CAIX ligand compound, metal complex and application thereof

Abstract

The invention provides a CAIX ligand compound, a metal complex and application of the CAIX ligand compound and the metal complex, the structure of the compound is shown as a formula (A), and in the formula (A), R1 is selected from hydrogen or-L1-E1; r < 2 >, R < 3 >, R < 4 >, R < 5 >, R < 6 > and R < 7 > are independently selected from hydrogen or-L2-E2; each of the E1 and the E2 is independently a chelating ligand moiety; l1 and L2 are respectively and independently composed of a plurality of amino acid residues L; the basic fragment L0 of the amino acid residue L is selected from at least one of-Z-,-N (R8)-,-N (R8) 4,-C (= Z)-,-((C (R9) p) q-,-SO3H,-S (= O) j-,-NR8-C (= O)-,-NR8-C (= O)-NR8-,-C (= O)-NR8-,-((C (R9) p) q-Z) x-(C (R9) p) q-,-(C (R9) p) q-(Z-(C (R9) p) q) x-, alkylene, heteroalkylene, cycloalkylene, heterocyclic alkylene, arylene or heteroarylene; under a reasonable condition, a plurality of L0 are mutually spliced to form L, and one or more L can be mutually combined to form L1 or L2; or one or more L0 can be combined with each other to form L1 or L2. The compound provided by the invention can effectively optimize in-vivo pharmacokinetic characteristics and tumor retention capacity, and is used for developing and treating ccRCC.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to an integrated diagnosis and treatment CAIX ligand compound, a metal complex and applications thereof. Background Art

[0002] Renal cell carcinoma (RCC) accounts for over 90% of renal malignancies, with approximately 400,000 new cases worldwide annually. Clear cell RCC (ccRCC), the most common histological subtype, is the leading cause of kidney cancer-related deaths. This situation stems primarily from the limitations of traditional diagnostic and treatment models, including challenges such as difficulty in early diagnosis, high recurrence and metastasis in late stages, and suboptimal treatment outcomes. Therefore, achieving precise diagnosis and treatment of ccRCC is of great clinical significance.

[0003] Radiotherapy, as an emerging precision medicine strategy, achieves biomarker-guided integrated diagnosis and treatment by combining targeting ligands with diagnostic / therapeutic nuclides. It is worth noting that carbonic anhydrase IX (CAIX) is highly expressed in more than 95% of ccRCC, making it an ideal target for diagnosis and treatment. Among the reported CAIX-targeted probes, [ 68 Ga]Ga-DPI-4452 shows clinical application potential due to its rapid tumor accumulation ability and high target-to-cost ratio. 68 Ga, t 1 / 2 = 67.7 minutes) has a short half-life and is dependent 68 Ge / 68 Ga generator preparation, a single production can only obtain 1-3 patient doses. In contrast, fluorine-18 ( 18 F, t 1 / 2 =109.8 minutes) is the most widely used medical nuclide. It can not only be mass-produced by cyclotron accelerator, but also has better physical properties (positron emission yield 96.7% vs 88.9%, average energy 0.635 MeV vs 1.92 MeV). 18 F-labeled probes have higher spatial resolution. 18 F-labeled CAIX probes still suffer from limitations such as insufficient tumor uptake and elevated background signal. In internal radiotherapy, ideal pharmacokinetic properties are crucial for improving the therapeutic index, but reported ccRCC radiotherapy studies still face bottlenecks such as prolonged systemic circulation time and insufficient tumor retention.

[0004] It can be seen from this that there is an urgent need to provide a CAIX ligand compound, a metal complex and applications thereof. Summary of the Invention

[0005] To address the above problems, the present invention provides a CAIX ligand compound, a metal complex, and applications thereof, to develop a novel radionuclide-labeled CAIX ligand therapeutic pair, optimize in vivo pharmacokinetic properties and tumor retention capacity, and be used for the imaging and treatment of ccRCC.

[0006] In a first aspect, the present invention provides a CAIX ligand compound or an ester or pharmaceutically acceptable salt thereof, the structure of which is shown in formula (A):

[0007] Among them, R 1 is selected from hydrogen or -L1-E1; R 2 、R 3 、R 4 、R 5 、R 6 、R 7 are each independently selected from hydrogen or -L2-E2; n and m are each independently selected from 0, 1, 2, 3, 4, 5; Said E1 and E2 are each independently a chelating ligand portion; L1 and L2 are each independently composed of a number of amino acid residues L; The basic fragment L0 of the amino acid residue L is selected from -Z-, -N(R 8 )-、-N(R 8 )4、-C(=Z)-、-((C(R 9 ) p ) q -、-SO3H、-S(=O) j -、-NR 8 -C(=O)-、-NR 8 -C(=O)-NR 8 -、-C(=O)-NR 8 -、-((C(R 9 ) p ) q -Z) x -(C(R 9 ) p ) q -、-(C(R 9 ) p ) q -(Z-(C(R 9 ) p ) q ) x-, at least one of an alkylene group, a heteroalkylene group, a cycloalkylene group, a heterocycloalkylene group, an arylene group, or a heteroarylene group; where appropriate, multiple L0s are spliced ​​together to form L, one or more Ls can be combined to form L1 or L2; or one or more L0s can be combined to form L1 or L2; Each Z is independently selected from O or S; Each p is independently selected from 0, 1 or 2; Each j is independently selected from 0 or 1; q and x are each independently selected from an integer of 0-30, for example selected from 0-20 or 0-10 or 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R 8 are independently H, cycloalkyl or alkyl; Each R 9 is independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, alkylene-COOH, -SO3H, alkylene-SO3H, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkyl; L0, R 8 and R 9 wherein the alkoxy, alkylthio, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene groups are further optionally and independently monosubstituted or polysubstituted by the same or different substituents R; wherein the substituents R are hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, alkylene-COOH, alkylene-S03H, -B(OH)2, hydroxyl, -S03H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

[0008] Further, the L0 is selected from -Z-, -N(R 8 )-、-N(R 8 )4、-C(=Z)-、-((C(R 9 ) p ) q -、-SO3H、-S(=O) j -、-NR 8 -C(=O)-、-NR 8 -C(=O)-NR 8 -、-C(=O)-NR 8 -、-((C(R 9 ) p ) q -Z) x -(C(R 9 )p ) q -、-(C(R 9 ) p ) q -(Z-(C(R 9 ) p ) q ) x -、C 1-6 Heteroalkylene, C 1-12 Alkylene, C 3-12 Cycloalkylene, C 4-12 Heterocycloalkylene, C 6-12 Arylene, or C 5-12 At least one heteroarylene group; under reasonable circumstances, multiple L0s are spliced ​​together to form L, one or several Ls can be combined with each other to form L1 or L2; or one or more L0s can be combined with each other to form L1 or L2.

[0009] Further, the L0 is selected from -Z-, -N(R 8 )-、-N(R 8 )4、-C(=Z)-、-((C(R 9 ) p ) q -、-SO3H、-S(=O) j -、-NR 8 -C(=O)-、-NR 8 -C(=O)-NR 8 -、-C(=O)-NR 8 -、-((C(R 9 ) p ) q -Z) x -(C(R 9 ) p ) q -、-(C(R 9 ) p ) q -(Z-(C(R 9 ) p ) q ) x -、C 1-6 Heteroalkylene, C 1-12 Alkylene, C 3-12 Cycloalkylene, C 4-12 Heterocyclic alkylene, phenylene, pyridylene or C 5-12 At least one heteroarylene group; under reasonable circumstances, multiple L0s are spliced ​​together to form L, one or several Ls can be combined with each other to form L1 or L2; or one or more L0s can be combined with each other to form L1 or L2.

[0010] Further, the L0 is selected from -O-, -S-, -NH-, -C(=O)-, -NH-C(=O)-, -NR 8 -C(=O)-NR 8 -、-C(=O)-NH-、-(CH2) q -、-SO3H、-(CHR 9 ) q -、-((CH2) q -O) x -、-((CH2) q -O) x -(CH2) q -、-(CH2) q -(O-(CH2) q ) x -、 (For example )、 (For example , cyclohexylene, cyclopentylene), ,(For example , phenylene); wherein each A is independently selected from CR 9 or N; each B is independently selected from -C(R 9 )2-、O、-S(=O) j -、-N(R 8 ) j - , or at least one of -C(=Z)-; the values ​​of q, x, A or B in the same structural formula can be the same or different and do not affect each other; under reasonable circumstances, multiple L0s are spliced ​​together to form L, one or several Ls can be combined to form L1 or L2; or one or more L0s can be combined to form L1 or L2.

[0011] Furthermore, the L is selected from at least one of the following fragments: .

[0012] Furthermore, L1 and L2 are each independently selected from at least one of the following fragments: .

[0013] Furthermore, each R 8 Independently H, C 3-12 Cycloalkyl or C 1-6 Alkyl; each R 9 are independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6alkyl-SO3H, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl or C 1-6 alkyl.

[0014] Further, the E1 and E2 are each independently selected from AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, CT A, cyclam, cyclen, TETA, Sarcophagine, CPTA, TEAMA, Cyclen, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5decapa, H2azapa, H2CHX DEDPA, DFO-Chx-MAL, DFO-p-SCN, DFO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, Diphosphine, DOTA, DOTAGA, DOTA-MFCO, DOTAM-monobasic acid, nitro-DOTA, nitro-PA-DOTA, p-NCS -Bz-DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, 3,4,3-(Li-1,2-HOPO), TREN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOXP, p-NCS-DOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-monoamide-DOTA, BCN-DOTA, butyne-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2 A(trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)acetamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimido-mono-amide-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p -SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone–benzothiazole, thiosemicarbazone–styrylpyridine tetradentate ligand H2L2–4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, Deferiprone, THP, HYNIC (2-hydrazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A,IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, Macropa, Macropaquin, Macroquin-SO3, N, x S 4-x, N2S2, N3S, N4, MAG3B, NOTA, NODAGA, SCN-Bz-NOTA-R, NOT-P(NOTMP), NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NO2A, N-Benzyl-NODA, C-NOTA, BCNOT-monoamine, maleimido-mono-amide-NOTA, NO2A-azide , NO2A-butyne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-Cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, T RAP, PEPA, BF-PEPA, Pycup, Pycup2A, pycup1A1Bn, pycup2Bn, SarAr-R, Diamsar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAM A.TAM B. TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, T E2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A,, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ -HTCPP, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid (DOTAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-N-pentanedioic acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid (NODA-MPAA), bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A), DFO, hexadentate tris(3,4-hydroxypyridone) (THP), dodecanetetraacetic acid, nitro-DOTA, 4-aminophenethyl-1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (partial acetic acid of 2-[4,7-bis(carboxymethyl)-1,4,7-triazolidin-1-yl])-NOTA, (triethylenetetramine)-TETA, deferoxamine, (ethylenediaminetetraacetic acid)-EDTA, penicillamine,. One or more of .

[0015] Furthermore, the E1 and E2 are each independently selected from but not limited to DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99m Tc(CO)3-chelating agents and analogs thereof, wherein: DOTA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA stands for 1,4,7,10-tetraazacyclododecane-1-(pentanedioic acid)-4,7,10-triacetic acid; NOTA stands for 1,4,7-triazacyclononanetriacetic acid; NODAGA stands for 1,4,7-triazacyclononane-N-pentanedioic acid-N',N"-diacetic acid; NODA-MPAA stands for 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid; HBED represents bis(2-hydroxybenzyl)ethylenediaminediacetic acid; TETA represents 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid; CB-TE2A represents 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane; DTPA represents diethylenetriaminepentaacetic acid; DFO represents a chelating agent of the Desferal or Desferrioxamine type, the chemical name of which is a non-limiting example of N-[5- ({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide; Macropa represents N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown; HOPO represents an octadecylhydroxypyridone type chelating agent group, the structure of a non-limiting example of which is shown below; TRAP represents 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphoryl]- THP represents hexadentate tris(3,4-hydroxypyridinone); DATA represents [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid; NOTP represents 1,4,7-triazacyclononane-N,N′N″-tri(methylenephosphonic) acid); Sarcophagine represents 3,6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane; FSC stands for 3,15,27-triamino-7,19,31-trihydroxy-10,22,34-trimethyl-1,13,25-trioxa-7,19,31-triaza-cyclohexatriacontane-9,21,33-triene-2,8,14,20,26,32-hexaone; NETA, {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazanonan-1-yl}-acetic acid; H4octapa represents N,N′-(6-carboxy-2-pyridylmethyl)-N,N′-diacetic acid-1,2-ethylenediamine; Pycup represents 1,8-(2,6-pyridyldimethylene)-1,4,8,11-tetraazacyclotetradecane; NxS4-x(N4, N2S2, N3S) represents a group of tetradentate chelating agents with a nitrogen atom (basic amine or non-basic amide) and a thiol donor, which stabilize Tc complexes, particularly Tc(V)-oxo complexes. The structure of a representative, non-limiting example, MAG3, is shown below; and MAG3 represents {2-[2-(3-mercapto-propionylamino)-acetylamino]-acetylamino}-acetic acid; HYNIC represents 6-hydrazino-nicotinic acid. 99m Tc(CO)3-chelator means a bidentate or tridentate chelator that can form a stable complex with a technetium tricarbonyl fragment; Its chemical structure is shown below: or

[0016]

[0017] Furthermore, the E1 and E2 are each independently selected from one of the following structural fragments: .

[0018] Furthermore, the compound or its ester or pharmaceutically acceptable salt is as shown in the following structural formula:

[0019] Among them, R 1 、R 2 、R 4 、R 7 , m, and n have the meanings as described in the present invention.

[0020] Furthermore, the compound of the present invention is selected from one of the following structures: .

[0021] In a second aspect, the present invention provides use of the compound according to the first aspect or an ester or pharmaceutically acceptable salt thereof.

[0022] Furthermore, the compound or its ester or pharmaceutically acceptable salt is used for preparing a radiolabeled compound.

[0023] In a third aspect, the present invention provides a metal complex.

[0024] Furthermore, the metal complex is formed by complexing a radioactive nuclide with the compound described in the first aspect or an ester or a pharmaceutically acceptable salt thereof.

[0025] Furthermore, the radionuclide includes 18 F. 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P. 44 Sc, 47 Sc, 165 Dy, 169 Second, 177 Lu, 142 Pr, 159 Gd, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co、 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y. 89 Y. 90 Y. 89 Sr. 89 Zr, 94mTc, 99m Tc, 111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P. 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I. 169 Second, 177 Lu, 186 Re、 188 Re、 211 At 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re、 188 Re、 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th, preferably 177 Lu, 68 Ga, 86 Y. 90 Y, 64 Cu, 67 Cu, 213 Bi, 225 Ac or 89 Y.

[0026] Further, for NOTA-C3-DPI, the metal complex is selected from the group consisting of compounds [ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-NOTA-C3-DPI, [ 64 Cu]Cu-NOTA-C3-DPI.

[0027] Furthermore, for the compound of the present invention, the metal complex is selected from one of the following compounds: compound [ 177Lu]Lu-C3-DPI, compound [ 68 Ga]Ga-C3-DPI, compound [ 86 Y]Y-C3-DPI, compound [ 89 Y]Y-C3-DPI, compound [ 90 Y]Y-C3-DPI, compound [ 64 Cu]Cu-C3-DPI, compound [ 67 Cu]Cu-C3-DPI, compound [ 213 Bi]Bi-C3-DPI, compound [ 225 Ac]Ac-C3-DPI, compound [ 177 Lu]Lu-DPI-ZH1, compound [ 68 Ga]Ga-DPI-ZH1, compound [ 86 Y]Y-DPI-ZH1, compound [ 89 Y]Y-DPI-ZH1, compound [ 90 Y]Y-DPI-ZH1, compound [ 64 Cu]Cu-DPI-ZH1, compound [ 67 Cu]Cu-DPI-ZH1, compound [ 213 Bi]Bi-DPI-ZH1, compound [ 225 Ac]Ac-DPI-ZH2, compound [ 177 Lu]Lu-DPI-ZH2, compound [ 68 Ga]Ga-DPI-ZH2, compound [ 86 Y]Y-DPI-ZH2, compound [ 89 Y]Y-DPI-ZH2, compound [ 90 Y]Y-DPI-ZH1, compound [ 64 Cu]Cu-DPI-ZH2, compound [ 67 Cu]Cu-DPI-ZH2, compound [ 213 Bi]Bi-DPI-ZH2, compound [ 225 Ac]Ac-DPI-ZH2,, compound [ 177 Lu]Lu-DPI-ZH3, compound [ 68 Ga]Ga-DPI-ZH3, compound [ 86 Y]Y-DPI-ZH3, compound [ 89 Y]Y-DPI-ZH3, compound [ 90 Y]Y-DPI-ZH3, compound [ 64 Cu]Cu-DPI-ZH3, compound [ 67Cu]Cu-DPI-ZH3, compound [ 213 Bi]Bi-DPI-ZH3, compound [ 225 Ac]Ac-DPI-ZH3, compound [ 177 Lu]Lu-DPI-ZH4, compound [ 68 Ga]Ga-DPI-ZH4, compound [ 86 Y]Y-DPI-ZH4, compound [ 89 Y]Y-DPI-ZH4, compound [ 90 Y]Y-DPI-ZH4, compound [ 64 Cu]Cu-DPI-ZH4, compound [ 67 Cu]Cu-DPI-ZH4, compound [ 213 Bi]Bi-DPI-ZH4, compound [ 225 Ac]Ac-DPI-ZH4, [ 177 Lu]Lu-P-DPI, compound [ 68 Ga]Ga-P-DPI, compound [ 86 Y]YP-DPI, compound [ 89 Y]YP-DPI, compound [ 90 Y]YP-DPI, compound [ 64 Cu]Cu-P-DPI, compound [ 67 Cu]Cu-P-DPI, compound [ 213 Bi]Bi-P-DPI, compound [ 225 Ac]Ac-P-DPI.

[0028] Furthermore, the structure of the metal complex is selected from one of the following:

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] .

[0039] In a fourth aspect, the present invention provides a composition.

[0040] A composition comprising: (1) the compound of formula (A) or its ester or pharmaceutically acceptable salt described in the first aspect, or the metal complex described in the third aspect or the ester or pharmaceutically acceptable salt of the metal complex described in the third aspect; and (2) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0041] In a fifth aspect, the present invention provides a kit.

[0042] A kit comprising the compound of formula (A) or its ester or pharmaceutically acceptable salt according to the first aspect, and auxiliary materials for preparing the metal complex according to the third aspect.

[0043] In a sixth aspect, the present invention provides an application.

[0044] Use of the compound or its ester or pharmaceutically acceptable salt described in the first aspect or the metal complex described in the third aspect in the preparation of a diagnostic tracer or therapeutic drug.

[0045] In some embodiments, the compound or its ester or pharmaceutically acceptable salt described in the first aspect or the metal complex described in the third aspect is used in the preparation of an agent for diagnosing a tumor having a CAIX receptor or its metastasis or an agent for treating a tumor having a CAIX receptor.

[0046] In some embodiments, the tumors having CAIX receptors include renal cell carcinoma, pancreatic cancer, colon cancer, esophageal cancer, breast cancer, and bladder urothelial carcinoma.

[0047] Beneficial effects: An embodiment of the present invention has at least one of the following beneficial effects: (1) The compounds provided by the present invention have good binding ability with CAIX. The IC of NOTA-C3-DPI is 50 The IC value of DOTAGA-DPI-ZH2 was 1.65 ± 0.31 nM, which was 1.8 times stronger than DOTA-DPI-4452. 50 The inhibitory effect was 0.04 ± 0.01 nM, which was 2.3 times more potent than DOTA-DPI-4452.

[0048] (2) Compared with the tracers or therapeutic agents in the prior art, such as DOTA-DPI-4452 or its radionuclide labeled compounds, the compounds provided by the present invention (such as [ 18 F]AlF-C3-DPI, [ 177 Lu]Lu-C3-DPI or [ 68 Ga]Ga-DPI-ZH2) showed comparable or even higher uptake values ​​in CAIX-expressing tumors.

[0049] (3) The compounds provided by the present invention (for example [ 18 F]AlF-C3-DPI, [ 177 Lu]Lu-C3-DPI or [ 68 The uptake of [Ga]Ga-DPI-ZH2) gradually increased over time in tumors with high CAIX expression, while the uptake gradually decreased in other non-specific expression organs (such as heart, brain, muscle, lung and liver).

[0050] (4) The compounds provided by the present invention (for example [ 18 F]AlF-C3-DPI, [ 68 The degradation rate of the Ga]Ga-DPI-ZH2 peptide was ≤5% in normal saline and serum within at least 2 hours in vitro, and the degradation rate of the Ga]Ga-DPI-ZH2 peptide was ≤5% in serum within at least 2 hours in vitro.

[0051] (5) After adding competitively bound DOTA-DPI-4452, the tumors with high CAIX expression were sensitive to the compounds provided by the present invention (e.g. [ 18 F]AlF-C3-DPI, [ 177 Lu]Lu-C3-DPI or [ 68 The uptake value of Ga]Ga-DPI-ZH2) was significantly weakened, and the inhibitory effect in vivo was significant, indicating that the compounds provided by the present invention have high specificity in vivo.

[0052] (6) The compounds provided by the present invention (for example [ 18 F]AlF-C3-DPI, [ 177 Lu]Lu-C3-DPI or [ 68 Ga]Ga-DPI-ZH2) is metabolized by the kidneys and has a low background of radioactive uptake, making it a highly specific tracer or therapeutic agent for targeting CAIX.

[0053] (7) Compared with the tracers or therapeutic agents in the prior art, the compounds provided by the present invention (e.g. [ 18 F]AlF-C3-DPI or [ 177 As for the tracer, the tumor response to the compound provided by the present invention ([ 18 F]AlF-C3-DPI) uptake was significantly higher than that of [ 68 As for therapeutic agents, the tumor showed no significant difference in response to the compounds provided by the present invention (e.g., [ 177 The uptake of Lu]Lu-C3-DPI) was significantly higher than that of [ 177 Lu]Lu-DPI-4452. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The different concentrations of substances in Example 15 are shown to be 177 Statistical graph of the inhibition results of Lu]Lu-C3-DPI and OS-RC-2 cells.

[0055] Figure 2 In Example 16, [ 18 [F] Statistical graph of the uptake values ​​of AlF-C3-DPI in OS-RC-2 cells with high CAIX expression (CAIX (+) uptake group) after incubation for 5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes.

[0056] Figure 3 In Example 16, [ 18Statistical graph of the uptake values ​​of [F]AlF-C3-DPI in OS-RC-2 cells with high CAIX expression (CAIX (+) uptake group) after incubation for 60 minutes with the addition of competitively bound DOTA-DPI-4452 (CAIX (+) inhibition group).

[0057] Figure 4 In Example 16, [ 177 Lu]Lu-C3-DPI and [ 177 Statistical graph of the uptake values ​​of Lu]Lu-DPI-4452 in OS-RC-2 cells with high CAIX expression (CAIX (+) uptake group) after incubation for 0.5 h, 1 h, 2 h, 4 h, and 12 h.

[0058] Figure 5 The cell outflow rate statistics of Example 17 are shown. 177 Lu]Lu-C3-DPI and [ 177 Statistical graph of cell efflux rate was plotted based on the uptake values ​​of Lu]Lu-DPI-4452 after incubation in CAIX-overexpressing OS-RC-2 cells (CAIX(+) uptake group) for 1 hour and cultured in radioactive-free medium for 0, 0.5, 1, 2, 4, and 12 hours.

[0059] Figure 6 The stability of the compound in Example 18 in vitro was detected by Radio-HPLC. 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 The stability of Ga]Ga-P-DPI in vitro is detected by Radio-HPLC. 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 Ga]Ga-P-DPI remained intact after incubation in PBS and in vitro serum (mouse and human) at 37°C for 2 h (prototype degradation rate ≤ 5%).

[0060] Figure 7 In Example 19, [ 18 F]AlF-C3-DPI and [68 PET imaging of Ga]Ga-DPI-4452 in a tumor-bearing animal model with high CAIX expression. This figure includes [ 18 F]AlF-C3-DPI and [ 68 PET images of Ga]Ga-DPI-4452 uptake at 1 hour, 2 hours, and 4 hours in the OS-RC-2 tumor model (CAIX (+) uptake group), and [ 18 PET images of 1-hour uptake and inhibition of [F]AlF-C3-DPI in the OS-RC-2 tumor model (Blocking (CAIX(+) inhibition group)) and the AsPC-1 tumor model (CAIX(-) uptake group).

[0061] Figure 8 In Example 19, [ 18 F]AlF-C3-DPI and [ 68 Bar graph of tumor uptake of [Ga]Ga-DPI-4452 in the OS-RC-2 tumor model (CAIX(+) uptake group) at 1 hour, 2 hours, and 4 hours.

[0062] Figure 9 In Example 19, [ 18 F]AlF-C3-DPI and [ 68 Bar graph of the uptake of [Ga]Ga-DPI-4452 in the stomach, small intestine, liver, brain, and femur at 1 hour in the OS-RC-2 tumor model (CAIX(+) uptake group).

[0063] Figure 10 In Example 19, [ 18 F]AlF-C3-DPI and [ 68 Histogram of tumor uptake of Ga]Ga-DPI-4452 in OS-RC-2 tumor models (CAIX(+) uptake group, CAIX(+) inhibition group) and AsPC-1 (CAIX(-) uptake group).

[0064] Figure 11 In Example 19, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4, [ 68 Ga]Ga-P-DPI and [ 68 PET images of [Ga]Ga-DPI-4452 in OS-RC-2 tumor-bearing nude mice within 120 minutes.

[0065] Figure 12In Example 19, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-P-DPI and [ 68 Bar graph of 1-hour uptake of [Ga]Ga-DPI-4452 in the stomach, lung, liver, kidney, and tumor in the OS-RC-2 tumor model (CAIX(+) uptake group).

[0066] Figure 13 In Example 19, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-P-DPI and [ 68 Bar graph of [Ga]Ga-DPI-4452 uptake in the stomach, lung, liver, kidney, and tumor at 2 h in the OS-RC-2 tumor model (CAIX(+) uptake group).

[0067] Figure 14 In the exemplary embodiment 19, [ 68 PET images of [Ga]Ga-DPI-ZH2 in the OS-RC-2 tumor model (CAIX(+) inhibition group).

[0068] Figure 15 In the exemplary embodiment 19, [ 68 Bar graph of the uptake of [Ga]Ga-DPI-ZH2 in the OS-RC-2 tumor model (CAIX(+) inhibition group).

[0069] Figure 16 In Example 20, [ 18 F]AlF-C3-DPI in OS-RC-2 ([ 18 F]AlF-C3-DPI uptake group) and OS-RC-2 ([ 18 F]AlF-C3-DPI inhibition group, with the addition of competitively binding DOTA-DPI-4452), and [ 68 Ga]Ga-DPI-4452 in OS-RC-2 ([ 68 Biodistribution diagram of the tumor-bearing nude mice (Ga]Ga-DPI-4452 uptake group) after 1 h.

[0070] Figure 17 In Example 20, [ 177 Lu]Lu-C3-DPI in OS-RC-2 ([ 177 Biodistribution of Lu in tumor-bearing nude mice (Lu-C3-DPI uptake group) at 1 h, 4 h, 24 h, 72 h, and 168 h.

[0071] Figure 18 In Example 20, [ 177 Lu]Lu-DPI-4452 in OS-RC-2 ([ 177 Biodistribution of Lu]Lu-DPI-4452 uptake group in tumor-bearing nude mice at 1 h, 4 h, 24 h, 72 h, and 168 h.

[0072] Figure 19 In Example 20, [ 177 Lu]Lu-C3-DPI and [ 177 Tumor and kidney uptake curves of Lu]Lu-DPI-4452 in OS-RC-2 (uptake group) tumor-bearing nude mice at 168 h.

[0073] Figure 20 In Example 20, [ 177 Lu]Lu-C3-DPI([ 177 Biodistribution of Lu]Lu-C3-DPI inhibition group (competitively bound DOTA-DPI-4452 added) in OS-RC-2 tumor-bearing nude mice for 4 hours.

[0074] Figure 21 In Example 20, [ 177 Lu]Lu-C3-DPI intake group and [ 177 Statistical graph of the area under the uptake curve of Lu]Lu-DPI-4452 in the tumor, kidney, gallbladder, small intestine, and stomach of OS-RC-2 and tumor-bearing mice.

[0075] Figure 22 In Example 20, [ 177 Lu]Lu-C3-DPI intake group and [ 177 Statistical graph of the ratios of the areas under the tissue uptake curves of interest (tumor / kidney, tumor / gall bladder, tumor / small intestine, and tumor / stomach) in the Lu]Lu-DPI-4452 uptake groups in OS-RC-2 and tumor-bearing mice.

[0076] Terminology Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl.

[0077] The heteroalkyl moiety can include four optionally different heteroatoms (eg, O, N, S, Si, or P).

[0078] Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.

[0079] Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. Examples of heterocyclic groups include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathiophenyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, oxepanyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.

[0080] "Alkylene" alone or as part of another substituent refers to a divalent radical of alkyl; for example, "cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively; and the same applies to other groups.

[0081] Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryls. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linker.

[0082] Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), and the like.

[0083] Cycloalkyl refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings are saturated. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as a C3-6 saturated or partially unsaturated cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from the group consisting of a saturated monocyclic cycloalkyl group, a saturated bicyclic cycloalkyl group, a saturated tricyclic cycloalkyl group, a partially unsaturated monocyclic cycloalkyl group, a partially unsaturated bicyclic cycloalkyl group, and a partially unsaturated tricyclic cycloalkyl group. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms.

[0084] In this article , the positions of the bonds can be combined at any reasonable position on the ring, which can be expressed as 、 、 etc.; as in this article, “ ", the positions of the bonds can be combined at any reasonable position on the ring, which can be expressed as 、 、 、 Etc.; and so on.

[0085] In the present invention, room temperature refers to ambient temperature, which is 10°C-45°C, or 10°C-30°C, or 20°C-28°C.

[0086] In the present invention, 68 Ga represents gallium-68; 177 Lu represents lutetium-177; 86 Y represents yttrium-86; 90 Y represents yttrium-90; 64 Cu represents copper-64; 67 Cu represents copper-67; 213 Bi represents bismuth-213; 225 Ac represents actinium-225; 89Y stands for yttrium-89, and the others are analogous. pip stands for piperidine; pH stands for pH; nmol / ml stands for nanomoles per milliliter; mg stands for milligrams; DMSO stands for dimethyl sulfoxide; PBS stands for phosphate-buffered saline; min stands for minutes; %ID / g stands for the percentage of the injected dose taken up per gram of tissue; %ID / 1 mio cells stands for the percentage of the injected dose taken up per million cells; μM stands for micromoles per liter; mmol stands for millimoles; GBq / µmol stands for 10 9 MBq stands for megabecquerel (10 6 Becquerel (Beck); μCi denotes microcuries of radioactivity; mio cells / well denotes millions of cells per well; SDS denotes sodium dodecyl sulfate; NaOH denotes sodium hydroxide; OS-RC-2 cells denote human renal cancer cells with high CAIX expression; AsPC-1 cells denote human metastatic pancreatic cancer cells with low CAIX expression. Final concentration denotes the concentration of the substance in the solution at the end of sample and reagent addition; Radio-HPLC denotes radioactive high-performance liquid chromatography; CAIX-Positive denotes cells with high CAIX expression; CAIX-Negative denotes cells with low CAIX expression.

[0087] The term "MIP" refers to Maximum Intensity Projection.

[0088] In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, a feature specified as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, "plurality" means two or more, unless otherwise specifically defined.

[0089] In the present invention, "pharmaceutically acceptable" means a substance or compound that is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reaction or similar reaction within the scope of sufficient medical judgment and has a reasonable benefit / risk ratio.

[0090] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", "further" or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0091] In the present invention, expressions such as "compound of formula (A)" and "compound represented by formula (A)" refer to the same compound; expressions such as "DOTA-C3-DPI", "compound DOTA-C3-DPI" and "DOTA-C3-DPI compound" refer to the same compound.

[0092] In the present invention, the structures of the compounds are shown in Table 1 below: DETAILED DESCRIPTION

[0093] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0094] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0095] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0096] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", "further", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and features of different embodiments or examples, unless they are contradictory.

[0097] In the following description, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% is expressly disclosed, where "+ / -" means plus or minus.

[0098] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0099] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur.

[0100] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0101] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0102] The technical solutions of the present invention are illustrated below with examples, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0103] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0104] In the present invention, DIPEA represents N,N-diisopropylethylamine; DMF represents N,N-dimethylformamide; DSC represents N,N'-disuccinimidyl carbonate; HOBt represents 1-hydroxybenzotriazole; DIC represents N,N'-diisopropylcarbodiimide; TFA represents trifluoroacetic acid; TIS represents triisopropylsilane; 2-PMPA represents 2-(phosphonomethyl)pentanedioic acid; HATU represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrobromide; DCM represents dichloromethane; TIS represents triisopropylsilane; EDCI represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and NMM represents N-methylmorpholine.

[0105] In the present invention, the evaluation of NOTA-C3-DPI, DOTA-C3-DPI, the control drug DOTA-DPI-4452 and their corresponding metal complexes was carried out in the same batch of cells and tumor models; the evaluation of DOTAGA-DPI-ZH1, DOTAGA-DPI-ZH2, DOTA-DPI-ZH3, DOTA-DPI-ZH4, DOTAGA-P-DPI, the control drug DOTA-DPI-4452 and their metal complexes was carried out in another identical batch.

[0106] Example 1: Preparation of compound NOTA-C3-DPI 1) Preparation of the compound of formula (1)

[0107] Deprotection: Rink Amide-MBHA Resin (1.5 mmol) was swelled in 5 mL of anhydrous DMF for 30 minutes, then washed and drained. The Fmoc protecting group was removed from the resin using 3 mL of a 20% piperidine / DMF solution (1:4, 3 mL, 2-20 minutes). This was repeated twice (first 5 minutes, second 15 minutes). The resin was then washed with either 3 mL of DMF or 4 mL of DCM to remove excess deprotection solution, yielding the resin. Coupling: Fmoc-Cys(Trt)-OH (3 mmol) and HOBt (3 mmol) were dissolved in 3 mL of anhydrous DMF and activated with DIC (3 mmol) for 5 minutes. This activated solution was then added to the resin (1.5 mmol) and reacted at room temperature for 60 minutes for coupling. After the coupling was completed, the resin was filtered and washed thoroughly with 3 mL of DMF. The resin was then treated twice with 3 mL of 20% piperidine / DMF solution (volume ratio 1:1) (first for 5 minutes, second for 15 minutes) to remove the Fmoc protecting group. The resin was then dried after each treatment. Finally, the resin was thoroughly washed with 3 mL of DMF to remove residual piperidine. After drying, the target product H-Cys(Trt)-Resin (Formula (1)) was obtained.

[0108] 2) Preparation of the compound of formula (2)

[0109] Repeat the coupling process of step 1) to sequentially couple the compound of formula (1) (1.5 mmol) prepared in step 1) with the following amino acids (all 1.5 mmol): Fmoc-Cys(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-DPro-OH , Fmoc-Glu(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-2-(piperazin-1-yl)acetic acid, Fmoc-Cys(SO3H)-OH, Fmoc-Cys(SO3H)-OH, Fmoc-Cys(SO3H)-OH to obtain the compound of formula (2).

[0110] 3) Preparation of the compound of formula (3)

[0111] The compound of formula (2) prepared in step 2) (4 mmol) was washed three times with 3 mL of anhydrous DMF; NOTA-bis( tBu)ester (4 mmol) was dissolved in 3 mL of anhydrous DMF, and HATU (4 mmol) and DIPEA (8 mmol) were added for activation for 2 minutes, and then transferred to the compound of formula (2). The N-terminal coupling was completed by shaking at room temperature for 3 hours. After filtration, the resin was washed with 3 mL of DMF and 3 mL of DCM in sequence. Subsequently, 3 mL of a mixture of TFA / water / TIS (volume ratio 95:2.5:2.5) was added to the filtrate and reacted for 2 hours under ice bath conditions at 0°C, and then filtered. The filtrate was poured into cold ether, and the solid initial product precipitated. The compound of formula (3) was then isolated by semi-preparative separation. An appropriate amount of the compound of formula (3) was taken for mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 89 H 134 N 24 O 39 S6 ([M + 2H] 2+ ), 1178.38, mass spectrum measured 1178.65.

[0112] 4) Preparation of NOTA-C3-DPI

[0113] The compound of formula (3) prepared in step 3) was dissolved in 3 mL of a 1:1 mixed solvent of ammonium carbonate aqueous solution (50 mM, pH = 8.5) and acetonitrile, 1,3-di(bromomethyl)benzene (1 mmol) was added, and stirred at room temperature for 2 hours to obtain the NOTA-C3-DPI compound. An appropriate amount of the NOTA-C3-DPI compound was subjected to mass spectrometry, hydrogen spectrum and high performance liquid chromatography detection, and the mass spectrometry results were: the molecular formula is C 97 H 140 N 24 O 39 S6 ([M + 2H] 2+ ), 1229.40, mass spectrometry measured 1229.78; HPLC results measured: purity >98%.

[0114] Example 2: 18 Preparation of F]AlF-C3-DPI compound Using NOTA-C3-DPI compound as precursor, the product was obtained by cyclotron. 18 F - Manual labeling is performed [ 18 The preparation of the compound F]AlF-C3-DPI comprises the following steps: 1) Add 40 nmol of compound NOTA-C3-DPI dissolved in DMSO (0.3 mL) to the reaction flask; 2) Add 10 μL of AlCl3 solution (0.2 M, pH = 4.0) to the reaction bottle and shake thoroughly for one minute; 3) 18 After eluting F- onto the QMA column, sodium acetate solution (0.5 M, pH = 3.9, 0.3 mL) was used to 18 F - Elute into the reaction bottle in step 2); 4) Heat the reaction flask to 105 0 C After reacting for 15 to 20 minutes, a reaction solution containing the product is obtained; 5) Add 3 mL of water to dilute the mixture to obtain a diluted reaction solution; 6) The diluted reaction solution was passed through a Sep-Pak C18 column (Waters, USA) to adsorb the product onto a Sep-Pak C18 column (Waters, USA); 7) Rinse the Sep-Pak C18 column (Waters, USA) twice with 10 mL of water each time to remove the residual 18 F - ion; 8) Elute the product from the Sep-Pak C18 column (Waters, USA) with 2 mL of ethanol into a transfer bottle and dilute with normal saline; 9) The product in the transfer bottle was filtered through a sterile membrane to obtain compound [ 18 F]AlF-C3-DPI.

[0115] Prepared from 18 F - ions, and the compound was successfully prepared within 30 to 40 minutes. 18 F]AlF-C3-DPI with a decay-corrected yield of 25%, a radiochemical purity of >98%, and a specific activity of 22 GBq / µmol.

[0116] Example 3: Preparation of DOTA-C3-DPI 1) Preparation of the compound of formula (4)

[0117] The compound of formula (2) (1 mmol) prepared in Example 1 was washed three times with 3 mL of anhydrous DMF; DOTA-tris( tBu)ester (4 mmol) was dissolved in 3 mL of anhydrous DMF, and HATU (4 mmol) and DIPEA (8 mmol) were added for activation for 2 minutes, and then transferred to the compound of formula (2). The N-terminal coupling was completed by shaking at room temperature for 3 hours. After filtration, the resin was washed with 3 mL of DMF and 3 mL of DCM in sequence. Subsequently, 3 mL of a mixture of TFA / water / TIS (volume ratio 95:2.5:2.5) was added to the filtrate and reacted for 2 hours under ice bath conditions at 0°C and filtered. The filtrate was poured into cold ether, and the solid initial product precipitated. The compound of formula (4) was then isolated by semi-preparative separation. An appropriate amount of the compound of formula (4) was taken for mass spectrometry detection, and the mass spectrometry results were measured: the molecular formula is C 93 H 141 N 25 O 41 S6 ([M + 2H] 2+ ), 1228.90, mass spectrum measured 1229.31.

[0118] 2) Preparation of DOTA-C3-DPI

[0119] The compound of formula (4) obtained in step 1) was dissolved in 3 mL of a 1:1 mixed solvent of ammonium carbonate aqueous solution (50 mM, pH = 8.5) and acetonitrile, 1,3-di(bromomethyl)benzene (1 mmol) was added, and stirred at room temperature for 2 hours to obtain the DOTA-C3-DPI compound. An appropriate amount of the DOTA-C3-DPI compound was subjected to mass spectrometry, hydrogen spectrum and high performance liquid chromatography detection, and the mass spectrometry results showed that the molecular formula was C 101 H 147 N 25 O 41 S6 ([M + 2H] 2+ ), 1279.93, mass spectrometry measured 1281.10; HPLC results: purity >98%.

[0120] Example 4: 177 Preparation of Lu]Lu-C3-DPI Using DOTA-C3-DPI compound as precursor, manual labeling was performed [ 177 The preparation of Lu]Lu-C3-DPI compound comprises the following steps: 1) Purchased 177 Sodium acetate solution (0.4 M, pH = 5.5, 0.4 mL) and gentisic acid (4 mg) were added to LuCl3 solution (370-740 MBq) to obtain a mixed solution; 2) Add the mixed solution obtained in step 1) to the compound DOTA-C3-DPI (73.6 μg, 50 nmol) and heat to 90-100 0 After 15-20 minutes of reaction, a reaction solution containing the product was obtained, which was cooled to room temperature. 3 mL of water was added to dilute the solution to obtain a diluted reaction solution. The diluted reaction solution was passed through a Sep-Pak C18 column (Waters, USA) to adsorb the product onto the Sep-Pak C18 column (Waters, USA). The Sep-Pak C18 column (Waters, USA) was then rinsed with 3 mL of water to remove any residual 177 Lu ion; the product was eluted from Sep-Pak C18 column (Waters, USA) with 2 mL of ethanol into a transfer bottle and diluted with physiological saline to obtain [[ 177 Lu]Lu-C3-DPI.

[0121] The radiochemical purity was >95% as determined by HPLC and the product was used directly after dilution with saline.

[0122] Example 5: Preparation of DOTAGA-DPI-ZH1 compound 1) Preparation of the compound of formula (5)

[0123] Repeat step 1) of Example 1 to couple the compound of formula (1) (1.5 mmol) with the following amino acids (1.5 mmol each): Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-D-Pro-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Lys(Dde)-OH, and Fmoc-PPAc to obtain the compound of formula (5).

[0124] 2) Preparation of the compound of formula (6)

[0125] According to the method of step 3) of Example 1, the compound of formula (5) (1 mmol) and DOTAGA-tetra ( t Bu)ester (4 mmol) was used to complete the N-terminal coupling to obtain the compound of formula (6). Mass spectrometry results: The molecular formula is C 163 H 235 N 21 O33 S3 ([M+ 2H] 2+ ), 1555.82, mass spectrometry measured 1555.73; HPLC results measured: purity >98%.

[0126] 3) Preparation of the compound of formula (7)

[0127] According to the method of step 3) of Example 1, the compound of formula (6) (1 mmol) and 4-sulfonylbutyric acid (4 mmol) were coupled at the N-terminus, and the compound of formula (7) was obtained after post-treatment using the same method.

[0128] 4) Preparation of the compound of formula (8)

[0129] The compound of formula (7) obtained in step 3) was added to 3 mL of DCM. The solution was cooled in an ice bath, and HOOBt (1 mmol), EDCI (1 mmol), and NMM (1 mmol) were added in sequence to activate the carboxyl group. Then, the dissolved 2-amino-N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]-acetamide (1 mmol) was added. The ice bath was removed and the mixture was heated to room temperature and stirred for 1 hour. Subsequently, TFA (1 mmol) was added for deprotection reaction to obtain the compound of formula (8). An appropriate amount of the compound of formula (8) was taken for mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 77 H 100 N 16 O 23 S3 ([M + 2H] 2+ ), 1222.94, mass spectrum measured 1224.24.

[0130] 5) Preparation of DOTAGA-DPI-ZH1

[0131] According to the method of step 4) of Example 1, DOTAGA-DPI-ZH1 compound was prepared from the compound of formula (8). An appropriate amount of DOTAGA-DPI-ZH1 compound was subjected to mass spectrometry, hydrogen spectrum and high performance liquid chromatography. The mass spectrum results showed that the molecular formula was C 104 H 151 N 27 O 36 S6 ([M + 2H] 2+ ), 1273.95, mass spectrometry measured 1273.90; HPLC results measured: purity >98%.

[0132] Example 6: 68Preparation of Ga]Ga-DPI-ZH1 Using DOTAGA-DPI-ZH1 compound as precursor, a germanium gallium generator was used to obtain 68 Manual labeling of GaCl3 was performed [ 68 The preparation of Ga]Ga-DPI-ZH1 comprises the following steps: 1) Add 10 nmol of DOTAGA-DPI-ZH1 dissolved in 1 mL of sodium acetate solution (sodium acetate concentration: 0.25 M, pH = 5.5) to the reaction flask. 2) Wash the GaGe generator with 0.5M hydrochloric acid solution (pH = 3.0, 4 mL). 68 Ga - Add to the reaction bottle and heat to 106 0 C. After reacting for 10 to 20 minutes, a reaction solution containing the product is obtained and cooled to room temperature; 3) Add 3 mL of water to dilute the mixture to obtain a diluted reaction solution; 4) The diluted reaction solution was passed through a Sep-Pak C18 column (Waters, USA) to adsorb the product onto a Sep-Pak C18 column (Waters, USA); 5) Rinse the Sep-Pak C18 column (Waters, USA) twice with 10 mL of water each time to remove the residual 68 Ga - ion; 6) Elute the product from the Sep-Pak C18 column (Waters, USA) with 2 mL of ethanol into a transfer bottle and dilute with normal saline; 7) The product in the transfer bottle was filtered through a sterile membrane to obtain compound [ 68 Ga]Ga-DPI-ZH1.

[0133] Prepared from 68 Ga - ions and were successfully prepared within 30 to 40 minutes. 68 Ga]Ga-DPI-ZH1 was prepared with a decay-corrected yield of 70%, a radiochemical purity >98%, and a specific activity of 30 GBq / µmol, which was consistent with the HPLC retention time of its standard.

[0134] Example 7: Preparation of DOTAGA-DPI-ZH2 1) Preparation of compound of formula (9)

[0135] Repeat step 1) of Example 1 to couple the compound of formula (1) with the following amino acids: Fmoc-Cys(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-DPro-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Dde)-OH, and Fmoc-2-(piperazin-1-yl)acetic acid to obtain the compound of formula (9).

[0136] 2) Preparation of the compound of formula (10)

[0137] According to the method of step 3) of Example 1, the compound of formula (9) (4 mmol) and DOTAGA-tetra ( t Bu)ester (4 mmol) was used to complete the N-terminal coupling to obtain the compound of formula (10).

[0138] 3) Preparation of the compound of formula (11)

[0139] According to the method of step 3) of Example 1, the compound of formula (10) (4 mmol) and 4-sulfonylbutyric acid (4 mmol) were coupled at the N-terminus, and then treated and separated by semi-preparative separation method to obtain the compound of formula (11). An appropriate amount of the compound of formula (11) was subjected to mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 92 H 141 N 23 O 33 S4 ([M + 2H] 2+ ), 1113.84, mass spectrum measured 1112.95.

[0140] 4) Preparation of DOTAGA-DPI-ZH2

[0141] According to the method of step 4) of Example 1, a DOTAGA-DPI-ZH2 compound was obtained from the compound of formula (11). An appropriate amount of the DOTAGA-DPI-ZH2 compound was subjected to mass spectrometry, hydrogen spectrum and high performance liquid chromatography. The mass spectrum results showed that the molecular formula was C 100 H 147 N 23 O 33S4 ([M + 2H]2+), 1165.30, mass spectrometry 1163.97; HPLC results: purity >98%.

[0142] Example 8: 68 Preparation of Ga]Ga-DPI-ZH2 The preparation process is the same as that of Example 6, except that DOTAGA-DPI-ZH2 compound is used as a precursor and a gallium germanium generator is used to obtain 68 Manual labeling of GaCl3 was performed [ 68 Preparation of Ga]Ga-DPI-ZH2.

[0143] Prepared from 68 Ga - ions and were successfully prepared within 30 to 40 minutes. 68 Ga]Ga-DPI-ZH2, with a decay-corrected yield of 65%, a radiochemical purity >98%, and a specific activity of 28 GBq / µmol, which is consistent with the HPLC retention time of its standard.

[0144] Example 9: Preparation of DOTA-DPI-ZH3 1) Preparation of the compound of formula (12)

[0145] Repeat step 1) of Example 1 to couple the compound of formula (1) with the following amino acids: Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-DPro-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, and Fmoc-Glu(OAll)-OH to obtain the compound of formula (12).

[0146] 2) Preparation of the compound of formula (13)

[0147] According to the preparation method of step 3) of Example 1, 2-piperazin-1-yl-N-(5-sulfonyl-1,3,4-thiadiazol-2-yl)acetamide (4 mmol) was coupled with the compound of formula (12) (4 mmol) in DIEA (4 mmol) and 3 mL DMF using HATU (1.5 mmol) as a coupling reagent. Finally, the compound was treated with 3 mL TFA solution for cleavage at room temperature for 2 hours to obtain the compound of formula (13). An appropriate amount of the compound of formula (13) was taken for mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 101 H 132 N 24 O 28 S6([M + 2H] 2+ ), 1065.86, mass spectrometry measured 1066.80.

[0148] 3) Preparation of compound of formula (14)

[0149] The compound of formula (13) obtained in step 2) was dissolved in 3 mL of a 1:1 mixed solvent of ammonium carbonate aqueous solution (50 mM, pH = 8.5) and acetonitrile, 1,3-di(bromomethyl)benzene (1 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. Then, mercaptoethylamine (1 mmol) was added and the mixture was reacted at room temperature for 30 minutes to obtain the compound of formula (14). An appropriate amount of the compound of formula (14) was taken for mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 101 H 132 N 24 O 28 S6 ([M + 2H] 2+ ), 1161.40, mass spectrum measured 1161.25.

[0150] 4) Preparation of DOTA-DPI-ZH3

[0151] The compound of formula (14) obtained in step 3) was washed three times with 3 mL of anhydrous DMF; DOTA-tris( tBu)ester (4 mmol) was dissolved in 3 mL of anhydrous DMF, activated with DIEA (8 mmol) for 2 minutes, and then transferred to the compound of formula (14). The N-terminal coupling was completed by shaking at room temperature for 3 hours. Subsequently, the compound of formula (14) was deprotected with 20% pip / DMF (1:4, 3 ml, 2-20 minutes). After filtration, the resin was washed with 3 mL of DMF and 3 mL of DCM in sequence. Subsequently, 3 mL of a mixture of TFA / water / TIS (95:2.5:2.5) (0 ° C) was added to the filtrate and reacted for 2 hours before filtration. The filtrate was poured into cold ether, and the solid initial product precipitated. DOTA-DPI-ZH4 was then isolated by semi-preparative separation. An appropriate amount of DOTA-DPI-ZH4 compound was taken for mass spectrometry, hydrogen spectrum and high performance liquid chromatography detection. The mass spectrometry results showed that the molecular formula was C 102 H 148 N 28 O 33 S6 ([M +2H] 2+ ), 1243.46, mass spectrometry measured 1243.97; HPLC results: purity >98%.

[0152] Example 10: 68 Preparation of Ga]Ga-DPI-ZH3 The preparation process is the same as that of Example 6, except that DOTA-DPI-ZH3 compound is used as a precursor and a germanium gallium generator is used to obtain 68 Manual labeling of GaCl3 was performed [ 68 Preparation of Ga]Ga-DPI-ZH3.

[0153] Prepared from 68 Ga - ions and were successfully prepared within 30 to 40 minutes. 68 Ga]Ga-DPI-ZH3, with a decay-corrected yield of 65%, a radiochemical purity >98%, and a specific activity of 26 GBq / µmol, which is consistent with the HPLC retention time of its standard.

[0154] Example 11: Preparation of DOTA-DPI-ZH4 1) Preparation of the compound of formula (15)

[0155] Repeat step 1) of Example 1 to couple the compound of formula (1) with the following amino acids: Fmoc-Cys(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-DPro-OH, Fmoc-Glu(OtBu)-OH, and Fmoc-Gln(Trt)-OH to obtain the compound of formula (15).

[0156] 2) Preparation of the compound of formula (16)

[0157] Dissolve Fmoc-Cys(Trt)-OH (3 mmol) and HOBt (3 mmol) in 3 mL of anhydrous DMF, add DIC (3 mmol) and activate for 5 minutes, then add this activated solution to the compound of formula (15) prepared in step 1) and react at room temperature for 120 minutes for coupling. After the coupling is completed, filter and wash the resin thoroughly with 3 mL of DMF. Then add 3 mL of TFA for deprotection to obtain the compound of formula (16). Take an appropriate amount of the compound of formula (16) for mass spectrometry detection, and the mass spectrometry results are: the molecular formula is C 77 H 100 N 16 O 23 S3 ([M + 2H] 2+ ), 857.32, mass spectrum measured 847.88.

[0158] 3) Preparation of compound of formula (17)

[0159] The compound of formula (16) prepared in step 2) was dissolved in 3 mL of a 1:1 mixed solvent of ammonium carbonate aqueous solution (50 mM, pH = 8.5) and acetonitrile. 1,3,5-tris(bromomethyl)benzene (1 mmol) and mercaptoethylamine (1 mmol) were added to the solution and stirred at room temperature for 2 hours to obtain the compound of formula (17). An appropriate amount of the compound of formula (17) was taken for mass spectrometry detection, and the mass spectrometry results were as follows: the molecular formula is C 88 H 113 N 17 O 23 S4 ([M + 2H] 2+ ), 952.86, mass spectrometry measured 953.59.

[0160] 4) Preparation of the compound of formula (18)

[0161] The compound of formula (17) prepared in step 3) was added to 3 mL of DCM. The solution was cooled in an ice bath, and DCC (1 mmol), HOSu (1 mmol) (N-hydroxysuccinimide), DIEA (1 mmol) and 3 mL of DMF were added in sequence for activation. Then, the dissolved 4-Boc-1-piperazineacetic acid (1 mmol) was added. The ice bath was removed and the mixture was heated to room temperature and stirred for reaction. Subsequently, TFA (1 mmol) was added for deprotection to obtain the compound of formula (18). An appropriate amount of the compound of formula (18) was subjected to mass spectrometry, and the mass spectrometry results were as follows: the molecular formula is C 94 H 123 N 19 O 24 S4 ([M + 2H] 2+ ), 1015.90, mass spectrum measured 1017.08.

[0162] 5) Preparation of DOTA-DPI-ZH4

[0163] According to the preparation method of step 4) of Example 9, the compound of formula (18) obtained in step 4) and DOTA-tris ( t Bu)ester (4 mmol) was used to complete the N-terminal coupling, and after treatment, DOTA-DPI-ZH4 was isolated by semi-preparative separation. An appropriate amount of DOTA-DPI-ZH4 compound was taken for mass spectrometry, hydrogen spectrum and high performance liquid chromatography detection, and the mass spectrometry results showed that the molecular formula was C 95 H 139 N 23 O 29 S4 ([M + 2H] 2+ ), 1097.95, mass spectrometry measured 1098.96; HPLC results showed: purity >98%.

[0164] Example 12: 68 Preparation of Ga]Ga-DPI-ZH4 The preparation process is the same as that of Example 6, except that DOTA-DPI-ZH4 compound is used as a precursor and a germanium gallium generator is used to obtain 68 Manual labeling of GaCl3 was performed [ 68 Preparation of Ga]Ga-DPI-ZH4.

[0165] Prepared from 68 Ga - ions and were successfully prepared within 30 to 40 minutes. 68Ga]Ga-DPI-ZH4, the decay correction yield was 69%, radiochemical purity was >98%, specific activity was 27 GBq / µmol, and the retention time was consistent with its standard in HPLC.

[0166] Example 13: Preparation of DOTAGA-P-DPI 1) Preparation of compound of formula (19)

[0167] The coupling process of step 1) in Example 1 was repeated to sequentially couple the following amino acids Fmoc-Cys(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Leu-OH, Fmoc-Af3(Cpsu)-OH, Fmoc-Asp(OAll)-OH, Fmoc-DPro-OH, Fmoc-Glu(OAll)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-2-(piperazin-1-yl)acetic acid to obtain the compound of formula (19).

[0168] 2) Preparation of compound of formula (20)

[0169] The coupling process of step 1) in Example 1 was repeated to couple Fmoc-Glu(OtBu)-OH to obtain the compound of formula (20) from the compound of formula (19). An appropriate amount of the compound of formula (20) was taken for detection, and the mass spectrum result was as follows: the molecular formula was C 98 H 139 N 25 O 30 S5 ([M + 2H] 2+ ), 1024.91, and the mass spectrum was 1025.15.

[0170] 3) Preparation of compound of formula (21)

[0171] The compound of formula (21) was prepared from the compound of formula (20) according to the method of step 4) in Example 1. An appropriate amount of the compound of formula (21) was taken for detection, and the mass spectrum result was as follows: the molecular formula was C 102 H 131 N 19 O 27 S3 ([M + 2H] 2+ ), 1075.94, and the mass spectrum was 1076.40.

[0172] 4) Preparation of the compound of formula (22)

[0173] [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid was deprotected with 20% pip / DMF (1:4, 3 ml, 2-20 minutes), and then HOOBt (1 mmol), EDCI (1 mmol) and NMM (1 mmol) were added in sequence in 3 mL DCM under ice bath cooling to activate the carboxyl group; then, the dissolved 2-amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide (1 mmol) was added, the ice bath was removed, and the mixture was heated to room temperature with stirring to obtain the compound of formula (22).

[0174] 5) Preparation of compound of formula (23)

[0175] The compound of formula (21) prepared in step 3) was deprotected with 20% pip / DMF (1:4, 3 ml, 2-20 minutes), and then HOOBt (1 mmol), EDCI (1 mmol) and NMM (1 mmol) were added in sequence in 3 mL DCM under ice bath cooling to activate the carboxyl group. Then, the compound of formula (22) prepared in step 4) dissolved in 3 mL DCM was added, the ice bath was removed, the temperature was raised to room temperature, and the reaction was stirred for 1 hour to obtain the compound of formula (23). An appropriate amount of the compound of formula (23) was taken for mass spectrometry detection, and the mass spectrometry results were: the molecular formula is C 98 H 139 N 25 O 30 S5 ([M + 2H] 2+ ), 1153.94 mass spectrum measured 1155.12.

[0176] 6) Preparation of DOTAGA-P-DPI

[0177] According to the preparation method of step 1) of Example 3, the compound of formula (23) and DOTAGA-tetra ( t Bu)ester (4mmol) was used to complete the N-terminal coupling. After preliminary treatment, DOTAGA-P-DPI was isolated by semi-preparative separation. An appropriate amount of DOTAGA-P-DPI compound was subjected to mass spectrometry, hydrogen spectrum and high performance liquid chromatography. The mass spectrometry results showed that the molecular formula was C 118 H 172 N 30 O 42 S5 ([M + 2H] 2+), 1343.01, mass spectrometry measured 1344.10; HPLC results measured: purity >98%.

[0178] Example 14: 68 Preparation of Ga]Ga-P-DPI The preparation process is the same as that of Example 6, except that DOTAGA-P-DPI compound is used as a precursor and a gallium germanium generator is used to obtain 68 Manual labeling of GaCl3 was performed [ 68 Preparation of Ga]Ga-P-DPI.

[0179] Prepared from 68 Ga - ions and were successfully prepared within 30 to 40 minutes. 68 Ga]Ga-P-DPI, with a decay-corrected yield of 66%, a radiochemical purity >98%, and a specific activity of 26 GBq / µmol, which is consistent with the HPLC retention time of its standard.

[0180] Example 15: Binding Ability Test OS-RC-2 cells were plated in a 24-well plate containing culture medium (cell count plate, 0.40 million cells / well) and cultured for 2 days. The culture medium was removed, leaving the cultured OS-RC-2 cells. Fresh culture medium without fetal bovine serum was added, and radioactive tracer was added to different wells of the cell plate. 177 Lu]Lu-DPI-4452 (0.5 μCi / well) and different concentrations of the compound DOTA-DPI-4452 (10 -5 ~ 10 -12 mol / L) (4 wells per group), NOTA-C3-DPI (10 -5 ~ 10 -12 mol / L) (4 wells per group), DOTA-C3-DPI (10 -5 ~ 10 -12 mol / L) (4 wells per group), DOTAGA-DPI-ZH1 (10 -5 ~ 10 - 12 mol / L) (4 wells per group), DOTAGA-DPI-ZH2 (10 -5 ~ 10 -12 mol / L) (4 wells per group), DOTA-DPI-ZH3 (10 -5 ~10 -12 mol / L) (4 wells per group), DOTA-DPI-ZH4 (10 -5 ~ 10 -12mol / L) (4 wells per group) or DOTAGA-P-DPI (10 -5 ~10 -12 mol / L) (4 wells per group). After incubation at 37°C for 60 minutes, the radioactive culture medium was removed, the cells were washed twice with PBS (0.5 mL), and then lysed with 0.2% SDS-containing NaOH solution (0.5 mL, 1 M). The lysate was counted using a gamma counter. This step was then repeated to test the binding capacity of DOTA-DPI-4452.

[0181] Table 2 Binding ability test results

[0182] Results: The different concentration groups (10 -5 ~ 10 -12 mol / L) (4 wells per group) and the IC values ​​of DOTA-DPI-4452 and NOTA-C3-DPI were calculated. 50 As shown in the table above, the affinity of NOTA-C3-DPI for CAIX receptor is 1.8 times stronger than that of single ligand DOTA-DPI-4452.

[0183] from Figure 1 It can be seen that compared with DOTA-DPI-445, NOTA-C3-DPI, DOTAGA-DPI-ZH1, DOTAGA-DPI-ZH2, DOTAGA-P-DPI IC 50 As shown in the table above, it shows that the affinity of DOTAGA-DPI-ZH2 for CAIX receptor is 2.3 times stronger than that of the single ligand DOTA-DPI-4452.

[0184] Example 16: Cellular uptake and inhibition experiments OS-RC-2 cells with high CAIX expression were plated in twelve-well plates (cell count was 0.39-0.41 million / well using a cell counting plate) and cultured in fresh culture medium without fetal bovine serum. 18 F]AlF-C3-DPI (1 μCi / well), [ 177 Lu]Lu-C3-DPI, [ 177 Lu]Lu-DPI-4452 and DOTA-DPI-4452 were treated and grouped according to Table 3. The cells were incubated at 37 °C for the corresponding time points ( 18 F]AlF-C3-DPI: 5, 15, 30, 60 and 120 min; [ 177 Lu]Lu-C3-DPI and [ 177Lu]Lu-DPI-4452: 0.5, 1, 2, 4, and 12 h; 4 wells per group). The radioactive culture medium was removed, and the cells were washed twice with PBS (1 mL). The cells were then lysed with NaOH solution containing 0.2% SDS (1 mL, 1 M), and the lysates were counted using a γ counter.

[0185] Table 3: Cellular uptake and inhibition experimental treatments and results

[0186] result: Figure 2 The present invention provides 18 F]AlF-C3-DPI was continuously and highly uptaken in OS-RC-2 cells with high CIAX expression at different time points of incubation: 5 min, 15 min, 30 min, 60 min, and 120 min. Figure 3 It was shown that uptake was significantly inhibited 1 hour after the addition of competitively bound DOTA-DPI-4452.

[0187] Figure 4 The present invention provides 177 The uptake values ​​of Lu]Lu-C3-DPI in OS-RC-2 cells with high CIAX expression at 0.5 h, 1 h, 2 h, 4 h, and 12 h were comparable to those of known single-ligand tracers [ 177 Lu]Lu-DPI-4452 equivalent.

[0188] show[ 18 F]AlF-C3-DPI and [ 177 Lu]Lu-C3-DPI both have high specificity for CAIX.

[0189] Example 17: Cell efflux experiment OS-RC-2 cells with high CAIX expression were plated in twelve-well plates (cell counts were performed using a cell counting plate, 0.39-0.41 million cells / well), and [ 177 Lu]Lu-C3-DPI (37 KBq / mL) and [ 177 Lu]Lu-DPI-4452 was added to OS-RC-2 cells and incubated at 37°C for 1 hour. The radioactive medium was removed, and the cells were washed twice with PBS (1 mL). The cells were then incubated in radioactive-free medium for 0, 0.5, 1, 2, 4, and 12 hours before being counted. The cells were washed with PBS (1 mL) and lysed with 1 mL of 1 M NaOH containing 0.2% SDS. The lysate was then counted using a gamma counter.

[0190] result: Figure 5 show[ 177 The efflux rate of Lu]Lu-C3-DPI in OS-RC-2 cells with high CAIX expression was lower than that of [ 177 Lu]Lu-DPI-4452. 177 Lu]Lu-C3-DPI has a stronger uptake and retention ability and a longer retention time in cells, which may have a stronger anti-tumor effect.

[0191] Example 18: Stability Test [ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 In vitro stability experiment of Ga]Ga-P-DPI: Pick[ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 Ga]Ga-P-DPI (30 μL, 300 μCi) was placed in 200 mL of PBS solution, mouse serum, and human serum, respectively. After incubation at 37°C for 2 hours, its radiochemical purity was determined by Radio-HPLC.

[0192] Results: As Figure 6 As shown, after incubation in PBS, mouse serum, and human serum at 37°C for 2 hours, [ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 The degradation rates of Ga]Ga-P-DPI were all ≤5%. 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [68 Ga]Ga-DPI-ZH4 and [ 68 Ga]Ga-P-DPI has good stability in vitro.

[0193] This indicates that the radioactive compound prepared by the present invention has good stability.

[0194] Example 19: Small Animal PET-CT Imaging (1) CAIX (+) intake group [ 18 F]AlF-C3-DPI intake group: 250 μCi of [ 18 F]AlF-C3-DPI was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; static small animal PET-CT scans were performed at 1, 2, and 4 hours.

[0195] [ 68 Ga]Ga-DPI-4452 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-4452 was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; small animal PET-CT static scans were performed at 1, 2, and 4 hours.

[0196] (2) CAIX (+) inhibition group (Blocking) [ 18 F]AlF-C3-DPI inhibition group: 18 F]AlF-C3-DPI (250 μCi) was added to DOTA-DPI-4452 (50 μg / mouse) and injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein. Small animal PET-CT was used for 1-hour static scanning.

[0197] (3) CAIX (-) intake group [ 18 F]AlF-C3-DPI intake group: 250 μCi of [ 18 F]AlF-C3-DPI was injected into nude mice bearing AsPC-1 tumors with low CAIX expression via the tail vein; imaging was performed using small animal PET-CT for 1 hour.

[0198] (4) CAIX (+) intake group 2 [ 68 Ga]Ga-DPI-ZH1 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-ZH1 was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0199] [ 68 Ga]Ga-DPI-ZH2 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-ZH2 was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0200] [ 68 Ga]Ga-DPI-ZH3 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-ZH3 was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0201] [ 68 Ga]Ga-DPI-ZH4 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-ZH4 was injected into CAIX-overexpressing OS-RC-2 tumor-bearing nude mice via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0202] [ 68 Ga]Ga-P-DPI intake group: 250 μCi of [ 68 Ga]Ga-P-DPI was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0203] [ 68 Ga]Ga-DPI-4452 uptake group: 250 μCi of [ 68 Ga]Ga-DPI-4452 was injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein; dynamic scanning was performed using small animal PET-CT for 2 hours.

[0204] (5) CAIX (+) inhibition group (Blocking) [ 68 Ga]Ga-DPI-ZH2 inhibition group: 68 Ga]Ga-DPI-ZH2 (250 μCi) was added to DOTA-DPI-4452 (50 μg / mouse) and injected into OS-RC-2 tumor-bearing nude mice with high CAIX expression via the tail vein. Small animal PET-CT was used for 1-hour static scanning.

[0205] result: (1) From Figure 7 It can be seen that in the CAIX (+) intake group, [ 18F]AlF-C3-DPI specifically and highly aggregated in the OS-RC-2 tumor sites where CAIX was highly expressed, and its uptake gradually increased with time. Figure 8 It can be seen that in OS-RC-2 tumors [ 18 F]AlF-C3-DPI uptake values ​​were similar to those of [ 68 The uptake values ​​of Ga]Ga-DPI-4452 were significantly higher than those of [ 68 Ga]Ga-DPI-4452. Depend on Figure 9 It can be seen that [ 18 F]AlF-C3-DPI and [ 68 Compared with [Ga]Ga-DPI-4452, the expression of IL-6 in organs other than kidney (such as stomach, lung, liver, brain, and femur) was significantly decreased.

[0206] (2) From Figure 7 and Figure 10 As can be seen in the CAIX (+) inhibition group, the OS-RC-2 tumors after adding DOTA-DPI-4452 [ 18 F]AlF-C3-DPI uptake value was significantly weakened, and the inhibitory effect in vivo was significant. At the same time, in AsPC-1 tumors with low CAIX expression (CAIX (-) uptake group) [ 18 F]AlF-C3-DPI uptake was very low, indicating that [ 18 F]AlF-C3-DPI has high specificity in vivo.

[0207] (3) From Figure 11 、 Figure 12 and Figure 13 It can be seen that compared with [ 68 Ga]Ga-DPI-4452, [ 68 Ga]Ga-DPI-ZH1 and [ 68 The tumor uptake of Ga]Ga-DPI-ZH2 was similar, [ 68 The tumor uptake of Ga]Ga-P-DPI was slightly reduced, and all three showed good tumor retention within 2 hours. 68 The tumor uptake of Ga]Ga-DPI-ZH3 was extremely low. 68 Ga]Ga-DPI-ZH4 was taken up in tumors, but its retention was poor. 68 Ga]Ga-DPI-ZH1 and [ 68 The uptake of Ga]Ga-P-DPI was significantly reduced in the stomach, but increased in other organs (such as lungs, liver, and kidneys). 68 The uptake of Ga]Ga-DPI-ZH2 in various organs (lung, liver, kidney, stomach) and [68 Ga]Ga-DPI-4452 is similar.

[0208] (4) From Figure 14 and Figure 15 As can be seen in the CAIX (+) inhibition group, the OS-RC-2 tumors after adding DOTA-DPI-4452 [ 68 Ga]Ga-DPI-ZH2 uptake value was significantly weakened, and the inhibitory effect in vivo was significant, indicating that [ 68 Ga]Ga-DPI-ZH2 has high specificity in vivo.

[0209] Small-animal PET / CT imaging showed that tumors were responsive to the compound [ 18 The uptake values ​​of F]AlF-C3-DPI were significantly higher than those of the known compounds [ 68 Ga]Ga-DPI-4452, compound [ 68 The tumor uptake values ​​of Ga]Ga-DPI-ZH2 were comparable to those of known compounds [ 68 Ga]Ga-DPI-4452 equivalent.

[0210] Example 20: 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-4452, [ 177 Lu]Lu-C3-DPI and [ 177 Biodistribution of Lu]Lu-DPI-4452 (1) [ 18 F]AlF-C3-DPI intake group, [ 18 F]AlF-C3-DPI inhibition group [ 18 F]AlF-C3-DPI OS-RC-2 intake group: 0.2 mL of compound [ 18 F]AlF-C3-DPI (1.48 MBq) was injected into the tail vein of nude mice bearing OS-RC-2 tumors with high CAIX expression for 1 hour (4 mice per group).

[0211] [ 18 F]AlF-C3-DPI inhibition group: 0.2 mL of compound [ 18 F]AlF-C3-DPI (1.48 MBq) and DOTA-DPI-4452 (50 μg / mouse) were injected into the tail vein of CAIX-overexpressing OS-RC-2 tumor-bearing nude mice for 1 hour (4 mice per group).

[0212] (2) [ 68 Ga]Ga-DPI-4452 uptake group [ 68 Ga]Ga-DPI-4452 OS-RC-2 uptake group: 0.2 mL of compound [ 68 Ga]Ga-DPI-4452 (1.48 MBq) was injected into the tail vein of nude mice bearing OS-RC-2 tumors with high CAIX expression for 1 hour (4 mice per group).

[0213] Procedure: One hour after injection of each compound, the OS-RC-2 uptake and inhibition groups were evaluated. Blood was collected and the animals were sacrificed by cervical dislocation. Tissue samples, including heart, liver, lung, kidney, femur, muscle, small intestine, tumor, blood, pancreas, spleen, stomach, gallbladder, and brain, were dissected and weighed, and radioactivity counts were measured using a gamma counter. All measurements were background-subtracted, decay-time-corrected, and averaged. Data are expressed as the percentage of the injected dose per gram of tissue (%ID / g).

[0214] (3) [ 177 Lu]Lu-C3-DPI intake group, [ 177 Lu]Lu-C3-DPI inhibition group [ 177 Lu]Lu-C3-DPI OS-RC-2 uptake group: 0.2 mL of compound [ 177 Lu]Lu-C3-DPI (1.48 MBq) was injected into the tail vein of OS-RC-2 tumor-bearing nude mice with high CAIX expression. The tumor-bearing nude mice after injection of the compound were divided into 1 hour group, 4 hour group, 24 hour group, 72 hour group and 168 hour group (4 mice in each group).

[0215] [ 177 Lu]Lu-C3-DPI inhibition group: 0.2 mL of compound [ 177 Lu]Lu-C3-DPI (1.48 MBq) and DOTA-DPI-4452 (50 μg / mouse) were injected into the tail vein of CAIX-overexpressing OS-RC-2 tumor-bearing nude mice for four hours (4 mice in each group).

[0216] (4) [ 177 Lu]Lu-DPI-4452 intake group [ 177 Lu]Lu-DPI-4452 OS-RC-2 uptake group: 0.2 mL of compound [ 177 Lu]Lu-DPI-4452 (1.48 MBq) was injected into the tail vein of nude mice bearing OS-RC-2 tumors with high CAIX expression. 177Tumor-bearing nude mice after Lu]Lu-DPI-4452 were divided into 1 hour group, 4 hour group, 24 hour group, 72 hour group, and 168 hour group (4 mice in each group).

[0217] Procedure: Tumor-bearing nude mice were treated with OS-RC-2 uptake at 1, 4, 24, 72, and 168 hours post-injection for each compound, respectively. Tumor-bearing nude mice were oculomotorly removed, blood was collected, and mice were sacrificed by cervical dislocation. Tissue samples of heart, liver, lung, kidney, femur, muscle, small intestine, tumor, blood, pancreas, spleen, stomach, gallbladder, and brain were dissected and weighed, and radioactivity counts were measured using a gamma counter. All measurements were background-subtracted, decay-time-corrected, and averaged. Data are expressed as the percentage of the injected dose per gram of tissue (%ID / g).

[0218] See the results Figure 16-22 , the analysis is as follows: (1) If Figure 16 As shown, [ 18 In the F]AlF-C3-DPI OS-RC-2 intake group, [ 18 F]AlF-C3-DPI has a higher uptake in tumors than in other organs, while other organs or tissues such as the heart, liver, lung, kidney, femur, muscle, small intestine, blood, pancreas, spleen, stomach, gallbladder and brain have lower uptake values. 18 F]AlF-C3-DPI inhibition group showed that after adding competitive binding DOTA-DPI-4452, 18 F]AlF-C3-DPI was significantly decreased in the stomach, gallbladder, small intestine and tumor, but there was no significant difference in other organs.

[0219] (2) If Figure 16 As shown, [ 18 F]AlF-C3-DPI was injected into OS-RC-2 tumor-bearing nude mice 1 hour later, and the tumor and kidney 18 The uptake of [F]AlF-C3-DPI was significantly higher than that of 68 Ga]Ga-DPI-4452, and its uptake in blood, liver, lung, pancreas, stomach, and small intestine was significantly lower than that in [ 68 Ga]Ga-DPI-4452, and no significant differences were found in other organs.

[0220] (3) If Figure 17 As shown, [ 177 In the Lu]Lu-C3-DPI OS-RC-2 uptake group, [ 177Tumors in vivo had a higher uptake of Lu]Lu-C3-DPI than other organs. The uptake values ​​of other organs or tissues such as heart, liver, lung, kidney, femur, muscle, small intestine, blood, pancreas, spleen, stomach, gallbladder and brain were all lower. The uptake of tumors continued to increase in the first 4 hours.

[0221] (4) If Figure 17 and Figure 20 As shown, [ 177 Lu]Lu-C3-DPI inhibition group showed that after adding competitive binding DOTA-DPI-4452 [ 177 The expression of Lu]Lu-C3-DPI was significantly decreased in the stomach and tumor, but there was no significant difference in other organs.

[0222] (5) If Figure 17 、 18 As shown in 19, [ 177 When Lu]Lu-C3-DPI was injected into OS-RC-2 tumor-bearing nude mice at 1 hour, 4 hours, 24 hours, 72 hours and 168 hours, the tumor 177 The uptake of Lu]Lu-C3-DPI was higher than that of [ 177 Lu]Lu-DPI-4452, and there was a significant difference at 168 hours.

[0223] (6) Calculate the area under the uptake curve of each tissue using the biodistribution data, such as Figure 21 As shown, [ 177 The area under the curve values ​​of [Lu]Lu-C3-DPI in stomach, kidney and tumor were higher than those in 177 Lu]Lu-DPI-4452,[ 177 The absorbed dose of Lu]Lu-C3-DPI in the gallbladder and small intestine is lower than that of [ 177 Lu]Lu-DPI-4452.

[0224] (7) The ratio of the area under the uptake curve of the tumor to the tissue of interest (kidney, stomach, gallbladder and small intestine) is as follows: Figure 22 As shown, [ 177 The area under the curve ratios of tumor / stomach, tumor / small intestine, and tumor / gall bladder for Lu]Lu-C3-DPI were higher than those for 177 Lu]Lu-DPI-4452,[ 177 The area under the curve ratio of tumor / kidney of Lu]Lu-C3-DPI was lower than that of [ 177 Lu]Lu-DPI-4452.

[0225] Conclusions of Example 15-Example 20: (1) In vitro cell experiments showed that 18 F]AlF-C3-DPI and [177 Lu]Lu-C3-DPI both have high specificity for CAIX.

[0226] (2) [ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-DPI-ZH1, [ 68 Ga]Ga-DPI-ZH2, [ 68 Ga]Ga-DPI-ZH3, [ 68 Ga]Ga-DPI-ZH4 and [ 68 Ga]Ga-P-DPI has good stability in vitro.

[0227] (3) Small-animal PET / CT imaging showed that tumors were sensitive to compounds [ 18 The uptake values ​​of F]AlF-C3-DPI were significantly higher than those of known compounds [ 68 Ga]Ga-DPI-4452, compound [ 68 The tumor uptake values ​​of Ga]Ga-DPI-ZH2 were comparable to those of known compounds [ 68 Ga]Ga-DPI-4452 equivalent.

[0228] (4) [ 177 Lu]Lu-C3-DPI is easy to prepare as a therapeutic radiopharmaceutical.

[0229] (5) The present invention modifies the structure of the known compound DOTA-DPI-4452 and selects a novel compound that is stable in structure, simple in preparation and highly efficient and can be introduced into 68 Preparation of compounds with Ga nuclides [ 68 Ga]Ga-DPI-ZH2 and introduction 18 F nuclide preparation compound [ 18 F]AlF-C3-DPI can be used as a tracer to introduce 177 Lu nuclide preparation compound [ 177 Lu]Lu-C3-DPI is used as a radiotherapy drug to realize the three CAIX ligands of integrated radiotherapy for diagnosis and treatment.

[0230] (6) In summary, compared with DOTA-DPI-4452, DOTAGA-DPI-ZH2, NOTA-C3-DPI, [ 68 Ga]Ga-DPI-ZH2 and [ 18 F]AlF-C3-DPI have comparable or even higher uptake in CAIX lesions. 177Lu]Lu-C3-DPI has a higher uptake and retention ability for CAIX lesions, and the compounds provided by the present invention have good application prospects.

[0231] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A CAIX ligand compound or an ester or pharmaceutically acceptable salt thereof, having a structure as shown in formula (A): ; in, R 1 is selected from hydrogen or -L1-E1; R 2 、R 3 、R 4 、R 5 、R 6 、R 7 are each independently selected from hydrogen or -L2-E2; n and m are each independently selected from 0, 1, 2, 3, 4, 5; Said E1 and E2 are each independently a chelating ligand portion; L1 and L2 are each independently composed of a number of amino acid residues L; The basic fragment L0 of the amino acid residue L is selected from -Z-, -N(R 8 )-、-N(R 8 )4、-C(=Z)-、-((C(R 9 ) p ) q -、-SO3H、-S(=O) j -、-NR 8 -C(=O)-、-NR 8 -C(=O)-NR 8 -、-C(=O)-NR 8 -、-((C(R 9 ) p ) q -Z) x -(C(R 9 ) p ) q -、-(C(R 9 ) p ) q -(Z-(C(R 9 ) p ) q ) x -, at least one of an alkylene group, a heteroalkylene group, a cycloalkylene group, a heterocycloalkylene group, an arylene group, or a heteroarylene group; where appropriate, multiple L0s are spliced ​​together to form L, one or more Ls can be combined to form L1 or L2; or one or more L0s can be combined to form L1 or L2; Each Z is independently selected from O or S; Each p is independently selected from 0, 1 or 2; Each j is independently selected from 0 or 1; q and x are each independently selected from an integer of 0-30, for example selected from 0-20 or 0-10 or 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R 8 are independently H, cycloalkyl or alkyl; Each R 9 is independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, alkylene-COOH, -SO3H, alkylene-SO3H, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkyl; L0, R 8 and R 9 wherein the alkoxy, alkylthio, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene groups are further optionally and independently monosubstituted or polysubstituted by the same or different substituents R; wherein the substituents R are hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, alkylene-COOH, alkylene-S03H, -B(OH)2, hydroxyl, -S03H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

2. The compound according to claim 1, characterized in that The L0 is selected from -Z-, -N(R 8 )-、-N(R 8 )4、-C(=Z)-、-((C(R 9 ) p ) q -、-SO3H、-S(=O) j -、-NR 8 -C(=O)-、-NR 8 -C(=O)-NR 8 -、-C(=O)-NR 8 -、-((C(R 9 ) p ) q -Z) x -(C(R 9 ) p ) q -、-(C(R 9 ) p ) q -(Z-(C(R 9 ) p ) q ) x -、C 1-6 Heteroalkylene, C 1-12 Alkylene, C 3-12 Cycloalkylene, C 4-12 Heterocycloalkylene, C 6-12 Arylene, or C 5-12 At least one heteroarylene group; under reasonable circumstances, multiple L0s can be spliced ​​together to form L, one or more Ls can be combined to form L1 or L2; or one or more L0s can be combined to form L1 or L2; More preferably, the L0 is selected from -O-, -S-, -NH-, -C(=O)-, -NH-C(=O)-, -NR 8 -C(=O)-NR 8 -、-C(=O)-NH-、-(CH2) q -、-SO3H、-(CHR 9 ) q -、-((CH2) q -O) x -、-((CH2) q -O) x -(CH2) q -、-(CH2) q -(O-(CH2) q ) x -、 、 、 ; wherein each A is independently selected from CR 9 or N; each B is independently selected from -C(R 9 )2-、O、-S(=O) j -、-N(R 8 ) j - , or -C(=Z)-; the values ​​of q, x, A or B in the same structural formula may be the same or different and do not affect each other; under reasonable circumstances, multiple L0s are spliced ​​together to form L, one or several Ls can be combined to form L1 or L2; or one or more L0s can be combined to form L1 or L2; or each R 8 Independently H, C 3-12 Cycloalkyl or C 1-6 Alkyl; each R 9 are independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-12 Cycloalkyl, C 4-12 Heterocycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 1-6 alkyl.

3. The compound according to claim 2, characterized in that The L is selected from at least one of the following fragments: ； Or, L1 and L2 are each independently selected from at least one of the following fragments: 。 4. The compound according to claim 1, characterized in that The active ingredients of E1 and E2 are AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, and CT A、cyclam、cyclen、TETA、Sarcophagin、CPTA、TEAMA、Cyclen、DO3A、DO2A、TRITA、DATA、DFO、D ATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5delayer, H2azapa, H2CHX DEDPA、DFO-Chx-MAL、DFO-p-SCN、DFO-1AC、DFO-BAC、p-SCN-Bn-DFO、DFO-pPhe-NCS、DFO -HOPO、DFC、DOTA、DOTAGA、DOTA-MFCO、DOTAM-Original-Dota-Pa-DOTA-PA-DOTA p-NCS-Bz-DOTA PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN -Bn-DOTA、DOTMA、NB-DOTA、H4NB-DOTA、H4TCE-DOTA、3,4,3-(Li-1,2-HOPO)、TRAIN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOXP, p-NCS-DOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-monoamide-DOTA, BCN-DOTA, butyne-DOTA, BCN-DOTA-GA, DO A3P, DO2a2p, DO2A (trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)acetamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimido-mono-amide-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p -NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, mixed thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligand H2L2 –4. HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, deferiprone, THP, HYNIC, NH S-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIMA,IAM B. MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, Macropa, Macropaquin, Macroquin-SO3, N, x S 4-x , N2S2, N3S, N4, MAG3B, NOTA, NODAGA, SCN-Bz-NOTA-R, NOT-P(NOTMP), NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NO2A, N-Benzyl-NODA, C-NOTA, BCNOT-monoamine, maleimido-mono-amide-NOTA, NO2A-azide, NO 2A-Butyne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-Cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, TRAP, PEPA, BF-PEPA, Pycup, Pycup2A, pycup1A1Bn, pycup2Bn, SarAr-R, Diamsar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAMA, TAM B. TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, T E2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A,, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ -HTCPP, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid (DOTAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-N-pentanedioic acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid (NODA-MPAA), bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A), DFO, hexadentate tris(3,4-hydroxypyridone) (THP), dodecanetetraacetic acid, nitro-DOTA, 4-aminophenethyl-1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (partial acetic acid of 2-[4,7-bis(carboxymethyl)-1,4,7-triazolidin-1-yl])-NOTA, (triethylenetetramine)-TETA, deferoxamine, (ethylenediaminetetraacetic acid)-EDTA, penicillamine,. One or more of; Further preferably, the E1 and E2 are each independently selected from one of the following structural fragments: 。 5. The compound according to claim 1, characterized in that It is shown in the following structural formula: 。 6. The compound according to claim 1, characterized in that The compound is selected from one of the following structures: 。 7. A metal complex, characterized in that It is formed by complexing a radionuclide with the compound according to any one of claims 1 to 6 or its ester or pharmaceutically acceptable salt; Further preferably, the radionuclide comprises 18 F. 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P. 44 Sc, 47 Sc, 165 Dy, 169 Second, 177 Lu, 142 Pr, 159 Gd, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co、 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y. 89 Y. 90 Y. 89 Sr. 89 Zr, 94m Tc, 99m Tc, 111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P. 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re, 188 Re, 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th middle class; More preferably, the metal complex is a compound [ 18 F]AlF-C3-DPI, [ 68 Ga]Ga-NOTA-C3-DPI, [ 64 Cu]Cu-NOTA-C3-DPI, compound [ 177 Lu]Lu-C3-DPI, compound [ 68 Ga]Ga-C3-DPI, compound [ 86 Y]Y-C3-DPI, compound [ 89 Y]Y-C3-DPI, compound [ 90 Y]Y-C3-DPI, compound [ 64 Cu]Cu-C3-DPI, compound [ 67 Cu]Cu-C3-DPI, compound [ 213 Bi]Bi-C3-DPI, compound [ 225 Ac]Ac-C3-DPI, compound [ 177 Lu]Lu-DPI-ZH1, compound [ 68 Ga]Ga-DPI-ZH1, compound [ 86 Y]Y-DPI-ZH1, compound [ 89 Y]Y-DPI-ZH1, compound [ 90 Y]Y-DPI-ZH1, compound [ 64 Cu]Cu-DPI-ZH1, compound [ 67 Cu]Cu-DPI-ZH1, compound [ 213 Bi]Bi-DPI-ZH1, compound [ 225 Ac]Ac-DPI-ZH2, compound [ 177 Lu]Lu-DPI-ZH2, compound [ 68 Ga]Ga-DPI-ZH2, compound [ 86 Y]Y-DPI-ZH2, compound [ 89 Y]Y-DPI-ZH2, compound [ 90 Y]Y-DPI-ZH1, compound [ 64 Cu]Cu-DPI-ZH2, compound [ 67 Cu]Cu-DPI-ZH2, compound [ 213 Bi]Bi-DPI-ZH2, compound [ 225 Ac]Ac-DPI-ZH2, compound [ 177 Lu]Lu-DPI-ZH3, compound [ 68 Ga]Ga-DPI-ZH3, compound [ 86 Y]Y-DPI-ZH3, compound [ 89 Y]Y-DPI-ZH3, compound [ 90 Y]Y-DPI-ZH3, compound [ 64 Cu]Cu-DPI-ZH3, compound [ 67 Cu]Cu-DPI-ZH3, compound [ 213 Bi]Bi-DPI-ZH3, compound [ 225 Ac]Ac-DPI-ZH3, compound [ 177 Lu]Lu-DPI-ZH4, compound [ 68 Ga]Ga-DPI-ZH4, compound [ 86 Y]Y-DPI-ZH4, compound [ 89 Y]Y-DPI-ZH4, compound [ 90 Y]Y-DPI-ZH4, compound [ 64 Cu]Cu-DPI-ZH4, compound [ 67 Cu]Cu-DPI-ZH4, compound [ 213 Bi]Bi-DPI-ZH4, compound [ 225 Ac]Ac-DPI-ZH4, [ 177 Lu]Lu-P-DPI, compound [ 68 Ga]Ga-P-DPI, compound [ 86 Y]YP-DPI, compound [ 89 Y]YP-DPI, compound [ 90 Y]YP-DPI, compound [ 64 Cu]Cu-P-DPI, compound [ 67 Cu]Cu-P-DPI, compound [ 213 Bi]Bi-P-DPI, compound [ 225 Ac]Ac-P-DPI.

8. A composition, characterized in that include: (1) the compound according to any one of claims 1 to 6, or an ester or pharmaceutically acceptable salt thereof, or the metal complex according to claim 7, or an ester or pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

9. A kit, characterized in that The invention comprises the compound according to any one of claims 1 to 6, or an ester or a pharmaceutically acceptable salt thereof, and an auxiliary material for preparing the metal complex according to claim 7, or an ester or a pharmaceutically acceptable salt thereof.

10. Use of the compound according to any one of claims 1 to 6, or its ester or pharmaceutically acceptable salt, or the metal complex according to claim 7, or the composition according to claim 8, or the kit according to claim 9 in the preparation of a diagnostic tracer or a drug for treating related diseases; Preferably, the use includes an agent for diagnosing a tumor having a CAIX receptor or its metastasis, or a drug for treating a tumor having a CAIX receptor; Preferably, the tumors having CAIX receptors include renal cell carcinoma, pancreatic cancer, colon cancer, esophageal cancer, breast cancer, and bladder urothelial carcinoma.

Images