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CN-122003253-A - PSMA diagnostic compounds assembled with tetrazine-trans-cyclooctene linkages

CN122003253ACN 122003253 ACN122003253 ACN 122003253ACN-122003253-A

Abstract

The present disclosure relates to ureido ligands targeting PSMA comprising a moiety that targets PSMA, a linker, and a pyridazine moiety. The disclosed ureido ligands that target PSMA are suitable for use as radiopharmaceuticals, as imaging agents (e.g., diagnostic agents), or for treating prostate cancer, or as diagnostic agents.

Inventors

  • M. M. Hurt
  • A. Kyle
  • U. M. Battisti
  • V. Shargunov
  • C. B.M. Puli
  • M. MUELLER
  • A. JENSEN

Assignees

  • 哥本哈根大学
  • 泰特凯科技有限责任公司

Dates

Publication Date
20260508
Application Date
20240816
Priority Date
20230816

Claims (15)

  1. 1. A PSMA-targeting ureido ligand having the formula (I): Wherein: a is independently carboxylic acid, sulfonic acid, phosphonic acid, tetrazole, or isoxazole; o is an integer selected from 1-4; m is an integer selected from 0-10; R 1 is-CH-CH 2 -Z or-CH-CH 2 -Y; wherein Z is selected from the following: Y is selected from the following: in the formula, Q 1 is-C-R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl; Q 2 is O, S or NH; Hal (halogen) is a radioisotope selected from the group consisting of a radioisotope of fluorine, a radioisotope of iodine, a radioisotope of bromine, and a radioisotope of astatine; Provided that when R 2 =-CH-CH 2 -Y, then R 1 must be-CH-CH 2 -Z; R 2 is-CH-CH 2 -Y or-CH 2 -T-; wherein T is an aromatic mono-or polycyclic ring system having from 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Y is selected from the following: in the formula, Q 1 is-C-R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl; Q 2 is O, S or NH; Hal (halogen) is a radioisotope selected from the group consisting of a radioisotope of fluorine, a radioisotope of iodine, a radioisotope of bromine, and a radioisotope of astatine; provided that when R 1 =-CH-CH 2 -Y, then R 2 must be-CH 2 -T; l is a moiety comprising a group selected from the group consisting of: -CO(CH 2 ) n NH-、-CO(CH 2 CH 2 O) n NH-、-M-、-CO(CH 2 ) n NHM l -、-CO(CH 2 CH 2 O) n NHM l -、-MnCO(CH 2 ) n NH-、-MnCO(CH 2 CH 2 O) n NH-、-LysG-、-LysJ-、-LysGCO(CH 2 CH 2 O) n NH-、-LysJCO(CH 2 ) n NH-、-LysGCO(CH 2 ) n NHM l -、-LysJCO(CH 2 ) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH 2 ) n NHM l -、-LysJCO(CH 2 ) n NHM l -、-LysGCO(CH 2 CH 2 O) n NHM l -、-LysJCO(CH 2 CH 2 O) n NHM l -、-LysGM n CO(CH 2 ) n NH-、-LysJM n CO(CH 2 ) n NH-、-LysGM n CO(CH 2 CH 2 O) l NH-、-LysJM n CO(CH 2 CH 2 O) l NH-、-CO(CH 2 CH 2 O) n NHLysG-、-CO(CH 2 ) n NHLysJ-、-CO(CH 2 ) n NHM l LysG-、-CO(CH 2 ) n NHM l LysJ-、-M n LysG-、-M n LysJ-、-CO(CH 2 ) n NHM l LysG-、-CO(CH 2 ) n NHM l LysJ-、-CO(CH 2 CH 2 O) n NHM l LysG-、-CO(CH 2 CH 2 O) n NHM l LysJ-、-M n CO(CH 2 ) l NHLysG-、-M n CO(CH 2 ) l NHLysJ-、-M n CO(CH 2 CH 2 O) l NHLysG-、-M n CO(CH 2 CH 2 O) l NHLysJ-, wherein n and l are integers independently selected from 0 to 10; m is selected from more than one natural amino acid, more than one saccharide and a combination of more than one natural amino acid and more than one saccharide; lys is a D-lysine or L-lysine amino acid residue modified with G or J in the side chain, G is a chelator which may comprise a metal, or tetrazine or a metabolic derivative thereof, J is-CO (CH 2 ) p R 4 or-CO (CH 2 ) p C(CH 3 ) 2 R 4 , wherein p is an integer selected from 0 to 5, R 4 is a pyridazine selected from the group consisting of: R 5 and R 6 are the same or different only in the isotopic mass number of the labelling agent and are independently selected from Wherein the wavy line represents a linkage to a six-membered aromatic ring of pyridazine and R 7 is-H, or (i) an isotopic labeling agent directly linked to the aromatic ring, or (ii) an isotopic labeling agent linked to the aromatic ring through a linker selected from -(CH 2 ) b 、WO(CH 2 ) b -WNH(CH 2 ) b 、-WCONH(CH 2 ) b 、-WNHCO(CH 2 ) b ,W being- (CH 2 ) h or- (CH 2 CH 2 O) h ), b and H being integers independently selected from 1-25, or (iii) an isotopic labeling agent chelated by a chelating agent linked to the aromatic ring through a linker selected from -(CH 2 ) r 、-WO(CH 2 ) r 、-WNH(CH 2 ) r 、-WCONH(CH 2 ) r 、-WNHCO(CH 2 ) r ,W being- (CH 2 ) q or- (CH 2 CH 2 O) q , R and q being integers independently selected from 1-25; When R 7 is (i) or (ii), the isotopic labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 I、 124 I、 125 I、 127 I、 131 I、 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re、 186 Re、 188 Re、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt; e and D are independently selected from-CH and-N-; R 8 is H or a moiety selected from the group consisting of hydroxy, sulfonamide, carboxy, sulfonyl, amine, substituted amine having 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally, the representative represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxy, sulfonyl, amino, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) alkylene, (C1-C10) alkoxy, (C2-C10) dialkylamino, (C1-C10) alkylthio, (C2-C10) heteroalkyl, (C2-C10) heteroalkylene, (C3-30C 10) cycloalkyl, (C3-C10) heterocycloalkyl, (C3-C10) cycloalkylene, (C3-C10) heterocycloalkylene, (C1-C10) haloalkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenyloxy, (C3-C10) alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, (C1-C6) alkoxy- (C1-C4) alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein the optional representation represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxyl, sulfonyl, amine, substituted amine with 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl, wherein optionally more than one substituent selected from halogen, hydroxy, sulfonamide, carboxyl, sulfonyl and amine groups; X is G or J, and the X is G or J, G is a chelator which may comprise a metal, or tetrazine or a metabolic derivative thereof, J is-CO (CH 2 ) p R 4 or-CO (CH 2 ) p C(CH 3 ) 2 R 4 , wherein p is an integer selected from 0 to 5, R 4 is a pyridazine selected from the group consisting of: R 5 and R 6 are independently selected from Wherein the wavy line represents a linkage to a six-membered aromatic ring of pyridazine and R 7 is-H, or (i) an isotopic labeling agent directly linked to the aromatic ring, or (ii) an isotopic labeling agent linked to the aromatic ring through a linker selected from -(CH 2 ) b 、WO(CH 2 ) b -WNH(CH 2 ) b 、-WCONH(CH 2 ) b 、-WNHCO(CH 2 ) b ,W being- (CH 2 ) h or- (CH 2 CH 2 O) h ), b and H being integers independently selected from 1-25, or (iii) an isotopic labeling agent chelated by a chelating agent linked to the aromatic ring through a linker selected from -(CH 2 ) r 、-WO(CH 2 ) r 、-WNH(CH 2 ) r 、-WCONH(CH 2 ) r 、-WNHCO(CH 2 ) r ,W being- (CH 2 ) q or- (CH 2 CH 2 O) q , R and q being integers independently selected from 1-25; When R 7 is (i) or (ii), the isotopic labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 I、 124 I、 125 I、 127 I、 131 I、 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re、 186 Re、 188 Re、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt; e and D are independently selected from-CH and-N-; R 8 is H or a moiety selected from the group consisting of hydroxy, sulfonamide, carboxy, sulfonyl, amine, substituted amine having 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally, the representative represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxy, sulfonyl, amino, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) alkylene, (C1-C10) alkoxy, (C2-C10) dialkylamino, (C1-C10) alkylthio, (C2-C10) heteroalkyl, (C2-C10) heteroalkylene, (C3-30C 10) cycloalkyl, (C3-C10) heterocycloalkyl, (C3-C10) cycloalkylene, (C3-C10) heterocycloalkylene, (C1-C10) haloalkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenyloxy, (C3-C10) alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, (C1-C6) alkoxy- (C1-C4) alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein the optional representation represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxyl, sulfonyl, amine, substituted amine with 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl, wherein optionally more than one substituent selected from halogen, hydroxy, sulfonamide, carboxyl, sulfonyl and amine groups; R 5 and R 6 are the same or differ only in the isotopic mass number of the labelling agent; formula (I) comprises at least one radioisotope selected from the group consisting of a radioisotope of fluorine, a radioisotope of iodine, a radioisotope of bromine, and a radioisotope of astatine; at least one of L and X contains J.
  2. 2. The PSMA-targeted ureido ligand of claim 1, wherein L is selected from the group consisting of: -CO(CH 2 ) n NH-、-CO(CH 2 CH 2 O) n NH-、-M-、-CO(CH 2 ) n NHM l -、-CO(CH 2 CH 2 O) n NHM l -、-MnCO(CH 2 ) n NH-、-MnCO(CH 2 CH 2 O) n NH-、-LysG-、-LysJ-、-LysGCO(CH 2 CH 2 O) n NH-、-LysJCO(CH 2 ) n NH-、-LysGCO(CH 2 ) n NHM l -、-LysJCO(CH 2 ) n NHM l -、-LysGM n -、-LysJM n -、-LysGCO(CH 2 ) n NHM l -、-LysJCO(CH 2 ) n NHM l -、-LysGCO(CH 2 CH 2 O) n NHM l -、-LysJCO(CH 2 CH 2 O) n NHM l -、-LysGM n CO(CH 2 ) n NH-、-LysJM n CO(CH 2 ) n NH-、-LysGM n CO(CH 2 CH 2 O) l NH-、-LysJM n CO(CH 2 CH 2 O) l NH-、-CO(CH 2 CH 2 O) n NHLysG-、-CO(CH 2 ) n NHLysJ-、-CO(CH 2 ) n NHM l LysG-、-CO(CH 2 ) n NHM l LysJ-、-M n LysG-、-M n LysJ-、-CO(CH 2 ) n NHM l LysG-、-CO(CH 2 ) n NHM l LysJ-、-CO(CH 2 CH 2 O) n NHM l LysG-、-CO(CH 2 CH 2 O) n NHM l LysJ-、-M n CO(CH 2 ) l NHLysG-、-M n CO(CH 2 ) l NHLysJ-、-M n CO(CH 2 CH 2 O) l NHLysG-、-M n CO(CH 2 CH 2 O) l NHLysJ-, wherein n and l are integers independently selected from 0 to 10; m is selected from more than one natural amino acid, more than one saccharide and a combination of more than one natural amino acid and more than one saccharide; lys is a D-lysine or L-lysine amino acid residue modified with G or J in the side chain, G is a chelator which may comprise a metal, or tetrazine or a metabolic derivative thereof, J is-CO (CH 2 ) p R 4 or-CO (CH 2 ) p C(CH 3 ) 2 R 4 , wherein p is an integer selected from 0 to 5, R 4 is a pyridazine selected from the group consisting of: R 5 and R 6 are independently selected from Wherein the wavy line represents a linkage to a six-membered aromatic ring of pyridazine and R 7 is-H, or (i) an isotopic labeling agent directly linked to the aromatic ring, or (ii) an isotopic labeling agent linked to the aromatic ring through a linker selected from -(CH 2 ) b 、WO(CH 2 ) b -WNH(CH 2 ) b 、-WCONH(CH 2 ) b 、-WNHCO(CH 2 ) b ,W being- (CH 2 ) h or- (CH 2 CH 2 O) h ), b and H being integers independently selected from 1-25, or (iii) an isotopic labeling agent chelated by a chelating agent linked to the aromatic ring through a linker selected from -(CH 2 ) r 、-WO(CH 2 ) r 、-WNH(CH 2 ) r 、-WCONH(CH 2 ) r 、-WNHCO(CH 2 ) r ,W being- (CH 2 ) q or- (CH 2 CH 2 O) q , R and q being integers independently selected from 1-25; When R 7 is (i) or (ii), the isotopic labeling agent is selected from the following: 1 H、 2 H、 3 H、 11 C、 12 C、 13 C、 14 C、 13 N、 14 N、 15 N、 18 F、 19 F、 123 I、 124 I、 125 I、 127 I、 131 I、 211 At、 15 O、 16 O、 17 O、 18 O、 43 Sc、 44 Sc、 45 Sc、 45 Ti、 46 Ti、 47 Ti、 48 Ti、 49 Ti、 50 Ti、 55 Co、 58m Co、 59 Co、 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 76 Br、 77 Br、 79 Br、 80m Br、 81 Br、 72 As、 75 As、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re、 186 Re、 188 Re、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 31 P、 32 P、 33 P、 32 S、 35 S、 45 Sc、 47 Sc、 84 Sr、 86 Sr、 87 Sr、 88 Sr、 89 Sr、 165 Ho、 166 Ho、 156 Dy、 158 Dy、 160 Dy、 161 Dy、 162 Dy、 163 Dy、 164 Dy、 165 Dy、 227 Th、 232 Th、 51 Cr、 52 Cr、 53 Cr、 54 Cr、 73 Se、 74 Se、 75 Se、 76 Se、 77 Se、 78 Se、 80 Se、 82 Se、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 135 La、 138 La、 139 La、 162 Er、 164 Er、 165 Er、 166 Er、 167 Er、 168 Er、 170 Er、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt; e and D are independently selected from-CH and-N-; R 8 is H or a moiety selected from the group consisting of hydroxy, sulfonamide, carboxy, sulfonyl, amine, substituted amine having 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, methyl, ethyl, propyl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein, optionally, the representative represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxy, sulfonyl, amino, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) alkylene, (C1-C10) alkoxy, (C2-C10) dialkylamino, (C1-C10) alkylthio, (C2-C10) heteroalkyl, (C2-C10) heteroalkylene, (C3-30C 10) cycloalkyl, (C3-C10) heterocycloalkyl, (C3-C10) cycloalkylene, (C3-C10) heterocycloalkylene, (C1-C10) haloalkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenyloxy, (C3-C10) alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, (C1-C6) alkoxy- (C1-C4) alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl; wherein the optional representation represents one or more substituents selected from the group consisting of halogen, hydroxy, sulfonamide, carboxyl, sulfonyl, amine, substituted amine with 1-5 polyethylene glycol units, - (O-CH 2 -CH 2 ) u -OCH 2 -COOH and u is an integer selected from 1-5, or hydrogen, methyl, ethyl, propyl, optionally substituted heteroaryl and optionally substituted aralkyl, wherein optionally more than one substituent selected from halogen, hydroxy, sulfonamide, carboxyl, sulfonyl and amine groups; R 5 and R 6 are the same or differ only in the isotopic mass number of the labelling agent.
  3. 3. The PSMA-targeted ureido ligand according to claim 1, wherein M is a polar natural amino acid or D-enantiomer thereof.
  4. 4. A PSMA-targeted ureido ligand according to any one of claims 1 to 3, wherein G comprises a chelating agent selected from the group consisting of: 1,4,7, 10-tetraazacyclododecane-N, N ', N', N '' -tetraacetic acid (DOTA), N, N '-bis (2-hydroxy-5- (carboxyethyl) benzyl) ethylenediamine-N, N' -diacetic acid (HBED-CC), 1,4, 7-Triazacyclononane-1, 4, 7-triacetic acid (NOTA), 2- (4, 7-Bis (carboxymethyl) -1,4, 7-triazacyclononan-1-yl) glutaric acid (NODAGA), 2- (4, 7, 10-Tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane-1-yl) glutaric acid (DOTAGA), 1,4, 7-Triazacyclononane phosphonic acid (TRAP), 1,4, 7-Triazacyclononane-1-methyl (2-carboxyethyl) phosphonic acid 4, 7-bis (methyl (2-hydroxymethyl) phosphonic acid (NOPO), 3,6,9,15-Tetraazabicyclo [9.3.1] pentadecane-1 (15), 11, 13-triene-3, 6, 9-triacetic acid (PCTA), N' - (5-acetyl (hydroxy) aminopentyl) -N- (5- (4- (5-aminopentyl) (hydroxy) amino-4-oxobutanoyl) amino) pentyl-N-hydroxysuccinamide (DFO), Diethylene Triamine Pentaacetic Acid (DTPA), Trans-cyclohexyl-diethylenetriamine pentaacetic acid (CHX-DTPA), 1-Oxa-4, 7, 10-triazacyclododecane-4, 7, 10-triacetic acid (OXO-Do 3A), P-benzyl isothiocyanate-DTPA (SCN-BZ-DTPA), 1- (P-benzyl isothiocyanate) -3-methyl-DTPA (1B 3M), 2- (P-Liporhodanic acid benzyl) -4-methyl-DTPA (1M 3B), 1- (2) -Methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).
  5. 5. The PSMA-targeted ureido ligand of claim 4, wherein the chelator comprises a metal.
  6. 6. The PSMA-targeted ureido ligand of claim 5, wherein the metal is selected from the group consisting of: 60 Cu、 61 Cu、 63 Cu、 64 Cu、 65 Cu、 67 Cu、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 86 Y、 89 Y、 90 Y、 89 Zr、 90 Zr、 91 Zr、 92 Zr、 94 Zr、 149 Tb、 152 Tb、 159 Tb、 161 Tb、 111 In、 113 In、 114 mIn、 115 mIn、 175 Lu、 177 Lu、 185 Re、 186 Re、 188 Re、 201 Tl、 203 Tl、 205 Tl、 206 Pb、 207 Pb、 208 Pb、 212 Pb、 209 Bi、 212 Bi、 213 Bi、 45 Sc、 47 Sc、 227 Th、 232 Th、 94 Tc、 99m Tc、 103 Rh、 103 mRh、 119 Sb、 121 Sb、 123 Sb、 193 mPt、 195 mPt、 192 Pt、 194 Pt、 195 Pt、 196 Pt、 198 Pt、 225 Ac.
  7. 7. The PSMA-targeted ureido ligand of any of claims 1-6, wherein the at least one radionuclide is selected from 18 F、 125 I、 123 I、 131 I、 124 I、 211 At、 77 Br and 80m Br.
  8. 8. The PSMA-targeted ureido ligand of claim 7, wherein at least one radionuclide is located on R 4 .
  9. 9. The PSMA-targeted ureido ligand of claim 7, wherein at least one radionuclide is located on R 1 or R 2 .
  10. 10. The PSMA-targeted ureido ligand of claim 7, wherein the radionuclide is located on R 4 and on R 1 or R 2 .
  11. 11. The PSMA-targeted ureido ligand of any of the preceding claims, wherein at least one radionuclide is located on R 4 、R 1 or R 2 , and further comprising an unlabeled chelator.
  12. 12. The PSMA-targeted ureido ligand of any of the preceding claims, wherein the PSMA-targeted ureido ligand comprises a J located on X or L, and J is selected from J (i) or J (ii).
  13. 13. The PSMA-targeted ureido ligand of any of the preceding claims, wherein R 7 comprises 18 F.
  14. 14. The PSMA-targeted ureido ligand of claim 1, wherein the PSMA-targeted ureido ligand is selected from the group consisting of: wherein F is 18 F or 19 F; I is 125 I、 123 I、 127 I、 131 I or 124 I; hal is 18 F、 19 F、 18 F、 125 I、 123 I、 127 I、 131 I、 124 I、 211 At、 77 Br、 79 Br or 80m Br.
  15. 15. A precursor for providing a PSMA-targeted ureido ligand according to claim 1, wherein the precursor is selected from the group consisting of: wherein R 9 is -Si(CH 3 ) 3 、-Si(CH 2 CH 2 CH 2 CH 3 ) 3 、-Sn(CH 3 ) 3 、-Sn(CH 2 CH 2 CH 2 CH 3 ) 3 、-B(OH) 2 or 。

Description

PSMA diagnostic compounds assembled with tetrazine-trans-cyclooctene linkages Technical Field The present invention relates to ureido ligands assembled by tetrazine ligation that target prostate specific membrane antigens and their use in radiation therapy and imaging. Background Prostate Cancer (PC) is one of the most frequently diagnosed cancers in men. Further complications caused by PC (e.g. bone metastases) can occur in a considerable number of patients, resulting in annual survival rates of only 40%. To complicate this situation, some of these patients do not respond to conventional hormone therapy, thereby developing so-called castration-resistant prostate cancer (CRPC). Currently, treatment methods for CRPC patients are limited. Potent and selective radiopharmaceuticals may represent an important diagnostic and therapeutic choice for this disease. Recently, prostate Specific Membrane Antigen (PSMA) has become a promising target due to its overexpression (8 to 12-fold higher) in PC cells compared to healthy tissue. However, some of the PSMA-targeted radiopharmaceuticals that have been developed and marketed show limited responses in patients as well as adverse side effects, such as nephrotoxicity and salivary gland accumulation。 Current state-of-the-art PSMA-targeted radiotherapy is based on 177 Lu-PSMA-617 (Pluvicto), which shows good molecular response in clinical evaluation, is able to clear considerable metastases and significantly reduce PSA concentrations to normal levels (below 4.0 ng/mL). However, 30% of patients of note do not respond to β - -emitter-based therapies (e.g., 177 Lu-PSMA-617), and therefore alternative strategies are needed。 Alpha emitting radionuclides have recently become a more efficient alternative to beta - -emitters because of their ability to deliver larger amounts of energy to cancer cells. Such approaches are currently being explored for PSMA-based therapies. For example, actinium-225 (225 Ac) has been widely studied, but it is not an ideal therapeutic radionuclide because it decays through four active alpha daughter radionuclide chains, with a total half-life of 10 days. This means extensive damage to healthy tissue, increasing the toxic effects on the patient and limiting the use of these radiopharmaceuticals. Astatin-211 (211 At) represents a useful alternative to 225 Ac based on its short half-life of 7.2 hours and the characteristic that its decay does not produce any long-lived alpha emitter. Both of these properties significantly reduce cytotoxicity to patients compared to 225 Ac-based PSMA derivatives。 Radioactive halogen-labeled PSMA-targeting drugs have been developed and show good, specific tumor uptake, but in the absence of blocker, these compounds are damaged by renal and salivary gland accumulation. Furthermore, synthesis and radiolabeling procedures are based on standard methods, which are not always easy to implement in radiopharmaceuticals, hospitals and clinics. Click chemistry has shown great potential in radiopharmaceutical synthesis for imaging and therapy. In particular, the inverse electron-demanding Diels-Alder cycloaddition reaction (IEDDA) between tetrazine and dienophile shows the fastest reaction kinetics in click chemistry and has been used in radiosynthesis of a variety of labeled radiopharmaceuticals. The main limitation of this reaction is the formation of multiple isomers after clicking. This problem has recently been solved by the synthesis of novel trans-cyclooctenes (IsoF-TCO), which in combination with the oxidation step can lead to the formation of a single isomer product (PCT/EP 2023/055930). It is shown herein that PSMA-targeting compounds with specific pharmacokinetic properties can be obtained by synthesizing compounds comprising urea-based moieties targeting PSMA, a linker, isoF-TCO, and radiolabelled tetrazine. Furthermore, the modularity of this approach enables rapid and efficient modification of radiopharmaceuticals, which may allow for rapid optimisation of certain properties, such as renal excretion and liver accumulation. As also shown herein, it has surprisingly been found that by adding increasing amounts of polar amino acids (D-glutamic acid and D-arginine) in the linker between the PSMA binding moiety and the pyridazine moiety, the excretion of ureido ligands targeting PSMA can be controlled by diverting the excretion from the liver to the kidneys and bladder. In particular, this effect is more pronounced at 2 to 6 amino acids. Furthermore, using the different radiolabelled tetrazines provided herein, PSMA compounds were allowed to be synthesized starting from the same PSMA-targeted ureido ligand precursor. Finally, the radiolabeled compounds provided herein show surprisingly higher tumor accumulation compared to PSMA-617, while retaining the same affinity for the target. Disclosure of Invention The present invention provides novel PSMA-targeting ureido ligands and pharmaceutically acceptable salts thereof having t