmol) was added to a solution of compound 80 (0.0055 g, 0.0039 mmol) in ACN (2 mL) and H₂O (2 mL) containing 1% TFA. The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.003 g (37%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1034.9.

[0520] Example 37: PSMA-3-I-Lys-DOTA-AAAAAA-NH-T4CO (Compound 87, Figures 14A-14BSynthesis of )

[0521] Figure 14A and Figure 14B A schematic diagram of the synthetic route for compound 88 is shown. The gray dots in the intermediate structures represent resins. The following reagents and conditions were used in steps i)-vi): i) a) Fmoc-tBuDOTA-L-Lys-OH, HATU, DIPEA, DMF, room temperature, 2 h; b) 50% piperidine in DMF, room temperature, 20 min; ii) a) Fmoc-D-Glu(OtBu)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iii) a) Fmoc-D-Arg(Pbf)-OH, HATU, DIPEA, DMF, room temperature, 2.5 h; b) 50% piperidine in DMF, room temperature, 20 min; iv) TFA, TIPS, H2O, room temperature, 2 h; v) Compound 5,4-methylmorpholine, DMF, room temperature, 6 h; I-Tz-DOTA, H2O, TFA, room temperature, 5 h.

[0522] PSMA-3-I-Lys-DOTA-AAAAAA-NH2 (Compound 86) Figure 14A Synthesis of )

[0523]

[0524] 1.4 equivalents of Fmoc-tBuDOTA-L-Lys-OH were activated with 1.2 equivalents of HATU and 4.2 equivalents of DIPEA relative to the resin and compound 56 (0.22 mmol). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give the deprotected intermediate 84. 4 equivalents of Fmoc-D-Glu(OtBu)-OH were activated in DMF with 3.92 equivalents of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) and 4 equivalents of DIPEA relative to the intermediate. After 2 minutes, the solution was added to resin-fixed glutamic acid-urea-lysine and shaken for 1 hour. The Fmoc protecting group was removed with a mixture of DMF and piperidine (1:1). The resulting product was reacted with 4 equivalents of Fmoc-D-Arg(Pbf)-OH (activated with 3.92 equivalents of HATU and 4 equivalents of DIPEA). The Fmoc group was deprotected with a mixture of DMF and piperidine (1:1) to give the deprotected compound. Coupling with Fmoc-D-Glu(OtBu)-OH and Fmoc-D-Arg(Pbf)-OH and the corresponding deprotection were repeated twice to give compound 85. The product was cleaved from the resin and deprotected with trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and water (95:2.5:2.5). Preparative HPLC yielded 0.09 g of target compound 86. ESI-MS [M+2H] 2+ = 1051.5.

[0525] PSMA-3-I-Lys-DOTA-AAAAAA-NH-T4CO (Compound 87) Figures 14A-14B Synthesis of )

[0526]

[0527] Under argon atmosphere, 4-methylmorpholine (0.064 mL, 0.58 mmol) was added to an anhydrous DMF (6 mL) solution of compound 86 (0.082 g, 0.039 mmol) and compound 5 (0.017 g, 0.039 mmol). The reaction was stirred at room temperature for 6 hours. The mixture was then diluted with 10 mL of mobile phase A (1% TFA in H2O) and purified by preparative HPLC. The collected fraction was lyophilized to give 0.04 g (41%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1211.3.

[0528] Example 38: PSMA-3-I-Lys-DOTA-AAAAAA-NH-T4CO-ITz-DOTA (Compound 87, Figures 14A-14B Synthesis of )

[0529]

[0530] I-Tz-DOTA (0.01 g, 0.014 mmol) was added to a solution of compound 87 (0.03 g, 0.012 mmol) in ACN (2 mL) and H₂O containing 1% TFA (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was purified directly by preparative HPLC. The collected fraction was lyophilized to give 0.013 g (34%) of the target compound as a white solid. ESI-MS [M+2H] 2+ = 1546.1.

[0531] Example 39: Before IEDDA coupling [ 18 Radioactive labeling of F]1

[0532] Radioactive labeling was performed according to published procedures. The data received from the cyclotron will be... 18 F] Fluoride aqueous solution was passed through a Sep-Pak Light QMA column pretreated with 5 mL of 0.5 M K3PO4. 18 F] Fluoride was eluted from a QMA column to a 4 mL V-vial using Bu4NOTf solution (20 mM solution in MeOH, 1 mL). The eluent was dried at 100 °C for 5 min under a nitrogen or helium atmosphere. After evaporation of MeOH, 0.5 mL of acetonitrile was added to the same vial, and evaporated under the same conditions to remove trace amounts of water. Acetonitrile additions were performed twice. Nosyl precursor 2 (1.5 mg) was dissolved in anhydrous acetonitrile (0.3 mL), diluted with tBuOH (0.7 mL), and added to a dry […]. 18 F] Fluoride residues. After reacting at 100 °C for 5 min, the reaction was cooled to 80 °C under ambient air, diluted with water (2 mL), and purified by semi-preparative HPLC: Discovery HS F5 5 μm, 250 mm × 10 mm column, isocratically eluted with 20 mM citrate buffer (pH 6.1) containing 50% acetonitrile at a rate of 5 mL / min. The product peak (retention time 9.0 min) was collected, diluted with water (50–100 mL), and extracted using a Sep-pak Plus C18 Short solid-phase extraction column (Waters, USA), which was pre-treated with an EtOH / water mixture (1 / 1 v / v, 10 mL). The Sep-pak extraction column was then rinsed with additional water (5 mL), purged with nitrogen, eluted with 1–2 mL of organic solvent (ACN or EtOH), and diluted with water to achieve the required organic solvent concentration for the next step.18 The radiochemical yield of F]1 was 16 ± 10% (n = 4), and the radiochemical purity was > 95%.

[0533] Example 40: Before IEDDA coupling [ 211 Radiolabeling of At]4

[0534] Add 5 μL of precursor 4 solution (5 mg / ml, in MeOH) to the concentrated [ 211 [At] (concentrated from chloroform), then 15 μL MeOH, 1 μL AcOH, and 1 μL NCS solution (20 mg / ml, in MeOH) were added. The reaction was allowed to proceed for 10 minutes. The reaction mixture was diluted with H₂O containing 0.1% TFA, and the compound was purified by HPLC. The separated fraction was used directly in the next step. 211 The radiochemical yield of At]4 was 67 ± 5% (n=5), and the radiochemical purity was >95%.

[0535] [ 211 At]4 separation of RCY and activity

[0536]

[0537] Example 41: TCO-functionalized PSMA derivatives and [ 18 F]1's IEDDA Coupling

[0538] Click reaction:

[0539] To 3-(4-(2-[ 18 F]fluoroethoxy)phenyl)-1,2,4,5-tetraazine ([ 18 To an acetonitrile (1 mL) solution of F]1), add 20-100 μL of a solution of PSMA-modified derivatives (15, 20, 24, 29, 34, 39, 43, 47, 51) in DMSO (2-5 mg / mL, total added mass 100-200 μg). After 5 minutes, confirm the result by radioactive HPLC. 18 F]1 is completely consumed. Figure 15 The total synthetic route starting from Nosyl precursor 2 is shown. Figure 16 It shows [ 18 The semi-preparative HPLC chromatogram of F]25.

[0540] Oxidation:

[0541] Following the click step, add 50 μL of tetrafluorop-benzoquinone solution (20 mg / mL in acetonitrile) to the click mixture. Allow the mixture to stand at room temperature for 30 minutes, following the previously reported procedure (PCT / EP2023 / 055930).

[0542] Optional purification

[0543] The crude oxidized [ 18 The F-labeled PSMA derivatives were diluted with water (3 mL) and purified by semi-preparative HPLC (methods described below). Product peaks (Table 1) were collected, diluted with water (50–100 mL), and passed through a Sep-pak Plus C18 Short solid-phase extraction column (Waters, USA), which was pre-treated with an EtOH / water mixture (1 / 1 v / v, 10 mL). The Sep-pak column was then rinsed with additional water (5 mL), purged with nitrogen, and eluted with 1 mL of ethanol. The conditions used were as follows: HPLC method: Luna C18 (2) 5 μm column, 250 × 10 mm, gradient elution with water / acetonitrile (both containing 0.1% TFA (v / v)). Gradient: 0 min - 30% acetonitrile, 11.7 min - 55% acetonitrile, 16.7 min - 55% acetonitrile, 30 min - 90% acetonitrile. Elution flow rate: 4 mL / min.

[0544]

[0545] Preparations used in rat experiments:

[0546] Purified [ 18 The ethanol solution of the F-labeled PSMA derivative was evaporated to dryness under a nitrogen stream at 40 °C. The residue was redissolved in 35 µL of ethanol and diluted with 350 µL of phosphoric acid (0.085% in water, v / v) and 350 µL of citrate buffer (20 mM, pH 6.1). The resulting solution (pH 4.5) was used for injection.

[0547] Example 42: TCO-functionalized PSMA derivatives and [ 211 At]4's IEDDA coupling

[0548] Tetraazine labeling:

[0549] Click reaction

[0550] Towards[ 211Add 45 μL of 29% MeCN / H2O solution (0.4 mg / 450 μL, 33% MeCN in H2O) to 250 μL of the At]4 MeCN / H2O solution.

[0551] Oxidation

[0552] Following the click step, add 50 μL of tetrafluoro-p-benzoquinone solution (20 mg / mL in acetonitrile) to the click reaction mixture. Allow the mixture to stand at room temperature for 30 minutes, following a previously reported procedure (PCT / EP2023 / 055930).

[0553] Optional purification

[0554] The compound was purified by HPLC. The product was collected on a C18 column and eluted with 1 mL of EtOH.

[0555] Figure 17 The total synthetic route starting from precursor 4 is shown. Figure 18 It shows [ 211 Semi-preparative HPLC chromatogram of At]31.

[0556] [ 211 At]31 separation of RCY and activity

[0557]

[0558] Preparations used in rat experiments:

[0559] Purified [ 211 The ethanol solution of At]31 was dried under N2 flow and diluted to the correct concentration with EtOH containing 5% ascorbic acid (v / w%). Before administration, the ethanol solution was diluted with PBS to 5% EtOH to obtain a solution containing 2 kBq / μL [ 211 At]31 solution.

[0560] Example 43: For [ 211 General procedure for stability evaluation of At-labeled derivatives

[0561] The stability of the compound was measured in pure EtOH containing 5% ascorbic acid (v / w%) and tracked over a period of 900 minutes. 211 The results of At]31 were reported in Figure 19 middle.

[0562] Example 44: A general procedure for autoradiography for affinity determination

[0563] By using [ ] on rat brain slices 111In-In-PSMA-617 as a radioligand was used in an in vitro autoradiography competition assay to measure the affinity of PSMA derivatives for PSMA.

[0564] [ 111 The preparation method of In-PSMA-617 is as follows: 2 µL of a 2 mg / mL solution of vitivitide tetrazacyclotetraxetan (purchased from MedChemExpress, USA) in milliQ solution is mixed with... 111 InCl3 (5-20 MBq) was mixed and buffered with ammonium acetate to pH 5.5 (final ammonium acetate concentration approximately 0.2 M, final volume 40-70 μL). The resulting mixture was heated at 60°C for 5 minutes. The [values] provided by this method were determined by reversed-phase HPLC. 111 The radiochemical yield of In]-PSMA-617 is >95%.

[0565] Rat brain sections were obtained from female Sprague-Dawley rats (approximately 250 g; Taconic Biosciences). Rats were euthanized by decapitation, and the brains were removed, frozen at -80 °C, and stored at the same temperature. To prepare sections for autoradiography, the brain was bisected along the sagittal plane of symmetry. Each hemisphere was mounted lateral-upward on a cryostat sample holder pre-treated with Tissue-Tek OCT compound and fixed by cryostating. After fixation, the brain tissue was sectioned into 20 μm thick sagittal sections at -22 °C using a Leica microtome. The sections were thawed and attached to Superfrost (70 × 22 mm, Fischer) slides, 3-4 sections per slide. Only sections containing the midbrain were used because midbrain structures express relatively high levels of PSMA. Dry the slices, then place them in a storage box and store at -80°C until use.

[0566] Following the guidelines of Hein et al., a saturation assay was designed to measure [ 111 The affinity of In-PSMA-617 for PSMA in brain slices was determined, and a competitive assay was designed to measure the affinity of PSMA derivatives for the same target. In short, for saturation assays, the slide is mixed with the assay buffer (170 mM Tris-HCl pH 7.2, 5 mM MgCl2, 1% BSA) at increasing concentrations (0.1-30 nM). 111 Incubate with In-PSMA-617 for 1.5 hours. For competitive assays, incubate the slide with 2 nM [ 111In]In-PSMA-617 and the analyte PSMA derivatives at increasing concentrations (0.1-30 nM) were incubated for the same time in the same assay buffer. [The text abruptly ends here, likely due to an incomplete translation or a missing section.] 111 Nonspecific binding was determined by adding 5 μM 2-(phosphonomethyl)glutaric acid (PMPA) to the In]In-PSMA-617 solution.

[0567] Incubation was performed as follows: a hydrophobic barrier was constructed along the edge of the slide using a PAP pen; 1 mL of the appropriate incubation solution was added to each slide; and then the slides were gently shaken in a sealed plastic box at room temperature. However, for low concentrations (<0.3 nM) in saturation assays... 111 In]In-PSMA-617, place the slide in a container containing the assay buffer solution. 111 Incubate in a bath of In-PSMA-617 solution (>20 mL / slide). Immediately before the start of incubation, add 1 mL of assay buffer to each slide, shake the slide at room temperature for 15 minutes as described above, and then replace the assay buffer with the appropriate incubation solution.

[0568] After incubation, the slides were rinsed by immersing them in ice-cold assay buffer for 5 minutes, followed by immersion in ice-cold distilled water for 0.5 minutes. The slides were then air-dried and exposed to a phosphor screen (Packard Instruments) for 24–72 hours, while simultaneously exposing 1 μL aliquots of the sample at known concentrations (0.1–30 nM) to a silica gel TLC strip. 111 Calibration curve prepared with In]In-PSMA-617 solution.

[0569] Subsequently, the phosphorescent screen was read using the Cyclone Plus phosphorescence storage system (Packard Instruments). Quantification of the readings was performed using Optiquant software (version 3.00, Packard Instruments). Specifically, elliptical regions of interest (ROIs) containing the midbrain and cerebellar nuclei were plotted within the brain slice images, while circular ROIs were plotted around the calibration curve spots, and the average exposure for both types of ROIs was calculated. The exposure was then recalculated as fmol per μL of tissue by fitting a linear function to the calibration curve values. 111 In]In-PSMA-617 (equivalent to nM). Then, nonlinear regression was performed using the fmol / μL value in GraphPad Prism (v9.4.1) to calculate the saturation determination [ 111 In]In-PSMA-617 of B max and K D Value, and IC50 of PSMA derivatives in competitive assays50 GraphPad Prism uses the Cheng-Prusoff equation to convert IC... 50 Values ​​are automatically converted to K i Value. The experiment was repeated twice, first using 9 different formulas I. 18 F-labeled tetrazines (Table 1), followed by eight other tetrazines of formula I with stable F or stable I atoms in their structures (Table 2).

[0570] Table 1: Data are expressed as mean ± standard deviation. The number of independent determinations (if >1) is shown in parentheses.

[0571]

[0572] Table 2

[0573]

[0574] The values ​​for all tested compounds were consistent with the published results for PSMA-617, indicating that the affinity for the target was preserved.

[0575] Example 45: General Procedure for Internalization Assay

[0576] Add 300 μL of poly-L-lysine (0.01% w / v in H2O) to each well of a 24-well plate (Greiner Bio). Incubate the plate at room temperature for 20–30 minutes. Afterward, aspirate the poly-L-lysine solution and wash each well with 500 μL of PBS. Then, add 1 mL of LNCaP cell suspension to each well to obtain 1010 cells. 5 Cells / well. Incubate the 24-well plate overnight until internalization experiments begin. Then, combine the previously plated cells with the selected... 18 F-labeled PSMA derivatives were incubated in 250 μL of growth medium at 37°C for 45 min (c = 32 nM). To determine specific uptake, excess 2-PMPA at a concentration of 500 μM / well was added to half the number of wells. After incubation, cell uptake was terminated by removing the medium and washing the cells with ice-cold PBS (3 × 1 mL). Surface-bound radioactivity was removed by washing with 50 mM glycine (pH 2.8, 2 × 500 μL). Finally, the internalization fraction was determined by lysing the cells with 0.3 M NaOH (1 × 500 μL). Fractions collected from the surface-bound active fraction and lysates were measured in a γ-counter. All counts were normalized to the initial activity, and specific surface binding and specific internalization were determined by subtracting the non-specific bindings obtained from the wells treated with 2-PMPA. The results were calculated and expressed as %AA / 10. 5Cells (% of applied activity / 10) 5 (Number of cells, n=4) represents the total number of cells. Choose [ 68 Ga-PSMA617 was used as a reference for comparing internalization values. The experiment was performed three times for different compounds. Data are shown in separate tables below (Tables 3, 4, and 5). PSMA-617 was used as a reference and internal control in all three experiments. The internalization values ​​of the control PSMA-617 were very similar, with only minor differences between the three tests, confirming the reproducibility of the test. To account for this minor difference and provide values ​​that can be directly compared between the three tests, the surface to internalization ratio is also shown in the tables.

[0577] Table 3

[0578]

[0579] Table 4

[0580]

[0581] Table 5

[0582]

[0583] Data show that the compounds presented in this paper exhibit better internalization compared to PSMA-617. This enhanced internalization may have a significant impact on the therapeutic efficacy of such molecules.

[0584] Example 46: [ 18 F] mark and [ 68 Positron emission tomography (PET) imaging of Ga-labeled PSMA derivatives in rats

[0585] animal

[0586] Female Long-Evans rats (Charles River, Calco, Italy), weighing 200-300 grams, were housed in cages of 2-3 rats in a temperature-controlled environment with a 12-hour light / dark cycle. Cages were equipped with environmental enrichment features (nest boxes, chew sticks). All rats were fed freely on commercially available breeding stock (1310 FORTI-Avlsfoder, Brogaarden, Altromin International) and had free access to water. All experiments were conducted in accordance with European Commission Directive 2010 / 63 / EU, FELASA, and the ARRIVE Guidelines for Animal Research, and were approved by the Danish Animal Ethics Committee (License Nos. 2017-15-0201-01283 and 2017-15-0201-01375) and the Department of Laboratory Medicine, University of Copenhagen.

[0587] PET procedure

[0588] Scans were performed using a Siemens HRRT (High Resolution Research Tomography) scanner (CPS Innovations / Siemens, Malvern, PA, USA). On the day of the experiment, rats were weighed and transported to the scanner at least two hours prior to the scan. Anesthesia was induced using an oxygen flow containing 3% isoflurane. All rats were placed in a custom-designed 2 x 2 rat scaffold, allowing for the simultaneous scanning of four rats. Rats were anesthetized in a custom-designed rat scaffold by a continuous flow of isoflurane (approximately 2% isoflurane in oxygen). A BD Neoflon 24G intravenous catheter was inserted into the dorsal or caudal tail vein of the rat and flushed with saline solution containing 4 units / mL heparin. The rat was placed in a scanner, kept warm using an infrared lamp or heating pad, and its respiration was monitored throughout the scan. A tracer (containing 5-25 MBq in 0.5-1.0 mL) was injected via the catheter, and 90 minutes of PET acquisition (emission scan) was initiated at the time of injection. A rotating point source was used before or after each emission scan. 137 Cs transmission scan .

[0589] Image Reconstruction

[0590] The PET list pattern emission files were reconstructed using the Ordinary Poisson 3D Subset Expectation-Maximization (OP-3D-OSEM) algorithm, including modeling the point spread function, employing 16 subsets, ten iterations, and standard correction. The transmission attenuation map was regenerated using the Maximum A posteriori (MAP) algorithm. The emission data was binned into time frames of increasing length: 6 × 10 seconds, 8 × 30 seconds, 5 × 60 seconds, and 16 × 300 seconds. Each reconstructed time frame image consists of 207 planes, each plane being 256 × 256 voxels, with a voxel size of 1.22 × 1.22 × 1.22 mm. .

[0591] Data Analysis

[0592] Data was analyzed using the PMOD program (PMOD Technologies, Zurich, Switzerland).

[0593] Figure 20 The results of these studies using compounds 21, 40, 45, 25, 30, 35, 49, and 54 labeled with 18F are shown. Figure 21 Showing the use 68Results of studies on Ga-labeled compounds 64, 69, 77, and 83. Surprisingly, by increasing the number of amino acids in the linker, excretion shifted from the liver to the kidneys and bladder. This effect was more pronounced for compounds with 2 to 6 amino acids. 18 F]16 (without amino acids) is mainly excreted through the liver, while [ 18 F]21 (2 amino acids) is not.

[0594] Example 47: [ 18 In vivo PET / CT imaging of F-labeled PSMA derivatives in tumor-bearing mice (PC3-PIP)

[0595] animal

[0596] For evaluation, 6-7 week old NOD-SCID mice (Janvier, Europe) were inoculated with PC3-PIP (PSMA-positive) cells in the left shoulder and PC3-flu (PSMA-negative) cells in the right shoulder. Once both tumor xenografts reached a size of at least 100 mm... 3 Imaging experiments were conducted. The mice weighed 22-29 g on the day of imaging.

[0597] PET / CT procedure

[0598] Injecting 5-9 MBq into the tail vein 18 Mice were anesthetized with a mixture of 1.5–2% isoflurane and 100% oxygen before bolus injection of 0.1 ml of the [F]-labeled PSMA derivative. To assess the specificity of the tracer binding to its respective target (PSMA), half of the mice were mixed with 100 μg of a cold competitive ligand (MEF98). 18 PET acquisition was initiated immediately after F]FlutraPros injection (90 minutes). Additional PET acquisitions were performed at 4 hours (15 minutes) and 8 hours (30 minutes) post-injection, with mice re-anesthetized prior to the scans as described above.

[0599] MEF98 PSMA ligand

[0600]

[0601] PET / CT imaging was performed in docking mode on a Siemens INVEON multimodal preclinical scanner (Siemens, Knoxville, Tennessee, USA). The imaging protocol included dual-bed CT for anatomical localization, performed with full rotation, 360-degree projection, and exposure conditions of 80 kV and 500 μA. PET scans were performed immediately after the static CT scans. CT and PET images were co-registered using transform.

[0602] Image Reconstruction

[0603] PET data was reconstructed using the OSEM3D / SP-MAP algorithm (2 OSEM iterations and 18 MAP iterations), including scattering correction and a 128×128 matrix size, with a final target resolution of 1.5 mm. The dynamically scanned list-pattern data was binned into time frames of increasing length: 3×10 seconds, 3×30 seconds, 3×60 seconds, 5×300 seconds, 3×600 seconds, and 2×900 seconds.

[0604] Data Analysis

[0605] Data were analyzed using the PMOD program (PMOD Technologies, Zurich, Switzerland). Normalized maximum intensity projection (MIP) images were prepared using total PET data from 60–90 minutes post-injection. The volume of interest (VOI) for the kidney and PC3-PIP tumors was plotted using the isocontour mapping function in PMOD.

[0606] Figure 22 The results obtained using [18F]25 are shown.

[0607] Example 48: [ 18 In vivo PET / CT imaging of F-labeled PSMA derivatives in tumor-bearing mice (LnCap).

[0608] animal

[0609] For evaluation, 6-7 week old NOD-SCID mice (Janvier, Europe) were inoculated with PC3-PIP (PSMA-positive) cells in the left shoulder and PC3-flu (PSMA-negative) cells in the right shoulder. Once both tumor xenografts reached a size of at least 100 mm... 3 Imaging experiments were then conducted. The mice weighed 22-29 g on the day of imaging.

[0610] PET / CT procedure

[0611] Injecting 5-9 MBq of [ [] into the tail vein 18 Mice were anesthetized with a mixture of 1.5–2% isoflurane and 100% oxygen before bolus injection of 0.1 ml of the [F]-labeled PSMA derivative. To assess the specificity of the tracer binding to its respective target (PSMA), half of the mice were mixed with 100 μg of a cold competitive ligand (MEF98). 18PET acquisitions were initiated immediately after FlutraPros injection (90 minutes). Additional PET acquisitions were performed at 4 hours (15 minutes) and 8 hours (30 minutes) post-injection, with mice re-anesthetized prior to scans as described above. PET / CT imaging was performed in docking mode on a Siemens INVEON multimodal preclinical scanner (Siemens, Knoxville, Tennessee, USA). The imaging protocol included dual-bed CT for anatomical localization, performed with full rotation, 360-degree projection, and exposure conditions of 80 kV and 500 μA. PET scans were performed immediately following the static CT scan. CT and PET images were co-registered using transform.

[0612] Image Reconstruction

[0613] PET data was reconstructed using the OSEM3D / SP-MAP algorithm (2 OSEM iterations and 18 MAP iterations), including scattering correction and a 128×128 matrix size, with a final target resolution of 1.5 mm. The dynamically scanned list-pattern data was binned into time frames of increasing length: 3×10 seconds, 3×30 seconds, 3×60 seconds, 5×300 seconds, 3×600 seconds, and 2×900 seconds.

[0614] Data Analysis

[0615] Data were analyzed using the PMOD program (PMOD Technologies, Zurich, Switzerland). Normalized maximum intensity projection (MIP) images were prepared using total PET data from 60–90 minutes post-injection. The volume of interest (VOI) for the kidney and PC3-PIP tumors was plotted using the isocontour mapping function in PMOD.

[0616] Figure 23 Showing the use of [ 18 F]25 and [ 18 The result obtained from F]30.

[0617] Example 49: [ 211 In vitro biodistribution of At-labeled PSMA derivatives in tumor-bearing mice

[0618] animal

[0619] For biological distribution, 7- to 8-week-old male BALC / c nu / nu mice (BALB / cAnN-Foxn1) nu / nu / Rj, Janvier, France) subcutaneously injected 5×10 [units of something] into the right flank. 6 1 LNCaP cell (1:1 in PBS:Matrigel). Once the tumor size is approximately 1 cm 3Subsequently, 200 kBq of [a specific substance] was injected into the mice via the tail vein. 211 At]31. Mice were sacrificed at 2 and 24 hours post-injection (n = 4–6 at each time point), and organs of interest were collected. Organs included: blood, heart, lung, liver, salivary glands, thyroid (trachea), spleen, stomach, small intestine, kidney, tail, and transplanted LNCaP tumors. After weighing, each organ was measured in an automated gamma counter (Hidex AMG, Hidex, Finland) with an energy window of 60–100 keV and a peak of 80 keV. %ID / g was calculated using the injected solution volume and animal / organ weight. All counts were decay-corrected and normalized to the injected solution. Figure 24 Showing the use of [ 211 The result obtained at]31.

[0620] References

[0621] 1.Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, RL; Torre, LA; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018, 68, 394-424.

[0622] 2. Antonarakis, ES; Feng, Z.; Trock, BJ; Humphreys, EB; Carducci, MA; Partin, AW; Walsh, PC; Eisenberger, MA The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU International 2012, 109, 32-39.

[0623] 3.de Bono, J. S.; Oudard, S.; Ozguroglu, M.; Hansen, S.; Machiels,J.-P.; Kocak, I.; Gravis, G.; Bodrogi, I.; Mackenzie, M. J.; Shen, L.;Roessner, M.; Gupta, S.; Sartor, A. O. Prednisone plus cabazitaxel ormitoxantrone for metastatic castration-resistant prostate cancer progressingafter docetaxel treatment: a randomised open-label trial. The Lancet 2010,376,1147-115.

[0624] 4.David, T.; Jean-Marc, F.; Manuel, B.; Palma, R.; Rodney, J. H.;Uwe, H. PSMA-Targeted Radionuclide Therapy and Salivary Gland Toxicity: WhyDoes It Matter? Journal of Nuclear Medicine 2018,59, 747.

[0625] 5.Martina, B.; Martin, S.; Ulrike, B.-W.; Ali, A.-O.; Clemens, K.;Walter, M.; Uwe, H.; Klaus, K.; Matthias, E. Preclinical Evaluation of aTailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety forImaging and Endoradiotherapy of Prostate Cancer. Journal of Nuclear Medicine 2015,56, 914.

[0626] 6.Sartor, O.; de Bono, J.; Chi, KN; Fizazi, K.; Herrmann, K.;Rahbar, K.; Tagawa, ST; Nordquist, LT; Vaishampayan, N.; El-Haddad, G.;Park, CH; Beer, TM; Armour, A.; Pérez-Contreras, WJ; DeSilvio, M.;Kpamegan, E.; Gericke, G.; Messmann, RA; Morris, MJ; Krause, BJLutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine 2021,385, 1091-1103.

[0627] 7.Marcu, L.; Bezak, E.; Allen, BJ Global comparison of targetedalpha vs targeted beta therapy for cancer: In vitro, in vivo and clinicaltrials. Critical Reviews in Oncology / Hematology 2018,123, 7-20.

[0628] 8.Feuerecker, B.; Tauber, R.; Knorr, K.; Heck, M.; Beheshti, A.;Seidl, J.; Bruchertseifer, F.; Pickhard, A.; Gafita, A.; Kratochwil, J.;Retz, M.; Gschwend, JE; Weber, WA; D'Alessandria, C.; Morgenstern, A.;Eiber, M. Activity and Adverse Events of Actinium-225-PSMA-617 in AdvancedMetastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. European Urology 2021,79, 343-350.

[0629] 9.Albertsson, P.; Bäck, T.; Bergmark, K.; Hallqvist, A.; Johansson,M.; Aneheim, E.; Lindegren, S.; Temperance, C.; Smerud, K.; Palm, S.Astatine-211 based radionuclide therapy: Current clinical triallandscape. Front Med (Lausanne) 2022.9, 1076210.

[0630] 10.Mease, RC; Kang, CM; Kumar, V.; Banerjee, SR; Minn, I.;Brummet, M.; Gabrielson, KL; Feng, Y.; Park, A.; Kiess, AP; Sgouros,G.; Vaidyanathan, G.; Zalutsky, MR; Pomper, MG The Improved 211 At-LabeledAgent for PSMA-Targeted α-Therapy. Journal of Nuclear Medicine 2022,63, 259-267.

[0631] 11.Otaru, S.; Paul, A.; Imlimthan, S.; Kuurne, I.; Virtanen, H.;Liljenbäck, H.; Tolvanen, T.; Auchynnikava, T.; Roivainen, A.; Helariutta,K.; Sarparanta, M.; Airaksinen, AJ Development of [18F]AmBF3 Tetrazine forRadiolabeling of Peptides: Preclinical Evaluation and PET Imaging of [18F]AmBF3-PEG7-Tyr3-Octreotide in an AR42J Pancreatic CarcinomaModel. Bioconjugate Chemistry 2022,33, 1393-1404.

[0632] 12.Allott, L.; Amgheib, A.; Barnes, J.; Braga, M.; Brickute, D.;Wang, N.; Wise.; Ghaem-Maghami, S.; Aboagye, EO Radiolabelling and 18Fbiologic via facile IEDDA “click” chemistry on the GE FASTLab™platform. Reaction Chemistry&Engineering 2021,6, 1070-1078.

[0633] 13.García-Vázquez, R.; Jørgensen, JT; Bratteby, KE; Shalgunov,V.; Sharp, L.; Herth, MM; Kjær, A.; Battisti, UM Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging.In Pharmaceuticals , 2022; Vol. 15.

[0634] 14.Garcia-Vazquez, R.; Battisti, UM; Jørgensen, JT; Shalgunov,V.; Hvass , L. ; Stares, DL; Petersen, IN; Crestey , F. ; Löffler , A. ;Svatunek , D. ; Christensen , JL ; Mikula, H.; Kjaer , A. ; Herth, MM DirectCu-mediated aromatic 18F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging. Chemical Science Rev. 2021.12, 11668–11675.

[0635] 15.Guilarte, TR; McGlothan , JL ; Foss, CA; Zhou, J.; Heston,WD; Kozikowski , AP ; Pomper, MG Glutamate carboxypeptidase II levelsin rodent brain using [125I]DCIT quantitative autoradiography. Neuroscience Letters Rev. 2005,387, 141–144.

[0636] 16.Hein, P.; Michel, MC; Leineweber , K. ; Wieland , T. ;Wettschureck , N. ; Offermanns, S. Receptor and Binding Studies. In Practical Methods in Cardiovascular Research , Dhein , S. ; Mohr , FW ; Delmar, M., Eds.Springer Berlin Heidelberg: Berlin, Heidelberg, 2005; pp 723-783.

[0637] 17.Keller, S. H.; L'Estrade, E. N.; Dall, B.; Palner, M.; Herth, M.Quantification Accuracy of a New HRRT High Throughput Rat Hotel UsingTransmission-Based Attenuation Correction: A Phantom Study. Ieee Nucl Sci Conf R 2016.

[0638] 18.Casado-Sainz, A.; Gudmundsen, F.; Baerentzen, S. L.; Lange, D.;Ringsted, A.; Martinez-Tajada, I.; Medina, S.; Lee, H.; Svarer, C.; Keller,S. H.; Schain, M.; Kjaerby, C.; Fisher, P. M.; Cumming, P.; Palner, M. Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypesassociated with obsessive-compulsive disorder. BioRxiv 2021.

[0639] 19.Shalgunov, V.; Xiong, M.; L'Estrade, E. T.; Raval, N. R.;Andersen, I. V.; Edgar, F. G.; Speth, N. R.; Baerentzen, S. L.; Hansen, H.D.; Donovan, L. L.; Nasser, A.; Peitersen, S. T.; Kjaer, A.; Knudsen, G. M.;Syvanen, S.; Palner, M.; Herth, M. M. Blocking of efflux transporters in ratsimproves translational validation of brain radioligands. EJNMMI Res 2020,10,124.

[0640] 20.Keller, S. H.; Svarer, C.; Sibomana, M. Attenuation correction forthe HRRT PET-scanner using transmission scatter correction and totalvariation regularization. IEEE Trans Med Imaging 2013,32, 1611-21.

Claims

1. Ureidic ligands of formula (I) targeting PSMA and their pharmaceutically acceptable salts: In the formula: A can be a carboxylic acid, sulfonic acid, phosphonic acid, tetrazolium, or isoxazole independently; o is an integer selected from 1 to 4; m is an integer selected from 0 to 10; R1 is either -CH-CH2-Z or -CH-CH2-Y; in, Z is selected from the following: Y is selected from the following: In the formula, Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl; Q2 is O, S, or NH; Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine. The condition is that when R2 = -CH-CH2-Y, then R1 must be -CH-CH2-Z; R2 is either -CH-CH2-Y or -CH2-T-; Wherein, T is an aromatic monocyclic or polycyclic system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; Y is selected from the following: In the formula, Q1 is -CR 3 Or N, where R 3 It is H or C1-C5 alkyl; Q2 is O, S, or NH; Hal (halogen) is a radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine and astatine. The condition is that when R1 = -CH-CH2-Y, then R2 must be -CH2-T; L represents the portion containing groups selected from the following: -CO(CH2) n NH-、-CO(CH2CH2O) n NH-、-M-、-CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-、-MnCO(CH2CH2O) n NH-、-LysG-、-LysJ-、-LysGCO(CH2CH2O) n NH-、-LysJCO(CH2) n NH-、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O) n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJM n CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-、-CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l CourtJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l CourtJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-, Where n and l are integers independently selected from 0 to 10; M is selected from one or more natural amino acids, one or more sugars, and combinations of one or more natural amino acids and one or more sugars; Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains. G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative. J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5. R4 is selected from the following pyridazines: R5 and R6 are identical or differ only in the isotopic mass number of the labeling agent, and are independently selected. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotope labeling agent of the aromatic ring, or (ii) connected to the isotope labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25; When R7 is (i) or (ii), the isotope labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 OF, 124 OF, 125 OF, 127 OF, 131 OF, 211 And、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Water, 46 Water, 47 Water, 48 Water, 49 Water, 50 Water, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 Through, 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 Let's go. 139 Let's go. 162 Is, 164 Is, 165 Is, 166 Is, 167 Is, 168 Is, 170 Is, 193 mPt, 195 mPt, 192 At this time, 194 At this time, 195 At this time, 196 At this time, 198 Pt; E and D are independently selected from: -CH and -N-; R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino; X is G or J. G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative. J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5. R4 is selected from the following pyridazines: R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotope labeling agent of the aromatic ring, or (ii) connected to the isotope labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25; When R7 is (i) or (ii), the isotope labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 OF, 124 OF, 125 OF, 127 OF, 131 OF, 211 And、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Water, 46 Water, 47 Water, 48 Water, 49 Water, 50 Water, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 Through, 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 Let's go. 139 Let's go. 162 Is, 164 Is, 165 Is, 166 Is, 167 Is, 168 Is, 170 Is, 193 mPt, 195 mPt, 192 At this time, 194 At this time, 195 At this time, 196 At this time, 198 Pt; E and D are independently selected from: -CH and -N-; R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino; R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent; Formula (I) contains at least one radioactive isotope selected from radioactive isotopes of fluorine, iodine, bromine, and astatine. At least one of L and X contains J.

2. The urea-ligand targeting PSMA according to claim 1, wherein, L is selected from the following: -CO(CH2) n NH-、-CO(CH2CH2O) n NH-、-M-、-CO(CH2) n NHM l -、-CO(CH2CH2O) n NHM l -、-MnCO(CH2) n NH-、-MnCO(CH2CH2O) n NH-、-LysG-、-LysJ-、-LysGCO(CH2CH2O) n NH-、-LysJCO(CH2) n NH-、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH2) n NHM l -、-LysJCO(CH2) n NHM l -、-LysGCO(CH2CH2O) n NHM l -、-LysJCO(CH2CH2O) n NHM l -、-LysGM n CO(CH2) n NH-、-LysJM n CO(CH2) n NH-、-LysGM n CO(CH2CH2O) l NH-、-LysJM n CO(CH2CH2O) l NH-、-CO(CH2CH2O) n NHLysG-、-CO(CH2) n NHLysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l CourtJ-、-M n LysG-、-M n LysJ-、-CO(CH2) n NHM l LysG-、-CO(CH2) n NHM l LysJ-、-CO(CH2CH2O) n NHM l LysG-、-CO(CH2CH2O) n NHM l CourtJ-、-M n CO(CH2) l NHLysG-、-M n CO(CH2) l NHLysJ-、-M n CO(CH2CH2O) l NHLysG-、-M n CO(CH2CH2O) l NHLysJ-, Where n and l are integers independently selected from 0 to 10; M is selected from one or more natural amino acids, one or more sugars, and combinations of one or more natural amino acids and one or more sugars; Lys represents D-lysine or L-lysine amino acid residues modified with G or J on their side chains. G may be a chelating agent containing a metal, or a tetrazine or its metabolic derivative. J stands for -CO(CH2) p R4 or -CO(CH2) p C(CH3)2R4, where p is an integer selected from 0 to 5. R4 is selected from the following pyridazines: R5 and R6 are selected independently. Wherein, the wavy line indicates the connection to the six-membered aromatic ring of the pyridazine, and R7 is -H, or (i) directly connected to the isotope labeling agent of the aromatic ring, or (ii) connected to the isotope labeling agent of the aromatic ring via a linker selected from -(CH2). b WO(CH2) b -WNH(CH2) b -WCONH(CH2) b -WNHCO(CH2) b W is -(CH2) h Or -(CH2CH2O) h b and h are independent integers selected from 1 to 25, or (iii) isotopic labeling agents chelated by means of a chelating agent linked to an aromatic ring via a linker selected from -(CH2). r -WO(CH2) r -WNH(CH2) r -WCONH(CH2) r -WNHCO(CH2) r W is -(CH2) q Or -(CH2CH2O) q r and q are independent integers selected from 1 to 25; When R7 is (i) or (ii), the isotope labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 OF, 124 OF, 125 OF, 127 OF, 131 OF, 211 And、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Water, 46 Water, 47 Water, 48 Water, 49 Water, 50 Water, 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 Through, 113 In、 114 mIn、 115 mIn、 175 Ridiculous, 177 Ridiculous, 185 Too, 186 Too, 188 Too, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Your, 166 Your, 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 The、 74 The、 75 The、 76 The、 77 The、 78 The、 80 The、 82 The、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 The、 138 Let's go. 139 Let's go. 162 Is, 164 Is, 165 Is, 166 Is, 167 Is, 168 Is, 170 Is, 193 mPt, 195 mPt, 192 At this time, 194 At this time, 195 At this time, 196 At this time, 198 Pt; E and D are independently selected from: -CH and -N-; R8 is H or selected from the following groups: hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino group having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkylene, (C1-C10)alkoxy, (C2-C10)dialkylamino, (C1-C10)alkylthio, (C2-C10)heteroalkyl, (C2-C10)heteroalkylene, (C3-30) (C10)cycloalkyl, (C3-C10)heterocycloalkyl, (C3-C10)cycloalkylene, (C3-C10)heterocycloalkylene, (C1-C10)haloalkyl, (C1-C10)perhaloalkyl, (C2-C10)enoxy, (C3-C10)alkynoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, (C1-C6)alkoxy-(C1-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aryl; wherein, optionally substituted means selected from one or more of the following substituents: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl, amino, substituted amino having 1-5 polyethylene glycol units, -(O-CH2-CH2). u -OCH2-COOH and u is an integer selected from 1 to 5; or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl; wherein, optionally substituted means one or more substituents selected from the following: halogen, hydroxyl, sulfonamide, carboxyl, sulfonyl and amino; R5 and R6 are the same or differ only in the isotopic mass number of the labeling agent.

3. The urea-ligand targeting PSMA according to claim 1, wherein, M is a polar natural amino acid or its D-enantiomer.

4. The urea-based ligand targeting PSMA according to any one of claims 1 to 3, wherein, The chelating agent contained in G is selected from the following: 1,4,7,10-Tetraazacyclododecane-N,N',N',N''-Tetraacetic acid (DOTA) N,N'-Bis(2-hydroxy-5-(carboxyethyl)benzyl)ethylenediamine-N,N'-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)glutaric acid (NODAGA) 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA) 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-methyl(2-carboxyethyl)phosphonic acid-4,7-bis(methyl(2-hydroxymethyl)phosphonic acid (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) N'-(5-acetyl(hydroxy)aminopentyl)-N-(5-(4-(5-aminopentyl)(hydroxy)amino-4-oxobutyryl)amino)pentyl-N-hydroxysuccinamide (DFO) Diethylenetriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (OXO-Do3A) p-Benzyl-DTPA isothiocyanate (SCN-BZ-DTPA) 1-(benzyl p-isothiocyanate)-3-methyl-DTPA (1B3M) 2-(benzyl p-isothiocyanate)-4-methyl-DTPA (1M3B) 1-(2)-Methyl-4-isocyanate benzyl-DTPA (MX-DTPA).

5. The urea-ligand targeting PSMA according to claim 4, wherein, The chelating agent contains a metal.

6. The urea-ligand targeting PSMA according to claim 5, wherein, The metal is selected from the following: 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 doesn't, 115 doesn't, 175 Lu、 177 Lu、 185 Re, 186 Re, 188 Re, 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Wind、 212 Wind、 213 Wind、 45 Scr、 47 Scr、 227 Th、 232 Th、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt、 225 But。 7. The urea-based ligand targeting PSMA according to any one of claims 1 to 6, wherein, At least one radionuclide is selected from 18 F, 125 I, 123 I, 131 I, 124 I, 211 At、 77 Br and 80m Br.

8. The urea-ligand targeting PSMA according to claim 7, wherein, At least one radionuclide is located on R4.

9. The urea-ligand targeting PSMA according to claim 7, wherein, At least one radionuclide is located on R1 or R2.

10. The urea-ligand targeting PSMA according to claim 7, wherein, The radionuclides are located on R4 and on R1 or R2.

11. A ureidyl ligand targeting PSMA according to any one of the preceding claims, wherein, At least one radionuclide is located on R4, R1 or R2, and it also contains an unlabeled chelating agent.

12. A ureidyl ligand targeting PSMA according to any one of the preceding claims, wherein, The ureidoligand targeting PSMA contains a J located at X or L, and J is selected from J(i) or J(ii).

13. A ureidyl ligand targeting PSMA according to any one of the preceding claims, wherein, R7 includes 18 F.

14. The urea-ligand targeting PSMA according to claim 1, wherein, The urea-ligands targeting PSMA are selected from the following: In the formula, F is 18 F or 19 F; I 125 I, 123 I, 127 I, 131 I or 124 I; Hal is 18 F, 19 F, 18 F, 125 I, 123 I, 127 I, 131 I, 124 I, 211 At, 77 Br, 79 Br or 80m Br.

15. A precursor for providing the urea-ligand targeting PSMA as described in claim 1, wherein, The precursor is selected from the following: In the formula, R9 is -Si(CH3)3, -Si(CH2CH2CH2CH3)3, -Sn(CH3)3, -Sn(CH2CH2CH2CH3)3, -B(OH)2 or .

Images