Manganese-based chelate conjugates for molecular MR imaging

Abstract

The present invention provides an MR contrast agent that does not contain gadolinium(III). [Solution] This specification provides examples of metal chelate ligands having high affinity for manganese. The resulting metal complexes can be used as MRI contrast agents and can be functionalized at moieties that bind to or induce relaxation changes in the presence of biochemical targets.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is a continuation of U.S. Provisional Patent Application No. 62 / 204,519 filed on August 13, 2015. and the specification of U.S. Provisional Patent Application No. 62 / 356,732 filed on June 30, 2016 (these The contents of (which are incorporated herein by reference in their entirety) claim priority.

[0002] Federal government-commissioned research or development This invention relates to the National Institutes of Health Government support based on grant number R01CA161221 awarded by (ith). It was carried out by [unspecified means]. The government has certain rights to this invention.

[0003] The present invention relates to metal chelate ligands, and more specifically to a metal chelate ligand for magnetic resonance imaging. This relates to the manganese chelate complex of this ligand, which can be used as a trusting agent. [Background technology]

[0004] Many of the metal chelate ligands currently used in magnetic resonance (MR) are gadolinium. Polyar designed for chelation of lanthanide (III) ions such as (III) It is a minopolycarboxylate metal-bonded chelate ligand. Commercially available MR Contrast All of the agents contain a gadolinium(III) metal chelate compound. However, For the past ten years, patients who have been taking gadolinium(III)-containing MR contrast preparations have There is growing awareness of gadolinium(III)-induced toxicity. This toxicity is related to nephrogenic total It manifests as physical fibrosis (NSF). Patients with chronic kidney disease may take gadolinium (I II) It is particularly prone to inducing NSF, and MR contrast agents are used in severe chronic kidney disease. It is generally not administered to patients who are ill. Therefore, gadolinium(III)-related toxins To avoid the possibility of sexual contact, MR contrast agents that do not contain gadolinium(III) Identifying this would be useful.

[0005] An effective contrast agent must contain several characteristics. To create contrast, it should have high relaxation properties. Relaxation properties are due to the metal chelate being water-soluble. This is the ability to relax protons, and the change in the relaxation rate of water is divided by the millimolar concentration of the chelate. It is defined as having a certain degree of relaxation. Relaxability depends on many molecular factors. To obtain high relaxation, high It is advantageous to use metal ions with spin quantum numbers, and the metal ions are directly bonded. It is advantageous to have one or more bound water molecules, and the bound water molecules are in the solvent with respect to other water molecules. A very rapid chemical exchange should occur with it. Most metal ions are MR contrast It is toxic at the concentration necessary to provide [the necessary substance]. Therefore, metal ions are significant. Chelates with a polydentate ligand that is stable enough to prevent release into the body in large quantities. It should be changed.

[0006] Forms highly relaxed compounds that bind to or alter the relaxability of biochemical targets. Identifying metal chelate ligands that bind to biochemical targets would also be worthwhile. The substance is a target protein, enzyme, or other substance that is eliminated from the body by excretion in a delayed phase. Alternatively, it would enable the detection of cells. It alters the relaxation properties in the presence of biochemical targets. The mixture will provide changes in MRI signal intensity at the target location. MRI will provide biochemical information. The ability to detect changes in the pathway is used for staging disease conditions such as cancer, inflammation, fibrosis, and thrombosis. This would provide a non-invasive means of monitoring the progression of the compound and imaging method. It would also provide a non-invasive means of tracking treatment response. [Overview of the project] [Means for solving the problem]

[0007] This disclosure relates to metal crystals that bind to or are obtained in the presence of a biochemical target. To improve rate relaxation or prevent metal ion dissociation in the body To provide additional stability to the metal chelate, or to provide a chelate ligand for either of the following purposes. This is based on performing one or more modifications. These modifications involve a donor group (which directly coordinates to a metal ion). Modification of functional groups, introduction of groups that organize water in the second coordination zone (for example, by hydrogen bonding). , introduction of groups that facilitate water exchange on metal ions, or by increasing molecular weight or macromolecules Molecular tamping can occur either by targeting metal chelates to (for example, proteins) or by other means. Introduction of groups that slow down the ring, and introduction of groups that support or promote changes in the metal oxidation state. It includes. The donor group is, for example, an oxidized state that responds to binding to a polymer target or enzymatic activity. This may include several functions that utilize highly relaxing mechanisms, including improved relaxation through changes in [specific mechanism]. .

[0008] Metal chelates prepared with chelating ligands exhibit slow reactions at various magnetic fields and temperatures. Nutability measurement and variable temperature 17 To investigate using techniques such as NMR measurement. This is possible.

[0009] Finally, the chelating ligand can be useful for preparing diagnostic and / or therapeutic compositions of radioactive metal ions. It may be useful for preparing.

[0010] This specification provides a compound of formula (I):

Chemical formula

[0011] In some embodiments, DG is [ka] That is the case.

[0012] In some embodiments, Q is CH. In some embodiments, Y is CH . In some embodiments, at least one Y is CZ (where Z is CO2R 4 , C1-C6 alkyl, and OR 4 selected from the group consisting of). In some embodiments one Y is CZ (where Z is CO2R 4 , C1-C6 alkyl, and OR 4 selected from the group consisting of), and all other Ys are CH. In some embodiments, each R 4 is H or C1-C6 alkyl (where the alkyl is optionally substituted by 1, 2 , 3, or 4 OH groups).

[0013] In some embodiments, R 2 and R 3 are H.

[0014] In some embodiments, DG is

Chemical formula

[0015] In some embodiments, DG is

Chemical formula

Chemical formula

[0016] In some embodiments, DG is [Chemical formula] as follows. In some embodiments, at least one Y is N, O, S, or NR 4 as follows For example, one Y is NR 4 and the remaining Ys are CH. In some embodiments DG is [Chemical formula] as follows.

[0017] In some embodiments, DG is [Chemical formula] as follows. For example, DG is [Chemical formula] <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2 H is H.

[0020] In some embodiments, R 3 H is H.

[0021] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] Selected from the group consisting of or pharmaceutically acceptable salts thereof.

[0022] Furthermore, this specification includes formula (VI): [ka] Compounds thereof or pharmaceutically acceptable salts thereof are also provided. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are classified as 1, 2, respectively. , 3, or 4 independently selected R X (Optionally substituted by the base), and R 1 R 1 Attached to adjacent nitrogen via the 1,2 or 1,3 positions above, R 2 , R3 and R 4 is of the formula:

Chemical formula

[0023] In some embodiments, R 1 It is 1,2-cyclohexylene, and R 2 , R 3 , oyo biR 4 This is equation VII, and R 5 and R 6 is H, DG is equation XI, and one Y is [L]-[TBM] (where [L] is -C(O)- and [TBM]) (is -NHNH2).

[0024] In some embodiments, the compound of formula (VI) is [ka] or a pharmaceutically acceptable salt thereof.

[0025] This specification includes formula (XV) [ka] Compounds thereof or pharmaceutically acceptable salts thereof are further provided. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are classified as 1, 2, respectively. , 3, or 4 independently selected R X (Optionally substituted by the base), and R 1 R 1 Attached to adjacent nitrogen via the 1,2 or 1,3 positions above, Each R 2 , R 3 , and R 4 CO2H, (C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHSO2R 5 CH2NHSO2R 5 , N(OH )C(O)R 5 , P(R 5 ) O2R 6 , and PO3R 5 R 6 And formula: [ka] Independently selected from the group consisting of the following compounds, X is CZ, N, O, S, or NR 5 And, Each W is independently CH, CZ, N, O, S, or NR 5 And, Each Z is independently H, OH, OR 4 CO2H, -(C 1~6 Alkyl)CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cyclo Alkyl, C6~C 10Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHSO 2R 5 CH2NHSO2R 5 N(OH)C(O)R 5 , P(R 5 ) O2R 6 , PO3 R 5 R 6 , and selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. X Based on the basis, arbitrarily (to be replaced), Each R 5 and R 6 It consists of H, C1-C6 alkyl, and -[L]-[TBM]. Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R X (Optionally substituted by the base), L is a linker, TBM is the target binding site, and Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] It is selected independently from the group.

[0026] In some embodiments, R 1 It is 1,2-ethylene, and R 2 is COOH, and R 3 is equation XVI (where X is N and all W are CH), and R 4 is chemical Selected from combination formula XVI. For example, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0027] In some embodiments, R 1 It is 1,2-ethylene, and R 2 is COOH, and R 3 is COOH and R 4 R is selected from compound formula XVI. For example, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0028] In some embodiments, the compound of formula (XV) is [ka] [ka] [ka] Selected from the group consisting of or pharmaceutically acceptable salts thereof.

[0029] Furthermore, this specification includes formula (XVII) [ka] Compounds thereof or pharmaceutically acceptable salts thereof are also provided. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are classified as 1, 2, respectively. , 3, or 4 independently selected R X (Optionally substituted by the base), and R 1 R 1 Attached to adjacent nitrogen via the 1,2 or 1,3 positions above, Each R 2 and R 3 H, CO2H, (C1~C6 alkyl)CO2H, C1~C6 Lukyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C 6~C 10 Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 CH2NHCOR 4 , C(O)N(OH)R 4 C(O)NHSO2R 4 CH 2NHSO2R 4 N(OH)C(O)R 4 , P(R 4 ) O2R 5 PO3R 4 R 5 ,oh Independently selected from the group consisting of [L]-[TBM], Each R 4 and R 5 This group consists of H, C1-C6 alkyl, and [L]-[TBM]. Independently selected from (where alkyl is 1, 2, 3, or 4 independently selected) R X (Optionally substituted by the base), DG is [ka] A group consisting of or selected from any structural isomers of formulas IV and V, Each Y can independently be CH, CZ, N, O, S, or NR 4 And, Q stands for CH, CZ, N, O, S, or NR 4 And, Each Z is H, OH, OR 4 CO2H, -(C 1~6 Alkyl)CO2H, C1~C6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)N R 4 R 5 CH2NHCOR 4 , C(O)N(OH)R 4 C(O)NHSO2R 4 , C H2NHSO2R 4 N(OH)C(O)R 4 , P(R 4 ) O2R 5 PO3R 4 R 5 , And independently selected from the group consisting of -[L]-[TBM] (where alkyl, aldehyde Kenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and hetero Each aryl is composed of 1, 2, 3, or 4 independently selected R X Arbitrary (Selectively replaced), L is a linker, TBM is the target binding site, Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I Selected from the group consisting of II), However, when Q is CH or CCOOH and all Y are CH, R 2 Also is R 3 At least one of them is not H.

[0030] In some embodiments, the compound of formula (XVII) is [ka] [ka] [ka] Selected from the group consisting of or pharmaceutically acceptable salts thereof.

[0031] This specification includes formula (XVIII) [ka] Compounds thereof or pharmaceutically acceptable salts thereof are further provided. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are classified as 1, 2, respectively. , 3, or 4 independently selected R X (Optionally substituted by the base), and R 1 R 1 Attached to adjacent nitrogen via the 1,2 or 1,3 positions above, R 2 , R 3 , and R 4 The formula is: [ka] Independently selected from the group of compounds, R 5 and R 6 H, CO2H, (C1~C6 alkyl)CO2H, C1~C6 alkyl Kill, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C6 ~C 10 Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R7 C(O)NHSO2R 7 CH2 NHSO2R 7 N(OH)C(O)R 7 , P(R 7 ) O2R 8 PO3R 7 R 8 , oyo Independently selected from the group consisting of [L]-[TBM], X is CZ, N, O, or S or NR 7 And, Each W is independently CH, CZ, N, O, S, or NR 7 And, Each Z is independently H, OH, OR 4 CO2H, C 1~6 CO2H, -(C 1~6 a Lukil)CO2H, C2~C6 alkenyl, C2~C6 alkinyl, C4~C6 cycloa Lukill, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C (O)NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R 7 C(O)NHSO2 R 7 CH2NHSO2R 7 N(OH)C(O)R 7 , P(R 7 ) O2R 8 PO3R 7 R 8 , and selected from -[L]-[TBM] (where alkyl, alkenyl, and Lukinyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are Each of these consists of 1, 2, 3, or 4 independently selected Rs. X The base can be arbitrarily placed (to be replaced), Each R 7 and R 8It consists of H, C1-C6 alkyl, and -[L]-[TBM]. Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R X (Optionally substituted by the base), DG is [ka] A group consisting of or selected from any structural isomer of formulas XIII to XIV, Each Y independently controls CH and CZ. 1 , N, O, S, or NR 7 And, Q is independent of CH and CZ. 1 , N, O, S, or NR 7 And, each Z 1 These are independently H, OH, OR 7 CO2H, -(C 1~6 Alkyl)CO2H , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cyclo R-alkyl, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl , C(O)NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R 7 C(O)NHS O2R 7 CH2NHSO2R 7 N(OH)C(O)R 7 , P(R 7 ) O2R 8 , PO 3R 7 R 8 Selected from , and -[L]-[TBM] (where alkyl, alkenyl) , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Each of the R's is one, two, three, or four independently selected R's. X Based on the arbitrary selection (to be replaced by), L is a linker, TBM is the target binding site, Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I Selected from the group consisting of II), However, Q is CH or CCOOH, all Y is CH, and R 2 , R 3 , and R 4When all of them are equation VII, R 5 or R 6 At least one of them is H Furthermore, R 2 , R 3 , or R 4 One of them is equation VIII, and R 5 and R 6 All of H When this is the case, the aromatic ring component of formula VIII (i.e., the ring containing X and W) is DG and They must be different.

[0032] Furthermore, this specification includes formula (XIX) [ka] Compounds thereof or pharmaceutically acceptable salts thereof are also provided. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are classified as 1, 2, respectively. , 3, or 4 independently selected R X (Optionally substituted by the base), and R 1 R 1 Attached to adjacent nitrogen via the 1,2 or 1,3 positions above, Each R 2 , R 3 , and R 4 CO2H, (C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHSO2R 5 CH2NHSO2R 5 , N(OH )C(O)R 5 , P(R 5 ) O2R 6 , and PO3R 5 R 6 And formula: [ka] Independently selected from the group consisting of the following compounds, X is CZ, N, O, or S or NR 4 And, Each W is independently CH, CZ, N, O, S, or NR 4 And, Each Z is independently H, OH, OR 4 CO2H, -(C 1~6 Alkyl)CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cyclo Alkyl, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHSO 2R 5 CH2NHSO2R 5 N(OH)C(O)R 5 , P(R 5 ) O2R 6 , PO3 R 5 R 6 , and selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. X Based on the basis, arbitrarily (to be replaced), Each R 5 and R 6 It consists of H, C1-C6 alkyl, and -[L]-[TBM]. Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R X (Optionally substituted by the base), L is a linker, TBM is the target binding site, Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I Selected from the group consisting of (II).

[0033] In some embodiments, the compound of formula (XVIII) is [ka] [ka] [ka] [ka] [ka] From the group consisting of or pharmaceutically acceptable salts thereof or any corresponding stereoisomer Selected.

[0034] This disclosure further includes formula (A): (D 1 ) a -(L 1 ) b -TBM-(L 2 ) c -(D 2 ) d (A) The present invention provides compounds of or pharmaceutically acceptable salts thereof. During the ceremony, TBM is the target binding site, Each D 1 This is independently a metal chelate according to any one of claims 44 to 48, Each D 2 This is independently a metal chelate according to any one of claims 44 to 48, L 1 It is a linker, L 2 It is a linker, a is an integer between 0 and 4. b is either 0 or 1. However, when a is 0, b is 0, c is either 0 or 1. d is an integer between 0 and 4. However, when d is 0, c is 0, At least one of a and d is an integer between 1 and 4.

[0035] In some embodiments, [TBM] is [ka] That is the case.

[0036] In some embodiments, [TBM] is [ka] That is the case.

[0037] In some embodiments, D 1 and D 2 is the compound described in claim 1, however, R 1 It is 1,2-cyclohexylene, and R 2 H is R 3 H is and DG is given by equation I I is CH, the α-position Y of Q is C-[L]-TBM and all other Ys are The compound is CH, and L is -C(O)-.

[0038] In some embodiments, the compound is [ka] It is selected from the group consisting of the following.

[0039] Furthermore, this specification also provides a method for performing magnetic resonance (MR) imaging of a patient. This method involves a) administering an effective amount of a compound containing the metal chelate provided herein to a patient. The process includes a) a) obtaining an MRI image of the patient. For example, in the patient, tumor A method for performing imaging is provided herein. This method is provided a) a) The process of administering an effective amount of a compound containing a metal chelate to the patient, and a) taking an MRI image of the tumor. The process includes the steps to obtain a blood clot image in the patient. In some embodiments, the method includes the steps to obtain a blood clot image in the patient. This may include a method for performing zing. This method may include a) a metal chelate provided herein. The steps include a) administering an effective amount of the compound to a patient, and b) obtaining an MRI image of the blood clot. In some embodiments, this method provides a method for imaging brain lesions in patients. This method may include: a) an effective amount of a compound containing the metal chelate provided herein. The procedure includes the steps of a) administering the drug to the patient and a) acquiring MRI images of the brain lesion.

[0040] This specification further describes a method for detecting the presence or absence of a damaged blood-brain barrier in a patient. The method is provided. a) a metal chelate provided herein where M is Mn(II) a) administering an effective amount of the compound to the patient, and b) obtaining a first MR image of the patient's brain. The process involves: a) obtaining a second MR image of the patient's brain, and comparing the images. Includes. In some embodiments, methods for detecting the presence or absence of arterial stenosis in a patient are proposed. The method provides a) a metal chelate provided herein where M is Mn(II) a) the process of administering an effective amount of the compound to the patient, and b) obtaining a first MRI image of the patient's artery. The steps include: a) obtaining a second MR image of the patient's artery immediately after injection of the compound, and d) This includes the process of comparing images.

[0041] Unless otherwise defined, all scientific and technical terms used herein refer to the inventions to which this invention belongs. It has the same meaning as that generally understood by those skilled in the art. Similar or equivalent methods and materials to those described herein may be used in carrying out or testing the present invention. However, preferred methods and materials are described below. Publications and patents cited herein Applications, patents, and other reference documents are all incorporated in their entirety by reference. In the event of a dispute, this specification, including its definitions, shall prevail. In addition, methods, materials, and The examples provided are merely illustrative and not intended to be limiting.

[0042] Details of one or more embodiments of the present invention are shown in the accompanying drawings and the following description. The features, purpose, and advantages will become apparent from the description and drawings and the claims. cormorant. [Brief explanation of the drawing]

[0043] [Figure 1] Figure 1 shows that fibrin-targeting compound 20 has high affinity for soluble fibrin degradation products, including a complex of the D-dimer domain and E-domain of a protein called DD(E). The fluorescence polarization anisotropy of the fluorescein-labeled fibrin-binding peptide in DD(E) solution is shown as a function of Mn-FBP (black circle) or a known fibrin-binding molecule EP2104R (white circle) added to determine Ki for DD(E). [Figure 2] Figure 2 shows that the Mn ion in compound 20 has one rapid exchange water ligand. The H2 17O transverse relaxation (white circles) in the presence of compound 20 is shown as a function of temperature. The solid line represents the fit to the data. [Figure 3]Figure 3 shows MR imaging of carotid artery thrombosis in a rat model using compound 20. Axial T1-weighted images before (A, C) and 35 minutes after (B, D) intravenous administration of compound 20 at 1.5T. (C) and (D) are enlarged areas from (A) and (B), respectively, showing the common carotid artery. Compound 20 produces significant signal enhancement in the ipsilateral vessel (hollow arrow, D) after injection of compound 20, but not in the contralateral vessel (filled arrow, D), nor in the vessel before Mn-FBP injection (C). (E) Hematoxylin-eosin stained sections of the contralateral (left) and ipsilateral (right) carotid arteries showing occlusive thrombi in the injured vessel. Scale bar = 300 μm. [Figure 4] Figure 4 shows the quantification of MR imaging data using compound 20. (A) and (B) show the normalized signal-to-noise ratio (nSNR) of thrombus (black circles), contralateral vascular region (white circles), and muscle (black diamonds) after administration of compound 20 and EP-2104R, respectively, illustrating the washout of signals from thrombus and background tissue that were sustainedly enhanced by each probe. (C) and (D) show the contrast-to-noise ratio (CNR) of thrombus vs. muscle (black circles) and contralateral vascular region vs. muscle (white circles) after administration of compound 20 and EP2104R, respectively, showing a large and sustainedly high CNR for thrombus by each probe. N=4 for each probe, and the error bars represent the standard error of the mean. [Figure 5] Figure 5 shows the blood clearance of compound 20 as a function of time (N=4). [Figure 6] Figure 6 shows the change in the relaxation properties of peroxidase-reactive compound 20 as a function of time in the presence of hydrogen peroxide, with or without horseradish peroxidase (black circles) and with horseradish peroxidase (white circles). A sevenfold increase in relaxation properties is observed with peroxidase exposure within 3 minutes. [Figure 7] Figure 7 shows that the conversion from compound 33 to compound 34 is carried out cleanly without any byproducts. The upper trace is compound 33, and the lower trace is compound 33 after treatment with hydrogen peroxide and horseradish peroxide (mostly converted to compound 34). [Figure 8] Figure 8 shows the relaxation change of thiol-reactive compound 33 as a function of time (1.41 T, 37°C) when incubated in human plasma with or without 5 molar equivalents of L-cysteine ​​(black circles) or with L-cysteine ​​(white circles). [Modes for carrying out the invention]

[0044] 1.Definition Chemical abbreviations not expressly defined in this disclosure are commonly used by The Americas. n Chemical Society Style Guide,Second Ed ition;American Chemical Society,Washingt on, DC (1997), “2001 Guidelines for Authors. "J.Org.Chem.66(1),24A(2001), and "A Short Guide to Abbreviations and Their Use in Peptide Science”J.Peptide.Sci.5,465-471 It can be found in (1999).

[0045] The terms "chelate ligand," "chelate moiety," and "chelate moiety" are defined as follows: Used synonymously, it refers to a group that can coordinate to a metal ion, either directly or after the removal of the protecting group. It means a polydentate ligand of the intent, or used in the synthesis of MR contrast agents, and final A suitable protecting group containing substantially all of the atoms that ultimately coordinate to the metal ion of the metal complex. This refers to any polydentate ligand that is present or absent in the reagent. "Chelate" or "metallic ligand" The term "rate" refers to the actual metal-ligand complex. Polydentate ligands are medically important. It is understood to be a substance that can ultimately coordinate to metal ions used for purposes or diagnostics.

[0046] As used herein, the term "specific binding affinity" refers to a comparison with other non-target biocomponents. and more highly, it is taken up by specific or targeted biological components, thereby retained. This refers to the volume of the contrast agent that is added to or bound to it. Trusts are said to be "targeted" against the "target" component. The lack of this property... These contrast agents are said to be "non-specific" or "non-targeting" agonists. The bond affinity of the bonding group is determined by the equilibrium dissociation constant "K d This is represented by ".

[0047] As used herein, the term “relaxability” refers to the properties of paramagnetic ions or contrast agents. This refers to an increase in either the MR amount per millimolar (mM) concentration (1 / T1 or 1 / T2). These amounts may vary if the contrast agent contains multiple paramagnetic ions. Here, T1 is the longitudinal relaxation time or spin-lattice relaxation time, and T2 is the water proton Or other imaging nuclei or spectroscopic spectroscopy, including protons found in molecules other than water. This is the transverse relaxation time or spin-spin relaxation time of the target nucleus. Relaxation is in mM. -1 s -1 unit It is represented as follows.

[0048] The terms “target binding” and “binding” are used herein to mean contrast agent and target This refers to non-covalent interactions. These non-covalent interactions are independent of each other. Specifically, hydrophobic, hydrophilic, dipole-dipole, π-stacking, hydrogen bonding, electrostatic bonding This could be a synthesis or a Lewis acid-base interaction.

[0049] The coordination of metal ions by water and other ligands often involves considering the coordination sphere (even if DTRichens, The Chemistry of Aqua Ions ,John Wiley and Sons,New York,1997,Chapter (See er 1). The first coordination sphere or primary coordination sphere is directly bonded to the metal ion. Represents all ligands and is defined by ligands. Water molecules and counterions are hydrogen-bonded. When a molecule is coupled to a group in the first coordination zone by electrostatic interaction, a second coordination zone exists. The coordination sphere and subsequent coordination sphere are typically referred to as "bulk water" or "bulk solvent." The differences between these categories are both spatial and temporal. The first coordination category is typically clearly The time that water or other ligands remain in the first coordination zone is defined as being longer than the time that they remain in other coordination zones. The second circle is not as clearly defined, but the water here has a diffusion time that is longer than the typical diffusion time of water. It has a long lifespan. Water outside the second sphere diffuses freely.

[0050] As used herein, references to "Mn(II)" or "manganese(II)" are All of these refer to the Mn(II) paramagnetic metal ion, and are referred to as "Mn(III)" or "manganese." All references to "(III)" refer to the Mn(III) paramagnetic metal ion. When used in this context, "alkyl" refers to a branched or linear chain containing only carbon and hydrogen. Chemical groups in a certain form, such as methyl, ethyl, n-propyl, iso-propyl, and n-butyl. iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pinch This refers to sec-pentyl and neo-pentyl. The alkyl group is unsubstituted. It may be or may be substituted with one or more substituents. In some embodiments, the alkyl group is , 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 Contains ~2 carbon atoms.

[0051] As used herein, "alkenyl" means a compound containing only carbon and hydrogen. A linear or branched chemical group containing at least one carbon-carbon double bond, even For example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1- This refers to tenyl, 2-butenyl, etc. In various embodiments, the alkenyl group is unsubstituted. It may or may be substituted with one or more substituents. Typically, the alkenyl group has 2 to 9 substituents. a number of carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms) It will likely contain atoms.

[0052] As used herein, "alkynyl" means a compound containing only carbon and hydrogen. A linear or branched chemical group containing at least one carbon-carbon triple bond, even This refers to various fruits such as ethynyl, 1-propynyl, 1-butynyl, and 2-butynyl. In the application form, the alkynyl group may be unsubstituted or substituted with one or more substituents. Typically, an alkynyl group consists of 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms). It will likely contain 2 to 4 carbon atoms, or 2 carbon atoms.

[0053] As used herein, "alkylene" means a divalent compound containing only carbon and hydrogen. Branched or linear chemical groups, such as methylene, ethylene, n-propylene, and is o-isopropylene, n-butylene, iso-butylene, sec-butylene, tert- Butylene, n-pentylene, iso-pentylene, sec-pentylene, and neo- It means pentylene. The alkylene group can be unsubstituted or have one or more substituents. Substitution is possible. The alkylene group may have one or more positions saturated or unsaturated. For example, it contains subunits of -C=C- or -C≡C-). Several embodiments So, an alkylene group consists of 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms) Contains 1 or 2 carbon atoms.

[0054] As used herein, "alkenylene" means a substance containing only carbon and hydrogen. A divalent branched or linear chemical group containing at least one carbon-carbon double bond, For example, etenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene This refers to nilen, 1-butenylene, 2-butenylene, etc. In various embodiments, it is called alke The nylene group can be unsubstituted or substituted with one or more substituents. Typically, The lukenylene group consists of 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms) It will contain an atom (or two carbon atoms).

[0055] As used herein, "alkynylene" means a compound containing only carbon and hydrogen. A divalent branched or linear chemical group containing at least one carbon-carbon triple bond, For example, it means ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, etc. In various embodiments, the alkynylene group may be unsubstituted or one or more substituted groups. It can be substituted with substitution groups. Typically, an alkynylene group has 2 to 9 carbon atoms (for example, 2 It will contain ~6 carbon atoms, 2~4 carbon atoms, or 2 carbon atoms.

[0056] As used herein, "cycloalkyl" or "carbocyryl" means a ring system Cyclic ring systems containing only carbon atoms in their skeleton, for example, cyclopropyl, cyclobutyl, This refers to cyclopentyl, cyclohexyl, and cyclohexenyl. (Carbocyclyl) It may contain multiple fused rings. Carbocyclyls have at least one ring in the ring system that is aromatic. Otherwise, it can have any degree of saturation. The carbocyclyl group can be unsubstituted or It can be substituted with one or more substituents. In some embodiments, the carbocyclyl group is 3- It contains 10 carbon atoms (for example, 3 to 6 carbon atoms).

[0057] As used herein, "cycloalkylene" refers to a ring system containing only carbon atoms. Containing divalent cyclic ring systems, for example, cyclopropylene, cyclobutylene, cyclobenzo This refers to cycloalkylene, cyclohexylene, and cyclohexenylene. Cycloalkylene is It may contain multiple fused rings. Cycloalkylenes have at least one aromatic ring in the ring system. Unless otherwise specified, it can have any degree of saturation. The cycloalkylene group can be unsubstituted or It can be substituted with one or more substituents. In some embodiments, the cycloalkylene group is 3 It contains approximately 10 carbon atoms (for example, 3 to 6 carbon atoms).

[0058] As used herein, “aryl” means that at least one ring in the system is aromatic Some have 5 to 14 ring atoms, or alternatively, 5, 6, 9, or 10 ring atoms. A ring skeleton having 6, 10, or 14 π electrons shared within the ring array. This refers to monocyclic, bicyclic, tricyclic, or polycyclic groups that contain only carbon atoms. The reel group can be unsubstituted or substituted with one or more substituents. Examples of aryl groups and For example, fluorenyl, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro Examples include -1H-indenyl. be.

[0059] As used herein, "arylene" means a compound in which at least one ring in the system is aromatic. Assuming that, 5 to 14 ring atoms, or alternatively 5, 6, 9, or 10 ring atoms ring bone having 6, 10, or 14 π electrons shared within the ring array This refers to a divalent monocyclic, bicyclic, tricyclic, or polycyclic group in which only carbon atoms are present within the group. The arylene group may be unsubstituted or substituted with one or more substituents. Examples of fluorenes include fluorenylene, phenylene, naphthylene, and tetrahydronaphthyl Examples include 2,3-dihydro-1H-indenylene. In some embodiments, Aryl is phenylene.

[0060] As used herein, "arylalkylene" means an aryl moiety and an alkyl The 'len' part refers to the aryl-alkylene group, as already described. In the application form, the arylalkylene group is C 1~4 Contains alkylene moieties. (Example of an ant) Examples of chloroalkylene groups include benzyl and 2-phenethyl.

[0061] As used herein, the term "heteroaryl" means at least one in a system Assuming the ring is aromatic, and at least one ring in the system is N, O, and S As those containing one or more heteroatoms independently selected from the following groups, 5 to 14 A ring atom having, alternatively, 5, 6, 9, or 10 ring atoms, and within a ring array Monocyclic, bicyclic, tricyclic, or having 6, 10, or 14 shared π electrons. This refers to a polycyclic group. Heteroaryl groups can be unsubstituted or have one or more substitutions. It can be substituted with a group. Examples of heteroaryls include thienyl, pyridinyl, furyl, and oxa. Zolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, Pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl Pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, Benzofuranil, benzimidazolyl, benzotriazolyl, cinnolinyl, indazoli Lu, indolyl, isoquinolinyl, isothiazolyl, naphthilidinyl, prinyl, thieno Pyridinyl, pyrido[2,3-d]pyrimidinyl, pyrolo[2,3-b]pyridinyl, ki Nazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl Lydinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-c]pyridinyl Zoro[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b [1,4]dioxin, benzo[d][1,3]dioxol, 2,3-dihydroben Zofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathio Examples include . In some embodiments, the heteroaryl is thienyl, pyridinyl Lu, fryl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl It will be selected.

[0062] As used herein, the term "heteroarylene" means at least one in the system Assuming that two rings are aromatic, and at least one ring in the system is N, O, and S It contains one or more heteroatoms independently selected from the group consisting of 5 to 1 Having 4 ring atoms, or alternatively 5, 6, 9, or 10 ring atoms, within a cyclic array Divalent monocyclic, bicyclic, and tricyclic rings having 6, 10, or 14 π electrons shared between them. , or a polycyclic group. A heteroarylene group can be unsubstituted or single. The above substituents can be used for substitution.

[0063] As used herein, "halo," "halide," or "halogen" means chrome This refers to the atomic groups of iodine, bromo, fluoro, or iodine. In some embodiments, Halos are chloro, bromo, or fluoro. For example, a halide is fluoro. Shut up.

[0064] As used herein, "haloalkyl" means one or more chloro, bromo, or flu Linear or branched alkyl, alkeni substituted with oro and / or iodine atoms. Haloal means a hydrocarbon substituent of alkynyl or alkynyl. In some embodiments, haloal Kill is a fluoroalkyl group in which one or more hydrogen atoms are substituted with fluoropolymers. In some embodiments, the haloalkyl has a carbon length of 1 to about 3 carbon atoms (for example, 1 to about 2 carbon atoms). (It is 1 carbon length). The term "haloalkylene" refers to the divalent group of a haloalkyl group. Such divalent groups can act as spacers between groups, between other atoms, or between a ring and other functional groups. It can have an effect.

[0065] As used herein, "heterocyclyl" means having at least one ring-system skeleton This refers to a non-aromatic cyclic ring system containing heteroatoms. Heterocyclines can contain multiple fused rings. Heterocyclines can be substituted with one or more substituents or they can be unsubstituted. In some embodiments, the heterocycle has 5 to 7 members. In a 6-membered monocyclic heterocycle, the heterogen The offspring are selected from 1 to 3 O, N, or S atoms, and if the heterocycle has 5 members, then O, N, It may have one or two heteroatoms selected from S. Examples of heterocyclines include These are azilinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2 -Dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanil, morpholinil, thiomorpholinil, piperazinil, pyranil, pi Loridinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiadinyl , thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazoli Examples include dinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, and thiomorpholinyl. In some embodiments, heterocyclyl is azetidinil, morpholinil, and pi. Selected from perazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0066] As used herein, "monocyclic heterocyclyl" means a ring system skeleton containing at least It refers to a single non-aromatic ring containing one heteroatom. A heterocyclyl is a ring containing one or more heteroatoms. It may be substituted with substituents or unsubstituted. In some embodiments, the heterocycle is 5 It has ~7 members. In a 6-membered monocyclic heterocycle, the heteroatoms are 1 to 3 of O, N, or S. If selected, and the heterocycle is 5-membered, then one or two selected from O, N, or S It may have heteroatoms. Examples of heterocyclyls include azilinyl, aziridinyl, and a Zetidinil, oxetanil, thietanil, 1,4,2-dithiazolyl, dihydropyridinyl Lu, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morphol Nyl, Thiomorpholinil, Piperazinil, Pyranil, Pyrrolidinil, Tetrahydrofuryl Tetrahydropyridinyl, oxazinyl, thiadinyl, thiinyl, thiazolidinyl, i Sothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazoli Examples include dinylimidazolidinyl and thiomorpholinyl.

[0067] The term "substitution" refers to a substituent that replaces one or more hydrogen atoms on a non-hydrogen atom of a molecule. It refers to the part that is replaced. "Substitution" or "replaced by ~" means that such substitution is replaced by ~ According to the allowable valencies of the atoms and substituents, and as a result of substitution, for example, rearrangement, cyclization, This implicitly includes the condition that a stable compound that does not undergo spontaneous transformation such as elimination is obtained. It will be understood that this is the case. Substituents are, for example, hydroxyl, -NH2, - NH(C 1~3 Alkyl), and -N(C 1~3 Choose one or more alkyl groups as you see fit. Selectively substituted -(C 1~9 Alkyl), -(C 1~9 Haloalkyl), halide, hi Droxyl, carbonyl [e.g., -C(O)OR and -C(O)R], thiocarb nil [for example, -C(S)OR, -C(O)SR, and -C(S)R], halide, Hydroxyl, -NH2, -NH(C 1~3 Alkyl), and -N(C 1~3 Alkyl -(C) is optionally replaced by one or more of the following: 1~9 Alkoxyl), -OPO( OH)2, phosphonates [e.g., -PO(OH)2 and -PO(OR')2], - OPO(OR')R'', -NRR', -C(O)NRR', -C(NR)NR'R'' -C(NR')R'', cyano, nitro, azide, -SH, -SR, -OSO2(O R), sulfonates [e.g., -SO2(OH) and -SO2(OR)], -SO2 NR'R'' and -SO2R may be included, and each R, R', and R '' is H, -(C 1~9 C (alkyl), optionally substituted with 1-3 R''' 6~10 It has 1 to 4 heteroatoms independently selected from aryl, N, O, and S. and a 5-10 member heteroaryl, which is optionally substituted with 1-3 R'''. C is optionally substituted with 1 to 3 R'''. 3~7 Carbocyclyl, and N It has 1 to 4 heteroatoms independently selected from O and S, and 1 to 3 R Independently selected from 3- to 8-membered heterocyclines that are optionally substituted with ''', each R' '' is -(C 1~6 Alkyl), -(C 1~6 Haloalkyl), halide (for example, F ), hydroxyl, -C(O)OR, -C(O)R, -(C 1~6 Alkoxyl), -N Independently selected from RR', -C(O)NRR', isothiocyanyl, and cyano, Each existing R and R' is independent of H and -(C 1~6 Selected from alkyl) In some embodiments, the substituent is -(C 1~6 Alkyl), -(C 1~6 Haloal Kill), halide (e.g., F), hydroxyl, -C(O)OR, -C(O)R, -( C 1~6 Selected from alkoxyl, -NRR', -C(O)NRR', and cyano Each existing R and R' independently corresponds to H and -(C 1~6 Selected from alkyl) ru.

[0068] As used herein, pseudohalide or pseudohalo group means a halide These are groups that behave substantially similarly. Such compounds can be used in the same way as halides. It is capable and can be processed in the same way. Pseudohalides include cyanides and cyanides. Examples include thiocyanates, selenocyanates, trifluoromethoxys, and azides. However, this is not limited to these.

[0069] As used herein, "sulfinyl" or "thionyl" means -S(O)- Meaning. As used herein, "sulfonyl" or "sulfuryl" means -S( It means -S(O)2O-. As used herein, "sulfo" means -S(O)2O-. It tastes good.

[0070] As used herein, "phosphinate" means -P(R)O2H, and "ho "Sphinate ester" means -P(R)O2R' as used herein. "Phosphonate" means -PO3H2, and "phosphonate ester" means -PO3 It means RR'. As used herein, "phosphodiester" means -OPO3R - means that "alkyl phosphodiester" means -OPO3RR'. The above group In this case, R is either H or alkyl, and R' is alkyl.

[0071] The term "mammal" is used in its usual biological sense. Therefore, specifically The targets are humans, cows, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, and This includes not only ghouls and non-human primates, but also many other species.

[0072] As used herein, "patient" refers to a human or non-human mammal, such as a dog or a neutron. Cod, mice, rats, cows, sheep, pigs, goats, non-human primates, or birds, even This means chickens, and even any other vertebrate or invertebrate. In terms of treatment methods, the patient is a human being.

[0073] Design of chelate ligands This specification provides chelating ligands useful for preparing highly relaxed metal chelates. In some embodiments, the chelate ligand is a nonspecific metal with high relaxation properties. It can be used for the preparation of chelates. In some embodiments, the chelating ligand is one The above target binding sites (TBMs) can be modified to incorporate one or more target binding sites. Chelating ligands that have a component are chelated in vivo with metal chelate ligands (and metal chelates). It is possible to target one or more sites with (t). The chelate ligand and metal chelate are (m A self-assembly mechanism that promotes the self-assembly of chelates into cells, liposomes, emulsions, etc. It can be modified to incorporate the set portion (SAM). In some embodiments, Chelated ligands and metal chelates also enable high throughput, multiplexing, and other applications of biological molecules. In / or real-time detection and analysis (e.g., immunoassay or real-time) It is also useful as a luminescent probe for use in PCR applications.

[0074] The chelating ligands described herein are based on derivatives of diamine-functionalized skeletons. The body uses 1 to 3 R groups and 1 or more heterocyclic-based donor groups ("DG") It is prepared by modifying the amine portion of the scaffold. The skeletal amine and DG The bonded carbon can be functionalized using an additional "R" group. Typically, the R group and DG can coordinate to metal ions. The R group and DG chelate in the form of metal chelates. This improves the relaxation of ligands and / or promotes specific oxidation states of metal ions. These capabilities are selectable. Relaxation, for example, affects the water exchange rate of metal chelates. The effect of DG, its ability to reduce the electron relaxation rate of metal ions, (for example, electrostatic reaction (By generating) its ability to prevent anionic coordination, or the biochemically generated oxidation state It can be improved by its ability to wrap. In some embodiments, DG also (for example For example, it is a group that increases relaxation by its ability to coordinate water in the second sphere (through hydrogen bonding). It is possible to incorporate the second circumferential portion (SSM). In some embodiments, DG is Furthermore, as discussed below, the TBM can be selectively incorporated via the linker (L). This is possible. Relaxation is achieved by binding TBM to the target, or by using liposomes, etc. Further improvement is possible by forming a self-assembling system.

[0075] It is possible to prepare a variety of chelate ligands.

[0076] In some embodiments, the chelate ligand is given by formula (I): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (where alkylenes, cycloalkylenes) N, heterocycloalkylene, arylene, and heteroarylene are each 1, Two, three, or four independently selected R X (It is optionally replaced by the base.) In one embodiment, R 1 The part is separated by neighboring atoms, for example, neighboring carbon atoms (for example, (bonds via the 1st and 2nd carbon atoms on ethylene), or separated by a single methylene group. A bond is formed through an atom (for example, a bond via the carbon atoms at positions 1 and 3 on propylene) to an adjacent nitrogen atom. It is joined to R. A similar join is R 1 In the cyclic portion, for example, a bond via an adjacent carbon atom This can be observed (for example, in bonds mediated by the 1st and 2nd carbon atoms on cyclohexylene).

[0077] In some embodiments, R 1 This refers to substituted or unsubstituted alkylenes, for example, below. The indicated 1,3-propylene or 1,2-ethylene, [ka] Or 2,3-propylene-1-carboxylate as shown below, [ka] Or the 3,4-butylene-1-carboxylic acid shown below, [ka] Or 1-hydroxy-3,4-butylene as shown below, [ka] Or 1-amino-5,6-hexylene as shown below, [ka] Substituted or unsubstituted cycloalkylenes, for example, those shown below, for example, The following cis- or trans-1,2-cyclohexylenes are shown below. [ka] Or trans-1,2-cyclohexylene as shown below, [ka] Or the cis- or trans-1,2-cyclopentylene shown below, [ka] Substituted or unsubstituted monocyclic heterocyclines, for example, the 2,5-dihydr shown below Ro-1H-Pylorene, [ka] The following 1,2,3,6-tetrahydropyridinene, [ka] The following 2,3,6,7-tetrahydro-1H-azepinene, [ka] and any corresponding isomer of substituted or unsubstituted monocyclic heterocyclyl compounds, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted heteroaryls. Alternative arylalkylenes, such as 1-propylene-4-isothiocyanate shown below, are available. Sodium benzene [ka] It is selected from the group consisting of the following.

[0078] In some embodiments, R 1 This is [L]-[TBM], for example, as shown below. Uni thiourea (-NH-C(S)-NH-)[L] and albumin-targeted substitution allies 2,2',4,4',5,6'-hexamethyl-1,1'-biface of alkylene TBM 1-propylenebenzene functionalized with nyl [ka] It is replaceable with, Each R 2 and R 3 H, CO2H, (C1~C6 alkyl)CO2H, C1~C6 Lukyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C 6~C 10 Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 CH2NHCOR 4 , C(O)N(OH)R 4 C(O)NHSO2R 4 CH 2NHSO2R 4 N(OH)C(O)R 4 , P(R 4 ) O2R 5 PO3R 4 R 5 ,oh Independently selected from the group consisting of [L]-[TBM], Each R 4 and R 5 H, substituted or unsubstituted C1-C6 alkyl, and [L]-[ Independently selected from the group consisting of TBM, and DG is [ka] A group consisting of or selected from any structural isomers of formulas IV and V, Y is CH, CZ, N, O, S, or NR 4 And, Each Q can independently be CH, CZ, N, O, S, or NR. 4 and Z is H, OH, OR 4 CO2R 4 ,-(C 1~6 Alkyl)CO2H, C1~C6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)N R 4 R 5 CH2NHCOR 4 , C(O)N(OH)R 4 C(O)NHSO2R 4 , C H2NHSO2R 4 N(OH)C(O)R 4 , P(R 4 ) O2R 5 PO3R 4 R 5 , Selected from the group consisting of -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. X Based on the basis, arbitrarily (to be replaced), L is a linker, TBM is the target binding site, and Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, isothiocyanyl, C1-C4 alkyl, C2-C4 Lukenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl , C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, Di(C1-C4 alkyl)amino, C1-C4 alkylamine, phosphinate, phosphine Phosphate ester, phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkyl phosphodiester, C3-C6 cycloalkyl, phenyl, 5-6 member heteroalkyl , 5-6 member heterocycloalkyl, (C1-C4 alkyl)phenyl, (where, The 'enyl' can be substituted or unsubstituted, and the group consisting of -[L]-[TBM] They are selected independently.

[0079] In some embodiments, Q is CH, CCOOH, or CCH2-(4-nitrobene) When it is a dilsulfonamide and all Y is CH, R 2 or R 3 few At least one of them is not H.

[0080] In some embodiments, the compound of formula (I) is formula (IA): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , and DG are formula As defined in (I).

[0081] In some embodiments, the compound of formula (I) is formula (IB): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , and DG are formula As defined in (I).

[0082] In some embodiments, the chelate ligand is given by formula (VI): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (where alkylenes, cycloalkylenes) N, heterocycloalkylene, arylene, and heteroarylene are each 1, Two, three, or four independently selected R X (It is optionally substituted by the base.)

[0083] In some embodiments, R 1 The portion is connected via adjacent carbon atoms (for example, on ethylene). (a bond via the carbon atoms at positions 1 and 2), or via a carbon atom separated by a single methylene group. (For example, a bond via the 1st and 3rd carbon atoms on propylene) is then bonded to the adjacent nitrogen. A similar bond is R 1 In the cyclic portion, for example, a bond via an adjacent carbon atom (for example) (This can be observed in bonds mediated by the carbon atoms at positions 1 and 2 on cyclohexylene.)

[0084] In some embodiments, R 1 This refers to substituted or unsubstituted alkylenes, for example, below. The indicated 1,3-propylene or 1,2-ethylene [ka] Or 2,3-propylene-1-carboxylate as shown below, [ka] Or the 3,4-butylene-1-carboxylic acid shown below, [ka] Or 1-hydroxy-3,4-butylene as shown below, [ka] Or 1-amino-5,6-hexylene as shown below, [ka] For example, the following cis- or trans-1,2-cyclohexylenes, [ka] Or the cis- or trans-1,2-cyclopentylene shown below, [ka] Substituted or unsubstituted monocyclic heterocyclines, for example, the 2,5-dihydr shown below Ro-1H-Pylorene, [ka] The following 1,2,3,6-tetrahydropyridinene, [ka] The following 2,3,6,7-tetrahydro-1H-azepinene, [ka] and any corresponding isomer of substituted or unsubstituted monocyclic heterocyclyl compounds, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted heteroaryls. Alternative arylalkylenes, such as 1-propylene-4-isothiocyanate shown below, are available. Sodium benzene [ka] It is selected from the group consisting of the following.

[0085] In some embodiments, R 1 This is [L]-[TBM], for example, as shown below. Uni thiourea (-NH-C(S)-NH-)[L] and albumin-targeted substitution allies 2,2',4,4',5,6'-hexamethyl-1,1'-biface of alkylene TBM 1-propylenebenzene functionalized with nyl [ka] It is replaceable with, R 2 , R 3 , and R 4 The formula is: [ka] Independently selected from the group of compounds, Each R 5 and R 6 H, CO2H, (C1~C6 alkyl)CO2H, C1~C6 Lukyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl, C 6~C 10 Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R 7 C(O)NHSO2R 7 CH 2NHSO2R 7 N(OH)C(O)R 7 , P(R 7 ) O2R 8 PO3R 7 R 8 ,oh Independently selected from the group consisting of [L]-[TBM] and independently selected from the group consisting of Re, X is CZ, N, O, S, or NR 4 And, W stands for CH, CZ, N, O, S, or NR 4 and Each Z is H, OH, OR 7 CO2R 7 ,-(C 1~6 Alkyl)CO2H, C1~C 6-alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl , C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O) NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R 7 C(O)NHSO2R 7 , CH2NHSO2R 7 N(OH)C(O)R 7, P(R 7 ) O2R 8 PO3R 7 R 8 , and independently selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. X Based on the basis, arbitrarily (to be replaced), L is a linker, TBM is the target binding site, and Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] They are independently selected from the group, Each R 7 and R 8 H, substituted or unsubstituted C1-C6 alkyl, and [L]-[ Independently selected from the group consisting of TBM, and DG is [ka] A group consisting of or selected from any structural isomer of formulas XIII to XIV, Each Y independently controls CH and CZ. 1 , N, O, S, or NR 4 And, Each Q is independent of CH and CZ. 1 , N, O, S, or NR 4 and each Z 1 H, OH, OR 7 CO2R 7 ,-(C 1~6 Alkyl)CO2H,C1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cycloalkyl Ru, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O )NR 7 R 8 CH2NHCOR 7 , C(O)N(OH)R 7 C(O)NHSO2R 7 CH2NHSO2R 7 N(OH)C(O)R 7 , P(R 7 ) O2R 8 PO3R 7 R 8 , and independently selected from the group consisting of -[L]-[TBM] (where alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and Each heteroaryl has 1, 2, 3, or 4 independently selected R X Based on (It is optionally replaced.)

[0086] In some embodiments, Q is CH, CCOOH, or CCH2-(4-nitrobene) It is a dilsulfonamide, where all Y is CH and R 2 , R 3 , and R 4 of When everything is equation VII, R 5 or R 6 At least one of them is not H.

[0087] In some embodiments, R 2 , R 3 , or R 4 One of them is equation VIII, and R 5 and R 6 When all of them are H, the aromatic ring components of formula VIII (i.e., X and W) The ring containing must be different from DG.

[0088] In some embodiments, the compound of formula (VI) is formula (XVa): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , R 4 , R 5 , oyo DG 4 This is as defined in equation (VI).

[0089] In some embodiments, the compound of formula (VI) is formula (XVb): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , R 4 , R 5 , oyo DG is defined as shown in equation (VI).

[0090] In some embodiments, the chelate ligand is given by formula XV [ka] It is a compound of or a pharmaceutically acceptable salt thereof. During the ceremony, R 1 These are C2-C6 alkylenes, C3-C 10 Cycloalkylene, 4-10 member heterozygotes Chloalkylene, C6~C 10 Arirene, 5-10 member heteroarirene, (C1-C6 ) Dialkyl (C6~C 10 Arylene, and (C1-C6) dialkyl (5-10 Selected from the group consisting of (where alkylenes, cycloalkylenes) N, heterocycloalkylene, arylene, and heteroarylene are each 1, Two, three, or four independently selected R X (It is optionally substituted by the base.)

[0091] In some embodiments, R 1 The portion is connected via adjacent carbon atoms (for example, on ethylene). (a bond via the carbon atoms at positions 1 and 2), or via a carbon atom separated by a single methylene group. (For example, a bond via the 1st and 3rd carbon atoms on propylene) is then bonded to the adjacent nitrogen. A similar bond is R 1 In the cyclic portion, for example, a bond via an adjacent carbon atom (for example) (This can be observed in bonds mediated by the carbon atoms at positions 1 and 2 on cyclohexylene.)

[0092] In some embodiments, R 1 This refers to substituted or unsubstituted alkylenes, for example, below. The indicated 1,3-propylene or 1,2-ethylene [ka] Or 2,3-propylene-1-carboxylate as shown below, [ka] Or the 3,4-butylene-1-carboxylic acid shown below, [ka] Or 1-hydroxy-3,4-butylene as shown below, [ka] Or 1-amino-5,6-hexylene as shown below, [ka] For example, the following cis- or trans-1,2-cyclohexylenes, [ka] Or the cis- or trans-1,2-cyclopentylene shown below, [ka] Substituted or unsubstituted monocyclic heterocyclines, for example, the 2,5-dihydr shown below Ro-1H-Pylorene, [ka] The following 1,2,3,6-tetrahydropyridinene, [ka] The following 2,3,6,7-tetrahydro-1H-azepinene, [ka] and any corresponding isomer of substituted or unsubstituted monocyclic heterocyclyl compounds, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted heteroaryls. Alternative arylalkylenes, such as 1-propylene-4-isothiocyanate shown below, are available. Sodium benzene [ka] It is selected from the group consisting of the following.

[0093] In some embodiments, R 1 This is [L]-[TBM], for example, as shown below. Uni thiourea (-NH-C(S)-NH-)[L] and albumin-targeted substitution allies 2,2',4,4',5,6'-hexamethyl-1,1'-biface of alkylene TBM 1-propylenebenzene functionalized with nyl [ka] It is replaceable with, Each R 2 , R 3 , and R 4 CO2H, (C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHSO2R 5 CH2NHSO2R 5 , N(OH )C(O)R 5 , P(R 5 ) O2R 6 , and PO3R 5 R 6 and formula [ka] Independently selected from the group consisting of the following compounds, X is CZ, N, O, S, or NR 4 And, Each W is independently CH, CZ, N, O, S, or NR 4 and Each Z is independently H, OH, OR 5 CO2R 5 ,-(C 1~6 Alkyl)CO2H , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 cyclo R-alkyl, C6~C 10 Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl , C(O)NR 5 R 6 CH2NHCOR 5 , C(O)N(OH)R 5 C(O)NHS O2R 5 CH2NHSO2R 5 N(OH)C(O)R 5 , P(R 5 ) O2R 6 , PO 3R 5 R 6 Selected from , and -[L]-[TBM] (where alkyl, alkenyl) , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Each of the R's is one, two, three, or four independently selected R's. X Based on the arbitrary selection (to be replaced by), L is a linker, TBM is the target binding site, and Each R X is OH, SH, CN, NO2, halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C1-C4 alkyl, C2-C4 alkenyl, C2-C 4-Alkynyl, C1-C4 Haloalkyl, C1-C4 Cyanoalkyl, C1-C4 Hydro Xyalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, di(C1-C4 alkoxy) Kill)amino, C1-C4 alkylamine, phosphinate, phosphinate ester, Phosphonate, phosphonate ester, phosphodiester, C 1~4 Alkylphosphodier Stellate, C3-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero From rocycloalkyl, (C1-C4 alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and Each R 5 and R 6 H, substituted or unsubstituted C1-C6 alkyl groups, and [L]-[T It is independently selected from the group consisting of [BM].

[0094] In some embodiments, the compound of formula (XV) is formula (XVa): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , and R 4 is, formula As defined in (XV).

[0095] In some embodiments, the compound of formula (XV) is formula (XVb): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. In the formula, R 2 , R 3 , and R 4 is, formula As defined in (XV).

[0096] In some embodiments, the targeting is made to target plasma proteins such as serum albumin. The DG modifier was applied to it.

[0097] Examples of chelating ligands provided herein include: [ka] [ka] [ka] [ka] Other examples include, but are not limited to, pharmaceutically acceptable salts thereof. .

[0098] In other embodiments, one or more TBMs having high affinity for fibrin (even if If, then, 2, 3, 4, 5 or 6 chelate ligands are attached. For example, such a compound The substance may have the formula shown below or a pharmaceutically acceptable salt thereof. [ka]

[0099] In other embodiments, one or more TBMs having high affinity for collagen (for example) It binds 2, 3, 4, 5, or 6 chelating ligands. For example, such a compound One of them may have the formula shown below or a pharmaceutically acceptable salt thereof. [ka]

[0100] In other embodiments, it has high affinity for protein carbonyls such as hydrazides. A chelate ligand was attached to TBM. For example, one of the chelate ligands is shown below. It has the formula or a pharmaceutically acceptable salt thereof. [ka]

[0101] In other embodiments, a chelate ligand is added to TBM having high affinity for elastin. They bonded. For example, one of the chelating ligands is expressed in the formula shown below or their pharmaceutical formulas. It contains a generally acceptable salt. [ka]

[0102] In other embodiments, the chelate ligand includes DG and R which are favorable for Mn(II) binding. In addition to possessing Mn(III), it also possesses auxiliary R which is favorable for Mn(III) bonding. However, each chelate Alternatively, the R group favoring Mn(II) in the chelating ligand is the same as the one favoring Mn(III). They are different. For example, if M=Mn, then R is favorable to Mn(II). 3 The base is COOH, PO3 It is independently selected from equation XVI where H2 or X=N, while being favorable to Mn(III). Na R 4 The base is COOH, PO3H2, or independently of equation XVI where X=C(OH). Selected. Examples of such compounds include: [ka] [ka] [ka] Other examples include, but are not limited to, pharmaceutically acceptable salts thereof. .

[0103] The synthesis protocol used for preparing the chelate ligands is common, and additional practical applications are available. It is broadly expandable to include application methods.

[0104] In some embodiments, the chelate ligand coordinates to the metal to form a compound of the following general formula. : [ka] or to form a pharmaceutically acceptable salt thereof. However, all parts are as defined above. For example, chelate ligands coordinated to metals are compounds with the following general formula: [ka] Or they form pharmaceutically acceptable salts thereof.

[0105] In such embodiments, M is Gd(III), Fe(III), Mn(II), Mn( III), Cr(III), Cu(II), Cu(III), Dy(III), Ho(I II), Er(III), Pr(III), Eu(II), Eu(III), Nd(II I), La(III), Lu(III), Sm(III), Tb(III), Tb(IV ), Tm(III), Y(III), In(III), Ga(III), Tc(III) , Tc(IV), Tc(V), Re(III), Re(IV), Re(V), Bi(II It can be a stable or unstable isotope selected from I) and Yb(III). In some embodiments, M is Mn(II) or Mn(III).

[0106] In some embodiments, the chelate metal complex DG is present in plasma such as serum albumin. The protein was modified to target other proteins.

[0107] Examples of metal chelates provided herein include: [ka] [ka] [ka] [ka] Other examples include, but are not limited to, pharmaceutically acceptable salts thereof. .

[0108] In other embodiments, one or more TBMs having high affinity for fibrin (even if For example, it binds 2, 3, 4, 5, or 6 chelate metal complexes. One of the metal complexes is given by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0109] In other embodiments, one or more TBMs having high affinity for collagen (for example) It binds 2, 3, 4, 5, or 6 chelate metal complexes. For example, chelate metal One of the complexes is given by the following formula [ka] or a pharmaceutically acceptable salt thereof.

[0110] In other embodiments, it has high affinity for protein carbonyls such as hydrazides. A chelate ligand was attached to TBM. For example, one of the chelate ligands is shown below. The formula [ka] or a pharmaceutically acceptable salt thereof.

[0111] In other embodiments, a chelate ligand is added to TBM having high affinity for elastin. They bonded. For example, one of the chelate ligands is given by the formula shown below. [ka] or a pharmaceutically acceptable salt thereof.

[0112] In other embodiments, the chelate metal complex contains DG and R which are favorable for Mn(II) bonding. In addition to possessing Mn(III), it also possesses auxiliary R which is favorable for Mn(III) bonding. However, each chelate Alternatively, the R group favoring Mn(II) in the chelating ligand is the same as the one favoring Mn(III). They are different. For example, in equation XIX, when M=Mn, the R group favorable to Mn(II) is CO Independently selected from equation XVI where OH, PO3H2, or X=N, on the other hand, Mn(I The one favorable to (II) is selected independently of equation XVI, where X = C(OH). Mn( II) When oxidized to Mn(III), the R group favorable to Mn(III) is oxidized to Mn (III) Binds to the ion. Switching from Mn(II) to Mn(III) results in relaxation. It decreases.

[0113] In one embodiment, the chelate metal complex is given by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0114] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0115] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0116] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0117] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0118] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0119] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0120] In the related scheme, the chelate metal complex has DG and R which are favorable for Mn(III) bonding. In addition, it also has auxiliary R which is favorable for Mn(II) bonding. However, each chelate and In chelation ligands, the R group favoring Mn(III) is different from the one favoring Mn(II). For example, if M=Mn, then R is favorable to Mn(III). 4 The base is X = C(OH) R is selected independently from equation XVI, while R is favorable to Mn(II). 3 The base is COOH, P It is independently selected from equation XVI, where O3H2 or X=N. Mn(III) is Mn When reduced to (II), the R group favorable to Mn(II) becomes the reduced Mn(II) ion. They bind. Switching from Mn(III) to Mn(II) increases relaxation.

[0121] In one embodiment, the chelate metal complex is given by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0122] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0123] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0124] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0125] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0126] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0127] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0128] In other embodiments, the chelate metal complex is expressed by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0129] Chelate metal complexes that can switch between the oxidation states of Mn(II) and Mn(III) are It can be switched "on" and "off" in response to biochemical stimuli. For example, The formula is as follows: [ka] As shown, compounds in which Mn ions are in the Mn(II) oxidation state or pharmaceutically acceptable compounds It can be an acceptable salt.

[0130] When a Mn(II) complex is reduced, the Mn ion is in the Mn(III) oxidation state. compound [ka] Alternatively, they may be pharmaceutically acceptable salts thereof. They respond slowly to oxidative or reducing stimuli. Such contrast agents, which can alter the compatibility and signaling properties, are used, for example, in acute coronary syndrome. Alternatively, myocardial ischemia associated with myocardial infarction, or stroke, or inflammation, or non-alcoholic beverages. Fatty liver disease, or inflammatory bowel disease, or multiple sclerosis, or high-risk atherosclerosis Sexual plaque, or other diseases characterized by ischemia of tissue or organ, or joints This method detects the areas of oxidative stress occurring in the body due to chronic inflammatory diseases such as rheumatoid arthritis and lupus. It can be used for this purpose. Cancer cells require a more reducing environment than normal cells to proliferate. So, can these contrast agents be useful in distinguishing cancerous tissue from normal tissue? Alternatively, it can be used to determine the invasive stage of certain cancers.

[0131] The synthesis protocol used for preparing the chelate ligands is common, and additional practical applications are available. It is broadly expandable to include application methods.

[0132] targeting group As mentioned above, chelating ligands incorporate one or more target binding moieties (TBMs). It can be modified in this way. TBM may contain peptides, nucleic acids, or small organic molecules. Examples are provided below. TBM is a chelate ligand and metal chelate in vivo. The TBM binds to the target. Typically, the TBM has affinity for the target. For example, TBM is a dissociation of less than 10 μM, less than 5 μM, less than 1 μM, or less than 100 nM. It can bind to its target at a constant rate. In some embodiments, TBM is used to bind to other physiological targets. It has specific binding affinity to specific targets compared to the general population. For example, TBM has a specific binding affinity to Collier. It may exhibit a smaller dissociation constant for fibrin compared to its dissociation constant for gen. Some TBMs do not necessarily adhere to their target, but in the presence of a specific target, It promotes changes in the relaxing properties of the trust agent. For example, TBM promotes changes in the peroxidase enzyme. The presence of more reactive oxygen species (ROS) can facilitate changes in relaxation.

[0133] TBM is performed using methods well known in this field, including standard peptide and nucleic acid synthesis methods. It can be synthesized and conjugated with chelate ligands. (For example, internationally publicly available) Pamphlet No. 01 / 09188, International Publication Pamphlet No. 01 / 08712, Nara Furthermore, U.S. Patent No. 6,406,297 and U.S. Patent No. 6,515,113 (and All of these are incorporated by reference (see reference). Several implementations In this state, TBM is covalently bonded to the chelate ligand. For example, TBM is arbitrarily selected It can be covalently bonded to the chelate ligand via a linker (L). As shown in the above structure Thus, TBM can be at any position on the chelate ligand. For example, TBM can be at any position. It can be selectively coupled to any R or DG via L. In some embodiments, By incorporating multiple TBMs onto the chelate ligand, a higher similarity to the target can be achieved. It can provide sexual and binding activity. The chelating ligand typically consists of 1 to 4 (LT) It will contain BM) units. For example, the chelate ligand will contain one L-TBM. It is possible to bind, or the chelate ligand is capable of binding to two L-TBM units. The chelate ligand can bind to three L-TBM units, or The chelate ligand can be bound to four L-TBM units. In other embodiments, To increase the MR signal generation ability of the trust agent, one or more chelate ligands are added. It is sometimes preferable to couple it to the L-TBM unit. In such embodiments, Trust agents typically consist of 1 to 4 (L-) bonded to 2 to 8 chelate ligands. It will contain TBM units. For example, two chelate ligands with one L- It is possible to bind to TBM, or to bind three chelate ligands to one L-TBM. Is it possible to bind four chelate ligands to one L-TBM? Alternatively, six chelate ligands can be bound to one L-TBM, or eight chelate ligands can be bound to one L-TBM. The methylated ligand can be bound to a single L-TBM.

[0134] Chelating ligands with TBMs can, for example, in the presence or absence of a target, each Therefore, if TBM binds to the target or does not bind, the relaxation value (as a metal chelate) Assays are possible regarding ( ). Typically, metal chelates with TBMs target When bonded, it will exhibit greater relaxation due to the RIME effect (for example, US patent Specification No. 4,899,755 and Specification No. 4,880,008 (both are in their entirety) (See also: The body is incorporated by reference).

[0135] Typical targets include human serum albumin (HSA), fibrin, and extracellular myocardial cells. Components (for example, collagen, elastin, and decorin) are secreted in inflammation or cancer. Extracellular enzymes (for example, peroxidase or protease enzymes), or lesions Extracellular components (for example, hyaluronic acid, heparin, chondroitin sulfate, dermatan sulfate) Heparan sulfate, keratan sulfate, versican, biglycan, abnormally regulated thiols / disulf Examples include (a diphthong composition).

[0136] TBMs for binding to HSAs are well known in the art, and various hydrophobic moieties or may include an amphiphilic moiety. For example, the TBM for binding to HSA is given by the following formula : [ka] (In the formula, n is between 2 and 20, and Ph is phenyl.) It may have one of the following (see, for example, International Publication No. 96 / 23526). stomach).

[0137] TBM, which is useful for binding to fibrin, was filed on July 30, 2002, as a peptide. U.S. Patent Application No. 10 / 209,18, entitled "Tide-based multimer targeted contrast agent" It is described in Specification No. 3 (which is incorporated in its entirety by reference). For example, fib Phosphate-bound peptides are cyclic disulfide cross-linked peptides CP * -Y * -XLC(array) You can choose from number 1). In the formula, P * This is proline or its derivative 4-hydroxypro It is phosphorus, Y * This is a component from the group consisting of tyrosine, F, Cl, Br, I, or NO2. It is a non-natural derivative in which the 3-position is substituted, and X is glycine or D- or It is one of the L-aspartic acid compounds. Another example is the peptide X1-X2-CP * -Y * - Selected from X3-LC-X4-X5-X6 (sequence number 2). In the formula, X1 X2 is selected from W, S, F, Y, or substitution Y or substitution F, and X2 is E, H, dH X3 is selected from S, X4 is selected from G, D, dD, X4 is selected from H, F, Y, and W X5 is selected from I, L, V, and N, and X6 is selected from N, Q, I, Either L or V is selected, or X6 does not exist.

[0138] As a TBM for binding to the extracellular components of lesions, hyaluronic acid (HA) Peptides with affinity are mentioned. Peptides with affinity for HA are known to be... For example, it binds to HA from a random 12-mer phage peptide library. Peptides were isolated (e.g., Mummert, M., Mohamedzadeh, M., Mummert, D., Mizumoto, N., and Takashima, AJ, Exp. Med. (2000) 769-779 (The entire article is incorporated by reference) See (for more information). One of these peptides (GAHWQFNALTVR(sequence) Number 3)) is K d It binds to HA at approximately 1 μM. When used herein, the peptide is All are written from the N-terminus to the C-terminus. Other HA-binding peptides include T SYGRPALLPAA (SEQ ID NO: 4), MDHLAPTRFRPAI (SEQ ID NO: 5), TLRAIWPMWMSS (SEQ ID NO: 6), and IPLTANYQGDFT (SEQ ID NO: 6) 7) is one example.

[0139] Other peptides that have affinity for HA include RHAMM, CD44, and Consensus bonds found in many HA-binding peptides, including link proteins. It may contain a consensus motif. The consensus motif may be B(X)7, where B is a salt. It is a basal residue (e.g., Lys, His, or Arg), and X is a non-acidic residue. ru.

[0140] In other embodiments, the lesion-targeting peptide has affinity for heparin, and hepar It may contain heparin-binding motifs found in heparin-binding proteins. It can be incorporated into peptides. The heparin-binding motif for this includes XBBXBX or XBBBXXBX. In the formula, B X is a basic residue (e.g., Lys, His, or Arg), and X is a non-acidic residue. For example, the heparin-binding peptide ACQWHRVSVRWG (SEQ ID NO: 8) is Matches the XBBXXXBX sequence (for example, Nielsen,PK,Gho,Y. S., Hoffman, M.P., Watanabe, H., Makino, M., No. mizu, M., and Yamada, YJBiol.Chem.(2000)2 See 75, 14517-14523 (the entire section is incorporated by reference). Finally, the heparin sulfate / heparin-interacting protein sequence (HIP) motif is also It can be found in peptides. One example of such a motif is CRPKAKAKAKAKDQTK( This is sequence number 9.

[0141] In other embodiments, the lesion-targeting peptide is a receptor protein tyrosine phosphata It may have similarities to the proteolytic fragments of transmembrane proteins such as -ase (PTPμ). (For example, Burden-Gully, SM, Zhou, Z., Craig, S) .EL,Lu,Z.-R.,Brady-Kalnay,SMTransl.O See ncol. (2013) 6, 329-337). An example of such a motif is , CGEGDDFNWEQVNTLTKPTSD (Sequence ID 10).

[0142] In other embodiments, the lesion-targeting peptide may have similarities to fibronectin. (For example, Zhou, Z., Qutaish, M. Han, Z. Schur, RM) .,Liu,Y.,Wilson,DL,and Lu,Z.-R.Nat.Com See mun. (2015) 6, 7984-7994). An example of such a motif. This is CREKA (sequence number 11).

[0143] TBMs that are useful for targeting fibrin are found in mammals (e.g., blood). This technology enables specific imaging of thrombi, solid tumors, and atherosclerotic plaques. Contains fibrin-binding peptides. Any peptide capable of binding to fibrin can be used. For example, see International Publication No. 2008 / 071679, U.S. 6,984 Specification No. 373, Specification No. 6,991,775, and Specification No. 7,238,341 The specification and the specification of U.S. Patent Application Publication No. 2005 / 0261472 (they are all The peptide disclosed in (which is incorporated by reference in its entirety) may be used. The peptide is Approximately 2 to approximately 25 amino acid lengths (for example, approximately 3 to approximately 20, approximately 5 to approximately 18, approximately 8 to approximately 15, approximately It can be approximately 10 to 14.

[0144] TBMs useful for targeting enzymes secreted in inflammation and cancer are shown below (5- Hydroxytryptamine [ka] and 5-hydroxytryptophan as shown below [ka] These include, and are produced by peroxidase enzymes such as myeloperoxidase. It is oxidized in the presence of ROS, followed by oligomerization (for example, Shazeeb, M.S., Xie, Y., Gupta, S., and Bogdanov, AAJr. .,Mol.Imaging.(2012)11,433-443(The whole thing is referenced (See also: incorporated). When oligomerized, it has higher relaxability. It produces larger chelates than those produced by slow tumbling.

[0145] In other embodiments, the ROS-targeted portion is oxygen, hydrogen peroxide, superoxide, peroxide DG or It may contain an R group. In the absence of an oxidizing agent, the DG or R group is a high-value group such as Mn(III). It is favorable for forming metal chelates with metal ions in their oxidized state. The DG or R group is acid When oxidized, the oxidized DG or R group then becomes a low-valent oxidation state such as Mn(II). It is favorable for forming metal chelates with metal ions. Mn(III) to Mn(II) Switching to ) increases mitigation.

[0146] In other embodiments, metal ions in a low-valence oxidized state, such as Mn(II), are favorably bonded. Metal chelates containing R groups and DG are in the oxidation state of high-value metals such as Mn(III). It may contain auxiliary non-coordinating R groups that are favorable for bonding to oxygen, hydrogen peroxide, and superoxide. By biological oxidizing agents such as oxides, peroxidase enzymes, hypochlorous acid, and disulfides. It can bind to and trap Mn(III), which is produced from the oxidation of Mn(II). Yes, switching from Mn(II) to Mn(III) reduces relaxation.

[0147] In other embodiments, it favorably binds to metal ions in high-value oxidation states, such as Mn(III). The metal chelate containing the R group and DG is a low-valent metal oxidation state such as Mn(II). It may contain auxiliary non-coordinating R groups that are favorable for bonding to thiols, ascorbic acid, and other similar groups. Organisms such as natic acid, mitochondria, superoxide, reductase enzyme, NADH, NADPH, etc. It binds to and traps Mn(II) produced from the reduction of Mn(II) by a chemical reducing agent. It is possible to do so. Switching from Mn(III) to Mn(II) increases relaxation. ru.

[0148] TBMs, which are useful for targeting enzymes secreted in inflammation and cancer, are protease enzymes. May contain peptide substrates (Jastrzebska, B., Lebel, R., Ther riault, H., McIntyre, J.O., and Escher, E., Guerin. ,B.,Paquette,B.,Neugebauer,WA,and Lepa ge, MJMed.Chem. (2009) 52, 1576-1581 (the whole thing) See also (which is incorporated by reference). Protease enzymes for peptide substrates Activity can cause changes in the solubility of chelate metal complexes. When solubility decreases, in It is retained at biochemical target sites in vivo.

[0149] TBMs, which are useful for targeting collagen, are known to bind to collagen. Contains peptides derived from the propolypeptide of vonwilland factor. When this is the case, all peptides are written from the N-terminus to the C-terminus. In addition, if there are two or more Peptides containing the above cysteine ​​residue can form disulfide bonds under non-reducing conditions. The peptide that targets collagen has the following general formula: X1-X2-X3-X 4-X5-X6-X7-X8-X9-X 10 (Sequence ID 12) may be included. In the formula, X1 is X2 can be W, C, or A, and X 3 can be E, C, A, K, or T, and X4 can be P, C, or A. X5 can be D, G, S, C, or A, and X6 can be F, R, C, or it can be A, X7 can be C, M, or A, X8 can be A, It can be E or C, and X9 can be L, M, R, C, or A. and X 10 can be S, N, G, L, C, or A, however X1~X 10 Three or fewer of these are independently C or A, and X1~X 10 The C and A residues in The total number is a maximum of 4. For example, the peptide has the following sequence: WREPSFCALS(peptide Column number 13), WREPSFMALS (sequence number 14), and WREPGFCALS ( It may have sequence number 15).

[0150] Another example of a peptide that binds to collagen is the following general formula: X1-X2-X3-X4-X 5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 (Sequence ID 16) In the formula, X1 can be W, C, or A, and X2 can be R, C, or A. X3 can be E, C, A, K, or T, and X4 can be P, C, X5 can be D, G, S, C, or A, X6 can be F, R, C, or A, and X7 can be C, M, or A X8 can be A, E, or C, and X9 can be L, M, R, C, or A. It is possible, X10 can be S, N, G, L, C, or A, and X 11 teeth It can be C, M, or A, X 12 It can be P, A, or C. and X 13 can be K, Q, P, H, G, C, or A, however X1~X 13 The following four or fewer are independently C or A, and X1 to X 13 Remaining C and A inside The total number of units is a maximum of 5.

[0151] The peptide used to bind to collagen also has the following general formula: X1-X2-X3-X4 -X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 ( It may have sequence number 17). In the formula, X1 can be V, I, C, or A, and X 2 can be A, G, R, D, or C, and X3 can be W, C, or A. X4 can be R, C, or A, and X5 can be E, C, A, K, and X6 can be T, X6 can be P, C, or A, X7 can be D, G, X8 can be S, C, or A, and X8 can be F, R, C, or A. X9 can be C, M, or A, X 10 It is E, A, or C. Yes, X 11 It can be L, C, A, M, or R, X 12 S, C, A, It can be N, G, or L, X 13 can be C, M, or A, X 14 can be P, A, or C, and X15 is K, Q, P, H, G, C, Or it can be A, however X1~X 15 Four or fewer of these are independently C or A And X1~X 15 The total number of C and A residues in the molecule is at most 6.

[0152] Further peptides targeting collagen were filed on December 29, 2006. U.S. Patent No. 8,034,898, titled "Collagen Imaging Method" It can be found in books (the whole of which is incorporated by reference). For example, collagen binding Butido is a cyclic disulfide crosslinked peptide WHC-X1-T-X2-FPHH -Selectable from YC (Sequence ID 18). In the formula, X1 can be selected from Y, T, or S. Selected, and X2 can be any amino acid. Other methods for targeting collagen Butide modifies the peptides described above (e.g., mutation, truncation, elongation). It can be identified by doing so.

[0153] Folic acid receptor, vitronectin, αvβ3 and αvβ5 integrins, MMP targets TBM, which is useful for binding to RGD peptides, porphyrins, and phosphonates, , International Publication No. 2004 / 112839, filed on June 17, 2004 (that (The entire thing is incorporated by reference) and is described in the references listed therein.

[0154] The TBM, which is useful for binding to elastin, is given by the following formula: [ka] Includes.

[0155] self-assembling part Magnetic resonance imaging of low-concentration targets may be limited by the resilience of the contrast agent. To improve the sensitivity of contrast agents, covalent bonding of chelating ligands and metal chelates Various strategies for unifying multiple chelates, including union and non-covalent sets. This method has been adopted. The non-covalent bonding method involves forming a molecular aggregate with itself or similar groups. This requires the use of a group capable of interaction. The chelate ligand is, as mentioned above, one The above self-assembly parts (SAMs) can be modified to incorporate them. SAMs are lipids, long-chain aluminum Kill groups or substituted alkyl groups, perfluorocarbons, peptides, nucleic acids, or small organic components It may contain children. SAM self-associates chelate ligands and metal chelates to form larger molecules. It can form large aggregates, particles, or assemblies.

[0156] SAM is based on methods well known in the art, including standard peptide and nucleic acid synthesis methods. It is more easily synthesized and can be conjugated with chelate ligands. For example, international public Pamphlet No. 01 / 09188, International Publication No. 01 / 08712, Furthermore, U.S. Patent No. 6,406,297 and U.S. Patent No. 6,515,113 ( They all need to be referenced (the whole thing is incorporated by reference). Typically, SA M is covalently bonded to the chelating ligand and chelates via an optional linker (L). It can covalently bond to the ligand. As shown in the structure above, SAM is chelate-coordinate. It can be in any position of the child. For example, SAM can optionally move through L to any R. It can be combined with DG.

[0157] Chelating ligands with SAM have a relaxation value (metal chelate) above the critical self-assembly concentration. It is possible to assay it as follows: At very low concentrations, the chelate is mainly monomer. They can exist in a non-assembled state, and beyond the critical self-assembly cardinality, chelates mainly self-assemble. It can exist in an aggregated form. Typically, metal chelates with SAM exist in RI when they are in a self-assembled form. The ME effect will likely result in greater relaxation (for example, U.S. 4,899,7 Specification No. 55 and Specification No. 4,880,008 (both are combined in their entirety by reference) (See also: [Inclusion]).

[0158] SAM is a micelle (for example, Nicolle, GM, Toth, E., Eise nwiener, KP, Macke, HR, and Merbach, AE. J Biol Inorg Chem. 2002 7:757-69 (The entire article is referenced) See also (more incorporated) or liposomes (e.g., Mulder, W.) J., Strijkers, G. J., van Tilborg, G. A., Griff. ioen, AW, and Nicolay, K., NMR Biomed.2006 See 19:142-64 (the whole thing is incorporated by reference) to form It may contain lipids and lipid-like groups. SAM is also a mixed liposome or emulsion. It can facilitate incorporation into (for example, U.S. Patent No. 6,869,591 (that (The whole thing is incorporated by reference) (Please refer to the reference).

[0159] SAM can also be a perfluoroalkyl group that promotes self-assembly (for example, rice Japanese Patent No. 6,916,461 and International Publication No. 2003 / 0232012 (Pan) See frets (both are incorporated entirely by reference). Alternatively, Peptides can also form self-assemblies (for example, International Publication No. 2004 / 020 Pamphlet No. 4561 (which is incorporated in its entirety by reference) and disclosed herein (Please refer to the peptide sequence shown.)

[0160] Linker In some embodiments, the TBM is shared with the chelate ligand via the linker (L). They are bound together. L may include, for example, a linear, branched, or cyclic peptide sequence. In the embodiment, L may include the linear dipeptide sequence GG (glycine-glycine). In embodiments where BM contains a peptide, L is the amide moiety of the N-terminus of the TBM peptide. The C-terminus, or both the N-terminus and C-terminus, can be capped. Other exemplary k The capping portion contains sulfonamides, ureas, thioureas, and carbamates. Linkers are also linear, branched, or cyclic alkanes, alkenes, or alkynes. These may include a phosphodiester moiety. L is a ketone, ester, amide, ether, One or more functional groups including carbonates, sulfonamides, or carbamates It can be substituted with a functional group. The intended specific linker is -(O-(CH2)2-O)n(formula). (N=1 to 20,000, more specifically n=1 to 6) NH-CO-NH-, -CO- (CH2) n -NH- (in the formula, n=1~10), dpr, dab, -NH-Ph-, -N H-(CH2) n -(in the formula, n=1~10), -CO-NH-, -(CH2) n -NH- (In the formula, n=1~10), -CO-(CH2) n-NH- (in the formula, n=1~10), -C S-NH-, and [ka] Includes.

[0161] In some embodiments, L is chelated via any R or DG. For example, chelates have the general formula: [ka] [ka] Or they may have pharmaceutically acceptable salts thereof.

[0162] Chelating ligands, in particular linkers for incorporation into chelating ligands containing peptides For additional examples and synthesis methods, see International Publication No. 01 / 09188, International Publication Pamphlet No. 01 / 08712, International Publication No. 2004 / 112839 The "peptide-based multimer targeting contrast agent" filed on July 30, 2002, and U.S. Patent Application No. 10 / 209,183, and December 29, 2006 U.S. Patent Application No. 11 / 618, filed on [date], titled "Collagen-binding peptide", These are shown in Specification No. 564 (all of which are incorporated by reference in their entirety).

[0163] Properties of chelate ligands and metal chelates Chelating ligands can bind to one or more metal ions to form metal chelates. Metal chelates can be prepared by methods well known in the art. For example, international publications Pamphlet No. 96 / 23526, U.S. Patent No. 6,406,297, and the same Specification No. 6,515,113 (all of which are incorporated by reference in their entirety) See also the following examples.

[0164] Metal chelates are metals with atomic numbers 21-29, 40, 42, or 57-83. They may contain ions. For example, metal chelates include Gd(III), Fe(III), and Mn. (II), Mn(III), Cr(III), Cu(II), Cu(III), Dy(I II), Ho(III), Er(III), Pr(III), Eu(II), Eu(II I), Nd(III), La(III), Lu(III), Sm(III), Tb(II I), Tb(IV), Tm(III), Y(III), In(III), Ga(III) , Tc(III), Tc(IV), Tc(V), Re(III), Re(IV), Re( A stable or unstable isotope selected from V), Bi(III), or Yb(III) It may contain ions. Metal ions can be paramagnetic. Typically, D on the chelate ligand. Due to the chemical properties and number of G, metal ions are strongly bound to chelate ligands, and It is possible to fabricate phytochemically compatible metal chelates. Generation constant (K f ) is an indicator of binding affinity, and is typically log K f Convert to scale This will be considered. Physiologically compatible metal chelates are within the log K range of 10 to approximately 25. f It may have K. f is 10 10 ~10 25 M -1 It is within the range of Mn(II). In metal chelates, log K f It should be greater than 12. K f The measurement method is in this technical field. This is well known. For example, Martell, AE and Motekaitis, R .J., Determination and Use of Stability C onstants,2d Ed.,VCH Publishers,New York( See 1992 (the entire document is incorporated by reference).

[0165] The relaxation value of metal chelates can also be evaluated. When metal chelates incorporate TBM, relaxation The relaxation property can be measured in the presence and absence of the target molecule. The method for measuring the relaxation property is described in this technical section. It is well known in the field. For example, see International Publication No. 96 / 23526 (the whole thing is available). See (which is incorporated by the reference).

[0166] One of the challenges in identifying new highly relaxed chelates is that they are observed in most metal chelates. The relaxation is limited by the tumbling speed (rotational diffusion) of the chelate. For more information on this, see RBClauffer, Chem. Rev. 1987, 87:90. 1-27 and P. Caravan et al., Chem. Rev. 1999, 99 Reviews such as :2293-2352 (the entire thing is incorporated by reference) demonstrate this well. This has been proven. The parameters listed above (e.g., water residence time and second-circle effect) Many of the effects of ) do not manifest in low (<1500 Da) molecular weight metal complexes. When the tumbling is slow, it binds to large molecules like proteins, and polymer structures These other parameters are either bonded to a structure or self-assembled into a larger aggregate. The effect of the ter can be observed. Therefore, metal chelates with very high relaxation capabilities can be used. One method for determining this is to screen chelates for their relaxability under conditions of slow rotational diffusion. That is the case.

[0167] One way to do this is to incorporate a standard TBM group or SAM group into each chelate under test. This is the process of having a normal TBM in the presence of a target protein (e.g., albumin). By comparing chelates, we can rank them from the most relaxing to the least relaxing. By linking them, it is possible to determine which donor group and SSM combination is the most advantageous. It is possible. The highly relaxed chelates thus identified can incorporate various TBMs. It can be further modified.

[0168] Metal chelates also affect the average residence time of water molecules within the first (or higher) coordination zone. It can be evaluated in this way. The average residence time of water molecules is the reciprocal of the water exchange rate and depends on temperature. The average residence time of water within the coordination zone of a metal chelate at 37°C can be 1 to 100 ns. In some embodiments, the average residence time of water within the coordination zone of a metal chelate at 37°C is 3 to It is 30ns. 17 NMR can be used to evaluate the average residence time of water molecules. For example, please refer to Example 7 below.

[0169] Luminescence lifetime measurement can be used to evaluate the number of water molecules bound to metal chelates. Methods for measuring lifetime are known in the art, and typically, a specific wavelength is used to determine lifetime. This involves monitoring the eclipse transition of the chelate and then fitting the eclipse decay data. Photovoltaic lifetime measurement is also useful for evaluating the suitability of metal chelates as luminescent probes. Alternatively, for Mn(II) chelates, 17O NMR can be used (Gal e EM, Zhu J, Caravan P. Direct Measurement of the Mn(II) Hydration State in Metal C complexes and metalloproteins through 17 O NMR Line Widths.J Am Chem Soc 2013;135: See 18600–18608 (the entirety of which is incorporated by reference).

[0170] Use of chelate ligands and metal chelates Chelating ligands can be used to prepare metal chelates for diagnostic purposes, as mentioned above. For example, metal chelates prepared using Mn(II) can be controlled by MR imaging. It may be useful as a trust agent. Contrast agents incorporating TBM can bind to the target. Because it is capable of targeting MR applications, for example, imaging of blood flow, blood clots, lesions, or myocardium. It can be particularly useful for sizing. In some embodiments, at least about the contrast agent 10% (for example, at least about 50%, about 80%, about 90%, about 92%, about 94%, Approximately 96% of the contrast agent and target bind to the desired target at physiologically compatible concentrations. It is possible. The degree of binding of the contrast agent to the target can be determined by various equilibrium binding methods, for example, limited External filtration, equilibrium dialysis, affinity chromatography, or competition of probe compounds. It can be evaluated by binding inhibition or displacement.

[0171] Contrast agents can exhibit high relaxation as a result of target binding, thus producing better MR images. This can result in improved image resolution. In some embodiments, the increased relaxation due to coupling can affect the target. Compared to chelate metal complexes that exist unbonded or in different oxidation states, It is also about 1.5 times (for example, at least 2, 3, 4, 5, 6, 7, 8, 9, or 1 (Relaxity increases by a factor of 0). For example, a targeted contrast agent is not bound to the target. Compared to chelate metal complexes existing in one or different oxidation states, the ratio is 7-8 times, 9-10 times, Furthermore, the relaxation can increase by more than 10 times. In some embodiments, 60 MHz and 3 The relaxability of the MRI contrast agents provided herein at 7°C is at least 8 mM. -1 s -1 / With paramagnetic metal ions (for example, at least 10, 15, 20, 25, 30, 35 40 or 60 mM -1 s -1 (Paramagnetic metal ions) For example, in this specification The provided contrast agent is 10 mM at 60 MHz and 37°C. - 1s -1 Ultra-relaxation It may have.

[0172] Lanthanide metal chelates can also be useful as luminescent probes. The probe can be used in a variety of assays, for example, high-throughput, real-time, and Chemical and biological analysis for research and diagnostic applications, including multiple applications. It can be useful for detection, separation, and / or quantification. For example, a pro that incorporates TBM. The nucleotide is capable of binding to the target analyte and has a long luminescence lifetime (e.g., 0.1 Since it can have a response time of μs or longer than 100 μs or 1 ms, it can be detected in various assay methods. It improves accuracy and applicability. Generally, it is suitable for incorporating luminescent metal chelate probes. For details of the assay, please refer to U.S. Patent No. 6,406,297 and No. 6,515. See Specification No. 113 (both are incorporated in their entirety by reference). Metal chelate probes are particularly useful in immunoassays and real-time PCR detection assays. It is useful.

[0173] Use of MRI contrast agents MRI contrast agents can be used in the same way as conventional MRI contrast agents. For example, if an effective amount of contrast agent is administered to a patient (for example, an animal such as a human), the patient An MR image is acquired. In embodiments having TBM, a combined contrast agent is provided. The magnetic resonance signal of the target and the magnetic resonance signal of the background blood or tissue, A contrast-enhanced imaging sequence that prioritizes increasing the trust ratio is available. Yes, there are. These techniques include methods to darken blood, such as high-speed spin echo sequencing. Attempting a black blood angiography sequence, flow spoil gradient Examples include tocho sequencing and out-of-volume suppression techniques that restrict blood inflow. However, these methods are not limited to these. These methods also target and background Inversion recovery preparation sequence or saturation recovery preparation sequence that increases contrast between the tissue and the surrounding tissue. Contrast enhancement is achieved by the T1 difference between the target and blood and tissue, as in the case of scalars. This includes flow-independent techniques to improve the stack difference. The preparation method for T2 techniques is also useful. This can be proven. Finally, preparation for magnetization transfer techniques also involves contrast agents. It can improve the situation.

[0174] Acquisition and / or comparison of contrast-enhanced and non-contrast images, and / or a method may be used that includes the use of one or more additional contrast agents. The final agent may exhibit affinity for the target. An exemplary method was published on February 7, 2001. U.S. Patent Application No. 09 / 778, entitled "Requested Magnetic Resonance Angiography Data", Specification No. 585 and the filed July 30, 2002, concerning targeted magnetic resonance imaging of the vascular system U.S. Patent Application No. 10 / 209,416, entitled "System and Method for Zing" This is shown in the specifications (both of which are incorporated in their entirety by reference).

[0175] The contrast agent can be formulated as a pharmaceutical composition according to routine procedures. When used in calligraphy, contrast agents may include their pharmaceutically acceptable derivatives. "Pharmacologically acceptable" means that the agent can be administered to animals without causing unacceptable adverse effects. It means that a "pharmaceutically acceptable derivative" is one that, when administered to the recipient, We can provide (directly or indirectly) tranquilizers, active metabolites, or their residues. Any pharmaceutically acceptable salt, ester, or ester salt of a contrast agent, if "ku" means other derivatives or compositions. Other derivatives are biologically beneficial when administered to mammals. To increase utilization (for example, to make orally administered compounds more easily absorbed into the bloodstream). (by means of) or directing the delivery of the parent compound to an intracellular compartment (e.g., the brain or lymphatic system). This increases exposure compared to the parent species by raising the level. (Pharmacological aspects of contrast agents) The salts that are permissible are not limited to sodium, calcium, and N-methyl Including ru-glucamine, pharmaceutically acceptable inorganic and organic acids known in the art It contains counterions derived from bases.

[0176] The pharmaceutical composition can be administered via any route, including both oral and parenteral administration. Parenteral administration methods include subcutaneous, intravenous, intraarterial, interstitial, intrathecal, and intracavitary administration. Examples include, but are not limited to, those administered intravenously. The product is administered as a bolus in two or more doses with time intervals between them, or as a constant or non-constant dose. It can be administered as a linear flow injection. Therefore, the contrast agent can be administered via any route of administration. It can be formulated for use in various applications.

[0177] Typically, compositions intended for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may include a solubilizer, a stabilizer, and a local anesthetic, for example, at the injection site. It may contain lidocaine to relieve pain. Generally, the ingredients are packaged individually, for example, in a kit. Supplied or, for example, as a dry freeze-dried powder or water-free concentrate, The mixture is combined into a single formulation. The composition is available in ampoules or packets, with the amount of active ingredient indicated in units of activity. It can be stored in a sealed container such as a fertilizer. When administering the composition by injection, use sterile pharmaceutical grade. Using an injection bottle containing "water for injection," physiological saline, or other suitable intravenous fluid It is dispenseable. When administering the composition by injection, the components can be mixed before administration. Ampoules of sterile water or physiological saline may be provided. The pharmaceutical composition may be any pharmaceutically acceptable Contrast agents and their pharmaceutically appropriate components, excipients, carriers, adjuvants, or media. Contains acceptable salt content.

[0178] In some embodiments, the contrast agent is administered to the patient in the form of an injectable composition. The method of administering contrast agents is parenteral, i.e., intravenous, intra-arterial, intrathecal, interstitial, or may include within the cavity. The pharmaceutical composition, like other diagnostic or therapeutic agents, is intended for use in humans and other animals. It can be administered to mammals. The dosage and mode of administration depend on age, weight, and sex. Furthermore, it will depend on various factors, including the patient's condition and genetic factors. Furthermore, ultimately, experimental determination of various dosages and subsequent images described herein This will be determined by medical professionals after the analysis. Generally, it will depend on diagnostic sensitivity or therapeutic effectiveness. The required dosage is approximately 0.001 to 50,000 μg / kg, preferably 0.0 The range is likely to be between 1 and 25.0 μg / kg of host body weight. [Examples]

[0179] method. General information. All chemicals and solvents must be purchased commercially and not subjected to further purification. I used it a lot.

[0180] NMR. Unless otherwise specified, NMR spectra are measured at 500 MHz Var at 25°C. The data was recorded using an ian spectrometer. Chemical shifts are reported in δ (ppm) units. 1 H and 13 C In NMR spectra, when dioxane is used as the internal reference, D 2 Recorded in O Ta 13 Except for 13C NMR, the residual solvent peak was used as the internal reference (Fulmer, O (rganometallics 2010, 29, 2176.) 1 Relaxation measurement is Br The test was performed using a uker mq60 Minispec at 1.41T and 37°C. (Vertical) T1) Relaxation is performed using 10 inversion durations within the ranges of 0.05 × T1 and 5 × T1. The results were obtained through reversal recovery experiments. Transverse (T2) relaxation was analyzed by Carl Purcell Maeboom Gill. The relaxation property (r) was measured using a spin echo experiment. 1,2 ) is 1 at least 4 concentrations / T 1,2 This was determined from the slope of the [Mn] plot. 17 The transverse (T2) relaxation time of O is H 2 17 The O signal was obtained at 11.7T from the full width at half maximum (Gale, Carvan, J.Am). (Chem.Soc.2013,135,18600). 17 O T2 relaxivity (r2 O ) This represents the increase in Mn addition of 1 / T2 relative to neat H2O (pH 3) divided by the Mn concentration in mM units. The calculation was performed by arithmetic. 0.7-1.0 mL of NMR sample is 18% of 10 μL. H2 17 It became enriched with O.

[0181] Relaxation in the presence of fibrin clots. Measurements were performed as already described (Carv an, J.Am.Chem.Soc.2008, 130, 6025). In short, CaCl2 is dissolved in the compound 20 shown below, thrombin, and human fibrinogen. When added to the solution, fibrin formation was triggered (CaCl2, fibrinogen, and thorax). The final concentrations of the brin were 10 mM, 10 mg / mL, and 0.6 U / mL, respectively. The resulting fibrin gel was incubated at 37°C for 20 minutes before measurement.

[0182] HPLC method. Liquid chromatography-mass spectrometry (LC-MS) is an LC / MSD tracking method. P, as well as Daly conversion dynos with UV detection at 220, 254, and 280 nm. This was performed using an Agilent 1100 series instrument equipped with a d-detector. The method used is as follows: (A1) Kromasil C18 column ( (100 x 4.6 mm), eluate C: 90% MeCN / 10% 10 mM ammonium acetate, D: 10 mM ammonium acetate, gradient from 5% C to 95% C over 14 minutes, flow rate 0.8 mL / min. Reverse-phase half-part purification is performed using a Phenomenex C18 or C5 column. Rainin D is detected by UV detection in the 220-280 nm range using a 250 × 21.8 cm (scale) sensor. The procedure was performed using a ynamax HPLC system. Mobile phase A was prepared by adding 0.1% TFA. It was water. Mobile phase B was MeCN with 0.1% TFA added. Mobile phase C The solution was 50 mM ammonium acetate buffer (pH 6.5). Mobile phase D was 5% 50 mM It was a mixture of M ammonium acetate buffer, pH 6.5, and 95% MeCN. The method used was as follows: (P1) Starting with 95%A / 5%B for 23 minutes. The fraction of B was increased to 70% over time. After washing the column with 95% B for 2 minutes, 5% B The system was changed to this extent. The system was re-equilibriumated with 5% B for 3 minutes, and then started with (P2)95% C / 5% D. The fraction of D was increased to 70% over 23 minutes. The column was washed with 95% D for 2 minutes. Next, the concentration was changed to 5% B. The system was re-equilibriumated with 5% B for 3 minutes, and (P3)95% A / 5% B Starting from [a certain point], the fraction of B was increased to 95% over 23 minutes. The column was then set to 95% B for 2 minutes. After washing, the concentration was changed to 5% B. The system was re-equilibriumated with 5% B for 3 minutes, and (P4) 95% Starting with C / 5%D, the fraction of D was increased to 95% over 23 minutes. After washing with %D for 2 minutes, the concentration was changed to 5%D. The system was re-equilibrium with 5%B for 3 minutes, and (P 5) Starting with 80% A / 20% B, the proportion of B was increased to 95% over 23 minutes. The column was washed with 95% B for 2 minutes, then changed to 5% B. The system was then leveled again with 5% B for 3 minutes. Balance the mixture, starting with (P6) 95% A / 5% B, and gradually increasing the fraction of B to 60% over 40 minutes. The solution was added. The column was washed with 95% B for 2 minutes, then changed to 5% B. The system was then treated with 5% B. Re-equilibrium for 3 minutes, starting with (P7) 95%C / 5%D, and the fraction of D over 23 minutes. The concentration was increased to 60%. The column was washed with 95% D for 2 minutes, then changed to 5% D. Re-equilibrium with 5%D for 3 minutes, then start with (P8)95%C / 5%D for 40 minutes. The fraction of D was increased to 60%. After washing the column with 95% D for 2 minutes, it was changed to 5% D. The system was re-equilibriumated with 5% D for 3 minutes, and then started with (P9)95% C / 5% D for 23 minutes. The fraction of D was gradually increased to 40%. After washing the column with 95% D for 2 minutes, 5% The concentration was increased to D. The system was re-equilibriumated at 5% D for 3 minutes.

[0183] DD(E) binding assay. Probe affinity is determined by the DD(E) fluorescence polarization change described above. Evaluation was performed using a positional assay. 5 Tetramethylrhodamine-labeled peptide from DD(E) The displacement of (TRITC-Tn6) is detected by observing the corresponding change in fluorescence anisotropy. The TRITC-Tn6 probe's K d As already mentioned, DD(E) tamper The fluorescence data obtained by titration using a chlorine was applied to determine the value (Carav an, Bioconjugate Chem. 2012, 23, 548). This experiment was conducted. The following assay buffers: Tris base (50 mM), NaCl (100 mM), CaC l2 ( 0.1 μM in 2 mM Triton X-100 (0.01%), pH=7.8 The test was performed at room temperature using TRITC-Tn6 concentrations. Anisotropy was measured using tetramethylrhodami. TECAN with a filter set suitable for (excitation 535nm, emission 590nm) The procedure was performed using an Infinity F200 Pro plate reader.

[0184] Quantitative determination of Mn in tissues and blood. Metal concentration was measured using Agilent 8800-QQQ I. The determination was made using a CP-MS system. All samples were 0.1% Triton X- in 5% nitric acid. Diluted to 100. For quantitative analysis, concentrations were set for each metal in the range of 0.1 ppb to 200 ppb. A linear calibration curve was created daily.

[0185] Estimated albumin binding. Measurement is performed in 4.5% wt / v BSA or bovine plasma. The experiment was conducted using a series of solutions within the range of 50-300 μM chelate metal complexes. 150 μL Each solution is filtered through a Millipore Ultra Free MC 5kDa cutoff filter. The solution was placed inside, and approximately 10 μL of the solution was compressed by centrifugation and passed through the filter material. Each unfiltered solution The Mn content of the filtrate was quantified by ICP-MS. [Mn( PyC3A)(H2O)] - The percentage is the difference in Mn concentration between the unfiltered solution and the filtrate. I estimated that.

[0186] A rat model of carotid artery thrombosis. All experiments were conducted at the National Institutes of Health. Guide to the Management and Use of Laboratory Animals (Institutes of Health) for the Care and Use of Laboratory Anima ls)(Guide for the care and use of labora The tory animals (Bethesda, MD, 1985) were carried out according to Masa Massachusetts General Hospital l) Institutional Animal Care Approved by the and Use Committee. Adult male Wistar rat ( N=4, weight 200~300g, Charles River Laboratory s) was used in this study. Arterial thrombosis is caused by 25% w / v AlCl3 (water-soluble) into the outer wall of blood vessels. It was induced by the application of AlCl3 solution. Under isoflurane anesthesia, the right common carotid artery was exposed and AlCl3 solution was applied. A small filter paper strip immersed in the liquid was applied. Damage was minimized to minimize fluctuations. The same researcher performed the procedure by placing the probe 1-2 cm close to the arterial bifurcation. Using an E-50 tube (Fisher Scientific), a catheter was inserted into the femoral artery. A probe was inserted. 30 minutes after embolization, a probe (compound 20 or gadolinium-containing control) was used. One of the compounds EP-2104R was injected. 0.01 mmol / kg probe (gold Each rat was injected with 0.04 mmol / kg (calculated as a group ion). In the blood sampling experiment, the injection To do this, catheters were inserted into the femoral vein and femoral artery of rats, and samples were taken from each. Yes. At 2, 5, 10, 15, 30, 60, and 120 minutes after the injection, and then 24 hours later. Blood was collected and placed in a heparinized vial. Immediately after collection, a portion of the blood was treated with 5000 rp. Centrifuge at m for 10 minutes, separate and weigh the plasma, dilute 2-fold with PBS buffer, and analyze at HP. It was injected onto an LC column.

[0187] MR imaging of thrombosis in rats. Imaging was performed using custom-made transmit and receive coils. A whole-body 1.5T system equipped with (Avanto, Siemens Healthcare) The experiment was conducted in Erlangen, Germany. During the experiment, isoflurane was used. The animals were anesthetized with (1-2%). Blood samples were taken and contrast doses were administered separately. Catheters were placed in the femoral vein and femoral artery. First, in the sagittal plane and then the coronal plane. , and the head and neck are visualized using T1-weighted images in the axial plane, followed by 3 in the lateral direction. D TOF angiogram was acquired. The next molecular imaging was performed using two different sequences. Kens, namely 3D T1-weighted gradient echo (GRE) and 2D T1-weighted The baseline was measured using Dark Blood Fast Spin Echo (DB-TSE). After all precontrast scans are completed, a 0.0 bolus is administered via the femoral artery. Use an imaging probe with a concentration of 1 mmol / kg (either EP-2104R or 18). Injected. The molecular imaging sequence used at baseline was contrast-contrast This was repeated for 60 minutes. A TOF angiogram was obtained using the following parameters. 3D T1-enhanced gradient echo sequence, TR / TE / flip angle = 26ms / 5.75ms / 25°, In-plane FOV = 85×85mm, Matrix = 320×320, 58 slices, slice thickness = 0.47 mm, voxel size = 0.3 × 0.3 × 0.47 mm, 1 mean, and acquisition time = 4:18 min. GRE sequencing for molecular imaging. The two had identical parameters in the TOF angiogram, but the 6:34 minute skip was different. Smaller head and foot coverage (48 slices) and longer TR (35m) result in longer run time. It had s). In addition, downward saturation was performed on the null-inflowing arterial blood. DB-TS E has TR / TE = 800ms / 20ms, in-plane FOV = 85×85mm, matrix. =320×320, 11 slices, slice thickness=2mm, voxel size=0.3×0. The test was performed using a 3x2mm microscope, eco-train length = 11, average value = 1, and acquisition time = 4 minutes. GRE The DB-TSE exhibited overlapping volumetric coverage and was acquired in the axial direction. The image shows how to plot the ROI and measure the mean SI of the blood clot, contralateral artery, and adjacent muscle. More, Matlab (Version R2104a, MathWorks, Native The analysis was performed using k,MA. Noise was defined as the standard deviation (SD) of the signal measured in the air outside the animal. We quantified it. SNR was calculated for each tissue type as described above. Furthermore, the contrast-to-noise ratio (CNR) for blood clots in muscle and contralateral arteries is CNR = (SI t issue -SI adj muscle ) / SD air The following were calculated: SNR and CNR This involves calculating the baseline (SNR) from the precontrast image. pre and CNR pre ) and various time points after contrast injection (SNR) post and CNR post ) The normalized SNR (nSNR) value is calculated by taking the SNR at each time point. pre To divide by The results were obtained from the following. Considering p<0.05 as significant, an unpaired Student's t-test was performed. It was used for statistical analysis.

[0188] Histological diagnosis. A carotid artery sample was taken 90 minutes after the start of thrombosis induction and carefully rinsed in phosphate buffer. Next, embed the sample in OCT mounting medium (Tissue-Tek) and soak it in isopentane at -45°C. Frozen sections were prepared using 20 μM slices of artery tissue, and hematological treatment was performed according to a standard protocol. The samples were treated with toxylin-eosin staining. The images were taken with a Nikon TE-2000 microscope (4 It was obtained using a magnification of 0x.

[0189] Example 1 Synthesis of chelate ligands that form protein-binding Mn(II) complexes A. N-((5-methoxycarbonyl)-pyridine-2-yl)methyl-N,N',N '-trans-1,2-cyclohexylenediamine triacetate (PyC3A5-Me Synthesis of (4) tyl ester [ka]

[0190] N-((5-methoxycarbonyl)-pyridine-2-yl)methyl-N,N',N'- trans-1,2-cyclohexylenediaminetri-tert-butylacetate ( 2) 6-(bromomethyl)-methylnicatinoate (0.450g, 1.95 mmol) ) 3 (1.00g, 2.01 mmol), potassium iodide (0.243g, 1.46m (mol), and 4 diisopropylethylamine (0.468 g, 3.62 mmol) The reaction was added while stirring in mL of DMF. After 3 hours, the reaction system was diluted to 100 mL with Et2O. Wash with saturated Na2CO3 (aqueous solution), a large amount of water, and brine, then Na Dehydration with 2SO4 and then concentration yielded brown oil. Flash chromatography (base The crude product is purified using alumina, hexane:siRNA (0%~20% siRNA). 1.02 g (1.68 mmol, 84%) of 6 was isolated as a clear colored oil. 1 H NMR (500 MHz, CDCl3, δ from prothio solvent): 9.07 (s, 1H) ,8.24(d,1H),8.03(d,1H),4.20(d,1H),3.04(s ,3H),3.86(d,1H),3.53-3.30(m,6H),2.73(brt ,1H),2.58(brt,1H),2.05(brm,2H),1.69(brm, 2H),1.65(brm,2H),1.45(s,18H),1.43(s,9H), 1.26-1.09 (m, 4H). 13 C NMR(125.7MHZ, CDCl3, δ from the medium): 171.8, 171.7, 166.4, 166.3, 149.9, 137 .5,124.3,123.7,80.7,80.6,63.7,62.0,56.4, 54.0,53.0,52.4,28.3,26.0,25.9. ESI-MS:m / z =606.4[M+H] + Calculated value: 606.4.

[0191] N-((5-methoxycarbonyl)-pyridine-2-yl)methyl-N,N',N'- trans-1,2-cyclohexylenediamine triacetate (PyC3A5-methyl Ester) (3). Mix 2 batches (0.390g, 0.645 mmol) in 5 mL at a 1:1 ratio. The mixture was stirred in TFA:CH2Cl2 for 16 hours. The reaction mixture was concentrated under reduced pressure and collected in a C18 column. The solution was purified by RP-HPLC using method P1, and 3 (0.184 g) of the solution was obtained as a white solid. 0.421 mmol was obtained, with a yield of 65%. 1 1H NMR (500 MHz, D 2O, 7 δ from prothio solvent at 0°C: 9.83 (brs, 1H), 9.42 (brs, 1H) ,8.68(brs,1H),5.04-4.80(brm,2H),4.61(brs ,3H),4.47-4.27(brm,6H),3.98(brs,1h),3.74 (brs,1h),2.86-2.77(brm,2H),2.46(brs,2H), 2.09-2.01(brm,2H),1.89(brs,2H). 13 C NMR (1 25.7MHz, CDCl3, 70℃): 173.5, 170.7, 165.3 (sky Due to simultaneous overlay with other resonances, one carboxylate C=O resonance is not decomposed. (was), 157.0, 146.0, 145.0, 128.7, 127.1, (probably) One carboxylate CH2 resonance was not decomposed due to simultaneous overlay with other resonances. ) 64.6, 62.9, 54.1, 53.0, 52.4, 24.7, 24.6, 24 .5,24.3. ESI-MS:m / z=438.2[M+H] + Calculated value: 438.2 .

[0192] Na[Mn(PyC3A-5-methyl ester)](4). 3(0.182g, 0.4 Dissolve a 16 mmol batch in 10 mL of H2O and use ammonium acetate to determine the pH. The concentration was adjusted to 6.5. MnCl2·4H2O (0.066g, 0.130 mmol) was added. The pH was readjusted to 6.5. RPLC was performed using a C18 column and method P2. The reaction mixture was purified and obtained as a white solid (4 (0.140 g, 0.273 mmol, yield 66)). The result was obtained as follows: ESI-MS: m / z = 491.1 [M+2H] + Calculated value: 491.1.

[0193] B. N-((5-hydroxymethyl)-pyridine-2-yl)methyl-N,N',N' -trans-1,2-cyclohexylenediamine triacetate (PyC3A-5-H Synthesis of droxymethyl (7) [ka]

[0194] N-((5-hydroxymethyl)-pyridine-2-yl)methyl-N,N',N'-t rans-1,2-cyclohexylenediamine tri-tert-butylacetate (5 ). Mix two batches (0.200 g, 0.331 mmol) in 20 mL of MeOH at room temperature. After stirring, gradually add NaBH4 (0.562g, 14.9 mmol) over 24 hours. The reaction was monitored by HPLC. At the end of the reaction, 10 mL of water was added. The mixture was concentrated under reduced pressure and allowed to dry. Crude product 5 was further processed and NMR characterized. The process moved directly to the next step without any further adjustments. ESI-MS:m / z=578.4[M+ H] + Calculated value: 578.4.

[0195] N-((5-hydroxymethyl)-pyridine-2-yl)methyl-N,N',N'-t rans-1,2-cyclohexylenediamine triacetate (PyC3A-6-hydro (6)(Xymethyl). Stir crude product 5 in 6 mL of 1:1 TFA:CH2Cl2 for 16 hours. Mixed. The reaction mixture was concentrated under reduced pressure and then processed using a C18 column and method P1 for RP-HP. Purified by LC, yielding 6 (0.036 g, 0.082 mmol, 27% yield) as a white solid. ) was obtained. 1 1H NMR (500 MHz, D 2O, 70°C, δ from prothio solvent):9 .32(brs,1H),9.07(brs,1H),8.65(brs,1H),5. 42(brm,2H),4.92-4.71(brm,3H),4.47-4.27(b rm,3H),4.16-4.07(brm,3H),3.61(brs,1H).2. 83-2.78(brm,2H),2.46(brs,2H),2.04(brs,2H ), 1.89 (brs, 2H). 13 ¹¹¹ NMR (125.7 MHz, CDCl3, 70 °C): 176.8, 171.5 (likely due to simultaneous overlay with other resonances) (The boxylate C=O resonance was not decomposed), 153.7, 147.7, 163.0 ,162.4,129.6,67.2,63.8,62.4,(probably due to the same resonance as other resonances) (Due to the overlay, one carboxylate CH2 resonance was not resolved), 55. 3,54.3,26.5,26.5,26.4,26.2. ESI-MS:m / z=41 0.2[M+H] + Calculated value: 410.2.

[0196] Na[Mn(PyC3A-5-hydroxymethyl)](7). 6(0.036g, 0. Dissolve a batch of 0.82 mmol in 4 mL of H2O, and add ammonium acetate to... The pH was adjusted to 6.5. MnCl2·4H2O (0.014g, 0.070mmol) The mixture was added and the pH was readjusted to 6.5. The reaction mixture was then prepared using a C18 column and method P2. The solution was purified to obtain 7 units (0.040 g, 0.082 mmol, yield 100) as a white solid. ESI-MS: m / z = 463.1 [M+2H] + Calculated value: 463.1.

[0197] C. N-((3-ethoxycarbonyl)-pyridine-2-yl)methyl-N,N',N '-trans-1,2-cyclohexylenediamine triacetate (PyC3A-3- Synthesis of ethyl ester (10) [ka]

[0198] N-((3-ethoxycarbonyl)-pyridine-2-yl)methyl-N,N',N'- trans-1,2-cyclohexylenediaminetri-tert-butylacetate ( 8) Dissolve a batch of 0.042 g (0.092 mmol) in 5 mL of MeCN. 52 g of ethyl 2-(bromomethyl)nicotinate (0.661 mmol) and 0.1 It was combined with 20g of K2CO3 (8.70 mmol) and heated at 50°C for 1 hour. Next... Then, the crude reaction mixture was concentrated to dryness and flash chromatography was performed (silica gel, 30: It was purified with 70 hexane:HCl. 8 was isolated as crude oil along with impurities, and the casing was removed. The reaction proceeded directly to the next step without performing lactalization.

[0199] N-((3-ethoxycarbonyl)-pyridine-2-yl)methyl-N,N',N'- trans-1,2-cyclohexylenediamine triacetate (PyC3A-3-meth (9). Dissolve 0.092 g (0.148 mmol) of 8 in 2 mL of TFA. The mixture was stirred for 16 hours. The TFA was removed under reduced pressure, and the crude product was placed in CH2Cl2 under reduced pressure. The product was concentrated. The product was purified by RP-HPLC using a C18 column and method P3. 24 mg (0.053 mmol, yield 36%) was obtained. 1 1H NMR (500 MHz, D 2 O, δ from prothio solvent): 8.67(d,1H), 8.41(d,1H), 7.4 7(t,1H),4.90(brs,1H),4.33(q,2H),4.16(d,1 H),3.80-3.30(m,6H),3.08(brm,2H),2.28(brm ,1H),2.11(brm,1H),1.84(brm,1H),1.76(brm, 1H),1.57(brm,1H),1.35(t,3H),1.35-1.21(m, 3H).) 1 H NMR(125.7MHZ, d6-DMSO):174.7,169 .6,166.4,154.0,152.6,144.1,126.4,124.8,6 6.3, 63.2, 61.9, 54.1, 50.4, 26.2, 26.2, 15.9, 2 5.6,14.6. ESI-MS:m / z=452.2[M+H] + Calculated value: 452. 1.

[0200] Na[Mn(PyC3A-3-ethyl ester)](10). 9(0.024g, 0. The pH was adjusted to 6.5 with a batch of 0.53 mmol. MnCl2·4H2O(0.01 5g (0.076 mmol) was combined in 1.5mL of water, and the pH was adjusted to 6.5. The reaction mixture was purified by RP-HPLC using a C18 column and method P4, and a white solution was obtained. 10 units (0.020 g, 0.031 mmol, 58% yield) were obtained as solid. ESI-M S: m / z = 505.0 [M + 2H] + Calculated value: 505.1.

[0201] D. N-((4-methoxy-3,5-dimethyl)-pyridine-2-yl)methyl-N, N',N'-trans-1,2-cyclohexylenediamine triacetate (PyC3 Synthesis of A-2-methoxy,3,5-dimethyl)(13) [ka]

[0202] N-((4-methoxy-3,5-dimethyl)-pyridine-2-yl)methyl-N,N' ,N'-trans-1,2-cyclohexylenediaminetri-tert-butylacetate Tate (11). Batch of 1 (0.127g, 0.278 mmol) in 10 mL of MeC 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (0.052g) in N Combined with (0.280 mmol) and K2CO3 (0.103, 0.746 mmol) The mixture was then heated to 72°C for 24 hours. The crude reaction mixture was then concentrated to dryness. The crude oil is isolated along with the other materials and proceeds directly to the next reaction without characterization. did.

[0203] N-((4-methoxy-3,5-dimethyl)pyridine-2-yl)methyl-N,N', N'-trans-1,2-cyclohexylenediamine triacetate (PyC3A-2 -methoxy,3,5-dimethyl)(12). The crude product 11 was stirred in 1 mL of TFA for 16 hours. Mix the oil, then concentrate it to obtain a yellow-colored oil, and perform RP-HP using a C18 column and method P3. Purified by LC. 12 was a white solid (0.022 g, 0.050 mmol, yield from 1). It was isolated with a fraction of 18%. ESI-MS: m / z = 438.2 [M+H] + Calculated value: 438.2.

[0204] Na[Mn(PyC3A-4-methoxy3,5-dimethyl)(13). 12(0.02 The pH was adjusted to 6.5 using a batch of 2g (0.050 mmol) of MnCl2·4H2O. Combine (0.012g, 0.061mmol) in 1.2mL of water and adjust the pH to 6.5. The reaction mixture was adjusted. The reaction mixture was purified by RP-HPLC using a C18 column and method P4. The mixture was prepared, yielding 13 units (0.021 g, 0.041 mmol, 82% yield) as a white solid. ESI-MS: m / z = 491.1 [M+2H] + Calculated value: 491.1.

[0205] N'-(6-methyl)nicatinoyl-,N',N'',N''trans-1,2-cy Chlohexyl ene diamine tri t Bu acetate (14). Lithium hydroxide (0.04 4g (1.84 mmol) and 2 (1.02g, 1.69 mmol) in 16 mL of 1: The mixture was combined in THF:H2O and stirred at room temperature for 3 hours. The reaction system was then concentrated to dryness. The solution was then purified by preparative RP-HPLC using a C18 column and method P5. Pure product was obtained. The fraction containing the substance was freeze-dried to obtain a white solid (0.670 g, 1.13 mmol). The product was obtained as 67%. 1 1H NMR (500 MHz, D 2 O, prothio solvent? (δ, stirred on K2CO3(s)): 9.09 (s, 1H), 8.15 (d, 1H), 7.07(d,1H),3.95(d,1H),3.63(d,1H),3.28(d, 1H),3.14-3.06(m,5H),2.33(brt,2H),1.94(m, 2H),1.68(m,2H),1.43(9H),1.38(18H),1.18-0 0.99 (m, 4H). 13 ¹¹C NMR (125.7 MHz, CDCl3, prothio solvent) (Agitated over δ, K2CO3(s)): 172.2, 171.9, 170.8, 158 .2,151.1,1380,131.1,122.9,81.8,81.5,62.1 ,59.5,55.9,53.0,52.6,29.8,28.1,28.0,25.9 ,25.7,25.4,24.8. ESI-MS:m / z=592.3[M+H] + , total Calculated value: 592.4.

[0206] E. N-((5-carboxylic acid-)pyridine-2-yl)methyl-N,N',N'-tr ans-1,2-cyclohexylenediamine triacetate (PyC3A-5-carbone) Synthesis of acid (15)

[0207] N-((5-carboxylic acid)pyridine-2-yl)methyl-N,N',N'-trans -1,2-Cyclohexylenediamine triacetate (PyC3A-5-carboxylic acid) 15). 14 (0.140 g, 0.237 mmol) batch in 5 mL of TFA. Stir for a while, then concentrate to obtain a white solid TFA adduct (0.12 g, 0.223 mmol). 15 was obtained with a yield of 94%. ESI-MS: m / z = 424.2 [M + H] + , total Calculated value: 424.2.

[0208] Na[Mn(PyC3A-5-carboxylic acid)(16). 15( adjusted to pH 6.5) In a batch of 0.12g, 0.223 mmol, add MnCl2·4H2O (0.047g, 0 (0.237 mmol) was added, and the pH was readjusted to pH 6.5. The reaction mixture was prepared using method P7. A portion of the compound was purified to obtain pure substance 15. ESI-MS: m / z = 477.0[M+2H ] + Calculated value: 477.1.

[0209] Example 2 Synthesis of Mn(II) fibrin-targeted chelate metal complex [ka]

[0210] N-(6-methyl)-N-Hydoxysuccinimidylnicatinoyl-,N,N',N' -trans-1,2-cyclohexylenediaminetri-tert-butylacetate (tBu-PyC3A-NHS) (17). (0.471g, 0.797mmol)14 Dicyclohexylcarbodiimide (0.167g, 0.809mg) in 10mL of THF (mol) and N-hydroxysuccinimide (0.109 g, 0.947 mmol) Both were stirred. A white precipitate formed within a few seconds. After 16 hours of stirring, LC-MS analysis was performed. Complete conversion was confirmed. The precipitate was removed by filtration, the clear mother liquor was concentrated, and a pale, colorless oil was obtained. The product was obtained. The product can be directly transferred to the next step, or to a C18 column and method. Purification is possible using P5 via RP-HPLC. 1 1H NMR (500MHz, D2 O, δ from prothio solvent): 9.15 (s, 1H), 8.32 (d, 1H), 8.21 (d,1H),4.33(d,1H),4.15(d,1H),3.55-3.25(m ,6H),2.91(s,4H),2.73(t,1H),2.50(t,1H),1. 91(m,2H),1.81(m,2H),1.45(18H),1.38(9H),1 0.18-1.02 (m 4H). 13 ¹¹¹ NMR (125.7 MHz, CDCl3, PRO δ from thio solvent): 171.5, 169.3, 169.2, 161.3, 150.3, 138.2,124.29,119.7,108.0,98.5,80.7,80.6( Two simultaneous peaks), 68.6, 63.9, 62.2, 54.0, 52.8, 49.3, 34.0, 28.2 (two simultaneous peaks), 29.3, 25.9, 25.9 (two simultaneous peaks) Peak), 25.8, 25.7. ESI-MS: m / z = 689.3 [M+H] + , calculation Value: 689.4.

[0211] t Bu-protected FBP-CyP3A4(18). Take 2 mL of oil in DMF and add 2 mL of D While stirring in MF, L-2,4-diamino-N-butylamide-[Tyr-dGlu- Cys-Hyp-Typ(3-Cl)-Leu-Cys-Ile-Gln(3→8) cys [Lufido]-1-(4-[(L-2,4-diaminobutyrylamino)-methyl]-benzylamino] Luamide (EP2104 / 24: 0.211g, 0.123mmol)) and 4-Dimethyl It was added to thylaminopyridine (0.016 g, 0.131 mmol). DIPEA The reaction system was adjusted to pH 6.5 and stirred at room temperature. After stirring for 16 hours, 250 mL of saturation solution was added. A solution of Sodium Cl was added dropwise to the reaction mixture to precipitate a white solid. C5 column and method P Using 6, RP-HPLC t Bu-protected FBP-CyP3A4 was purified. The product contained The fraction was freeze-dried and obtained as a white solid (0.177 g, 0.0441 mmol, 35 The product was obtained as follows: ESI-MS: m / 4z = 1004.0 [M + 4H] 4+ , total Calculated value: 1004.0. m / 3z=1338.4[M+3H] 3+ , calculated value 1338.4. m / 2z=2007.6[M+2H] 2+ The calculated value is 2007.6.

[0212] FBP-CyP3A4(19). TFA: Methanesulfonic acid: n-Dodecanethiol: Compound 18 (0.177 g, 44.1 μmol) in a 91:3:3:3 mixture of 5 mL of water. The mixture was stirred for 90 minutes, then diluted with 50 mL of Et2O. The cotton-like white solid was centrifuged. The material was then formed into solid pellets, and the supernatant was decanted. After washing several times with Et2O, the solid was dried. The pure product was obtained as a white powder (0.147 g, 44.0 μmol, 100%). ESI-MS: m / 3z = 1113.6 [M + 3H] 3+ Calculated value 1113.8. ESI -MS:m / z=1670.1[M+2H] 3+ The calculated value is 1670.2.

[0213] Mn-FBP(20). 10 mL solution of 19 (0.018 g, 5.4 μmol) Adjust H to pH 6.5 to obtain MnCl2·4H2O (0.0053g, 27.0μmol) It was added to the solution. The solution was readjusted to pH 6.5 and RP-H was performed using a C5 column and Method P7. Purified by PLC. The product-containing fraction was freeze-dried to obtain a white powder (0.008 The pure product was obtained using 0g, 2.2μmol, 41%). ESI-MS: m / 3z = 11 84.6 [M+8H] 3+ The calculated value is 1184.4. m / 2z = 1776.4 [M + 6H] 2+ The calculated value is 1776.5.

[0214] Example 3: Synthesis of collagen-targeted chelate metal complexes of Mn(II) t Bu-protected CBP-PyC3A4(21). Using DIPEA (wet pH test strip). While stirring in 3 mL DMF / 1 mL H2O adjusted to pH 9, EP-3533 Peptide batch (Caravan, P., Biplab, D., Dumas, S., E pstein, F.H., Helm, P.A., Jacques, V., Koerner. ,S.,Kolodziej,A.,Shen,L.,Sun,W.-C.,Zhang See Z. Angew. Chem. Int. Ed. 2007, 46, 8171. )(0.154g, 0.067mmol) to 17(0.280g, 0.407mmol) It was added little by little. After stirring for 16 hours, the solution was diluted with 100 mL of water and frozen. The compound was treated with rye treatment to obtain a crude white residue. Compound 21 was then taken to the next step without further purification. It has been switched to ESI-MS: m / 3z = 1337.0 [M+3H]. 3+ , calculated value 1337 .0. CBP-PyC3A4(22). 4 mL of 91:3:3:3 TFA:methanesulfone Compound 21 was stirred for 2 hours in acid:1-dodecanethiol:H2O. Then the reaction mixture was mixed. The substance was added to 100 mL of cold Et2O, and the product was precipitated. 50 mL was obtained by centrifugation. The solid was collected at the bottom of the conical tube and separated by decantation. Further purification was performed. Compound 22 was moved to the next step without performing the following procedure: ESI-MS: m / 3z = 116 8.0 [M+3H] 3+ The calculated value is 1167.8. MnCBP(23). MnCl2·4H2O (0.047g, 0.237mmol) The batch was added to the crude product 22, and then purified by HPLC to form 23. ESI -MS:m / 6z=1221.0[M+6H] 3+ The calculated value is 1221.1.

[0215] Example 4 Synthesis of Mn(II) oxidized collagen-targeted chelate metal complex N-((5-hydrazide)-pyridine-2-yl)methyl-N,N',N'-tran s-1,2-Cyclohexylenediamine triacetate (PyC3A-5-hydrazide) (24). 17 batches (0.180 g, 0.262 mmol) and tert-butyl Carbazate (0.070g, 0.606 mmol) 5 mL MeOH / 2 mL TH The mixture was stirred in F. The pH of the reaction mixture was adjusted to approximately 9 (using wet pH test paper). Stirring for 2 hours. After mixing, the reaction mixture was concentrated to dryness and placed in 5 mL of 6 M HCl. The mixture was stirred for 2 hours. Next, the reaction mixture was concentrated to form a white solid, which was then placed in H2O. All solids were filtered. Removed. Small aliquots of this reaction mixture were taken out and purified by method P7 to obtain a white powder. The result was 24. ESI-MS: m / z = 438.2 [M+H] + Calculated value: 438. 2.

[0216] Na[Mn(PyC3A-5-hydrazide)](25). Compound 25 in situ Prepared as follows: 24 solutions of MnCl2·4H in Tris buffer (50mM) at pH 7.4. 2O was added by titration. Mn chelation was monitored by HPLC. ESI-MS: m / z = 491.2 [M + 2H] + Calculated value: 491.1.

[0217] Example 5 Synthesis of peroxidase-reactive complex [ka]

[0218] 2-((hydroxypyridine-2-yl)methyl)phenol (26). 50 mL C A batch of 10.4 g (111 mmol) of phenol in H2Cl2 is mixed with 18.4 g (19 3 mmol (3 mmol) of magnesium chloride and 8.42 g (115 mmol) of N,N-dimethyl Stirred with ethylamine for 30 minutes. Add 5.5 of CH2Cl2 to this mixture. 85 g (55.0 mmol) of 2-pyridinecarboxaldehyde was administered dropwise over 3 hours. After the addition was complete, the resulting heterogeneous bright orange mixture was stirred at room temperature for 72 hours. H2O is added to the reaction, the mixture is titrated to pH 1 with concentrated HCl, and then concentrated Na The pH was adjusted to 9 by adding 2CO3. The organic layer was separated, and the aqueous portion was added to 100 mL of CH4. The mixture was washed again with 2Cl2. The organic portion was pooled, dehydrated with Na2SO4, concentrated, and turned orange. A colored syrup was obtained. Flash chromatography (silica gel, hexane:EtOA) was performed. The product was purified with c, 0-60% alkyl alcohol (HCl), and 7.08 g (35. 2 mmol of 26 (64% yield) was obtained. 1 ¹H NMR (500 MHz, CDCl3, T) δ from MS): 8.47 (d, 1H), 7.72 (t, 1H), 7.45 (d, 1H) ,7.21(d,1H),7.21(m,2H),6.95(d,1H),6.89(t ,1H),6.96(s,1H). 13 ¹¹¹ NMR (125.7 MHz, CD3Cl, T) δ from MS): 161.7, 155.3, 147.6, 138.2, 129.5, 12 8.3,127.0,123.0,120.4,120.2,118.5,74.4. E SI-MS: m / z = 202.0 [M+H] + Calculated value: 202.0.

[0219] 2-Picroylphenol (27). 1.41 g (7.01) in 40 mL of dioxane. 0 in a batch of 2-(hydroxy(pyridine-2-yl)methyl)phenol mmol 0.418 g (3.77 mmol) of selenium(IV) dioxide was added. The mixture was heated under reflux. The mixture was then stirred for 90 minutes. Next, the reaction system was cooled and filtered through Celite to remove the black insoluble material. The mother liquor was removed and concentrated to obtain a yellowish-green oil. Flash chromatography (silica gel, he The oil is refined using xane (0-70% alkylammonium compounds), yielding 1,190g (0.5 It was isolated as a bright yellow oil of 97 mmol, 85.2%.

[0220] 2,2'-((1Z,1'Z)-(ethane-1,2-diyrbis(azanylylidene)) Bis(pyridine-2-ylmetanylylidene)diphenol (28). 40 mL of MeOH In a batch of 0.168g (2.80 mmol) of ethylenediamine, add 1.190g (5 27 (0.98 mmol) was added. The reaction system was heated under reflux, stirred for 30 minutes, and then allowed to cool to room temperature. It was cooled and stirred for 16 hours. The resulting yellow solid was isolated by filtration and dried under reduced pressure. 28 units of 0.942 g (2.22 mmol, 79.6% yield) were isolated as a colored solid. Ta. 1 1H NMR (500 MHz, CDCl3, δ from TMS): 12.36 (s, 1 H),8.75(d,1H),8.13(d,1H),7.95(m,2H),7.53 (m,2H),7.07(d,1H),6.92(t,1H). 13 14C NMR (125 .7MHz, CD3Cl, δ from TMS): 197.3, 163.6, 155.5, 1 48.4, 137.6, 136.8, 134.5, 126.3, 124.7, 119.3 ,119.0,118.6. ESI-MS:m / z=200.0[M+H] + Calculated value: 200.1.

[0221] (+ / -) (R,R / S,S) 2,2'-((Ethane-1,2-diylbis(aza Bis(pyridine-2-ylmethylene)diphenol(31). 50 mL While stirring in MeOH, add 0.758 to 28 batches of 2.90g (6.87 mmol). 20.0 mmol of sodium boride was added. The color changed from yellow to transparent beige. Foaming was observed as a color change in the bleached solution. After 1 hour, the reaction was citric acid with 10 mL of water. Then, the MeOH was removed under reduced pressure. Next, the reaction system was divided into 50 mL each of saturated NaHCO3 (water-soluble). The aqueous solution was partitioned between the CH2Cl2 solution and the CH2Cl2 solution. The layers were separated, and the aqueous portion was mixed with another 100 mL of CH2Cl2 solution. Washed with 2Cl2. The organic portion was pooled, dehydrated with Na2SO4, concentrated, and 2.92 29 g of yellow oil (6.85 mmol, 100% conversion to racemideamine) was obtained. The oil was divided into 3 Take 2.490g of Zn(OTf)2(6) in 0mL MeOH / 10mL H2O. 85 mmol) was added. The solution was adjusted to pH 6.5 by adding solid ammonium acetate. The mixture was stirred for 16 hours, then concentrated to dryness. R was then analyzed using a C18 column and method P7. P-HPLC analysis reveals Zn-chelated R, R / S, S and R, S / S, R isomers (30) The following was separated: a batch of 0.075 mmol (0.154 mmol) R, R / S, S isomers. It was dissolved in 200 mM diethylenetriaminepentaacetic acid and the pH was adjusted to 5.0. (2 hours) After stirring, adjust the pH to >8.0, extract 31 with CH2Cl2, and deconjugate with Na2SO4. The product was diluted with water, dried under reduced pressure, and 0.066 g (0.154 mmol) of pure product was isolated. 1 H NMR (500 MHz, CDCl3, δ from TMS): 8.57(d,2H),7. 60(t,2H),7.21(m,4H),7.03(m,4H),6.84(m,4H ), 4.94 (s, 2H), 2.94 (s, 4H).

[0222] Janus HBED / BPED "JED" (32). 0.082 g in 20 mL of MeOH. 31 batches of (0.192 mmol) each contain 1.03 g (12.3 mmol) of NaHCO3 3 and 0.889 g (9.66 mmol) of glyoxylic acid monohydrate were added. 0. A batch of 119 g (1.89 mmol) sodium borohydride was administered over 8 hours. It was added little by little. After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness and C18 ka Purified by RP-HPLC using Lamb and preparation method P8. Pure substance 32 was obtained at 0.10 It was isolated as a 4g (0.192 mmol, 100% yield) white solid. ESI-MS: m / z = 543.0 [M + H] + Calculated value: 543.2.

[0223] Mn(II)-JED(33). 0.1 in 4 mL of H2O:MeCN while stirring. 32 batches of 0.04g (0.192 mmol) each contain 0.037g (0.187 mmol) Add MnCl2·H2O and then add solid ammonium acetate to adjust the pH of the solution to 6.5. The preparation was completed. The reaction mixture was purified by RP-HPLC using a C18 column and method P7. 0.041 g (0.069 mmol, yield 35.9%) of pure substance 33 was obtained as a white solid. It was isolated. ESI-MS: m / z = 596.0 [M+H] + Calculated value: 596.2.

[0224] Example 6 Synthesis of Thiol-Reactive Complexes [ka]

[0225] Mn(III)-JED(34). Stirring in 10 mL of H2O at pH 9.1. 32 batches of 0.053g (0.098 mmol) each contain 0.009g (0.080 mmol) MnF3 was added, and the solution was adjusted to pH 6.5. A C18 column and method P9 were used. The reaction mixture was purified by RP-HPLC. 0.018 mmol (0.029, condensate) Pure substance 34 was isolated as a brown solid with a concentration of 36.3%. ESI-MS: m / z=595 .0[M+2H] + Calculated value: 595.1.

[0226] Example 7 Relaxation of protein-targeting Mn(II) complexes at 1.41T and 37°C The incorporation of lipophilic functions into chelate metal complexes involves plasma proteins such as serum albumin. It improves binding to [substance]. This binding is measured in human plasma compared to that measured in PBS. Provides the change in relaxation to be measured. In most cases, the magnitude of relaxation (r1 or r2) A significant increase (40-170%) was observed (Table 1).

[0227] [Table 1]

[0228] Example 8: 18 has high affinity for soluble fibrin degradation product DD(E). Probe affinity was evaluated using the DD(E) fluorescence polarization displacement assay (using the method described above). (See reference). From DD(E) as a function of concentration of 18 or EP-2104R Tetramethylrhodamine-labeled derivative of ibrin-conjugated peptide (referred to as TRITC-Tn6) The displacement of (T) was detected by observing the corresponding change in fluorescence anisotropy (Figure 1). K of the RITC-Tn6 probe d Kolodziej (Bioconjugate) As described in Chem. 53:548-556, droplets with DD(E) protein It was determined by applying the fluorescence data obtained by setting. 18 is K d =110nM It binds to DD(E). We use the same DD(E) preparation as K for EP-2104R. d = A reading of 240 nM was recorded.

[0229] Example 9: Mn 20 has a rapidly exchanging insular water co-ligand. Rapid exchange water coligand (exchange rate=10 8 s -1 The existence of ) is 20 H2 17 O transverse relaxivity This was confirmed by monitoring the temperature dependence (Figure 2) (see the method described above). .

[0230] Example 10 shows high relaxation in the presence of fibrin. The relaxation value of 20 was 1.4T, pH 7.4 Tris buffer, bovine plasma, 4 Recorded in 0.5% wt / v BSA, human fibrinogen, and human fibrin gel. (Table 2). 18 compared to human fibrinogen or abundant plasma proteins. It exhibits greater relaxation in the presence of Ibringer.

[0231] [Table 2]

[0232] Example 11 20 detects carotid artery thrombosis. Compound 20 provides visualization of arterial thrombi with high visibility, and its imaging is This is supported by ex vivo histology (Figure 3). Surprisingly, 20 is even higher The Gd-based fibrin imaging probe EP-2104 is known to have relaxing properties. Provides thrombus nSNR and thrombus-to-muscle contrast-to-noise ratio (CNR) equivalent to R. (J.Am.Chem.Soc.2008,130:6025)(Figure 4). This data This further enhances the effectiveness of Mn in creating MR contrast.

[0233] Example 12: Intravenous injection of Mn-FBP is completely eliminated within 24 hours. Compound 20 is cleared from the blood with a half-life of 22.6 ± 6.8 minutes (Figure 5). Significant increases in Mn above baseline levels were found only in the kidneys and muscles, and These represent 0.37±0.14 and 0.02±0.02 percent of the injection dose per gram, respectively. The team remains in the league (Table 3).

[0234] [Table 3]

[0235] Example 13: The difference in relaxation between compounds 33 and 34 is very large and magnetic field independent. The relaxation properties of compounds 33 and 34 were measured in water and human plasma (Table 4). The relaxation change observed when switching between the 34 oxidation states was 660% for each of the conditions A to D. These are 900%, 500%, and 400%.

[0236] [Table 4]

[0237] Example 14 Compound 33 undergoes a 7-fold relaxation change and is converted by the peroxidase enzyme to compound Quickly converted to 34 The relaxation level of compound 33 in PBS (1.41 T, 37°C) is equivalent to that of 10 U / mL glucose. In the presence of a steady-state concentration of hydrogen peroxide produced by oxidase + 8 mM glucose The measurements were taken in the absence or presence of horseradish peroxidase. The experiment was conducted using the following methods. The black and white circles indicate the absence and presence of the peroxidase enzyme, respectively. This represents the degree of relaxation. The solid line represents the fit to the data.

[0238] Figure 7 shows the HPLC trace obtained after 1 hour of incubation. The HPLC trace of the race corresponds to 33, and the lower trace is hydrogen peroxide and This corresponds to the one incubated with peroxidase for 1 hour. 34 is formed It is the only product produced.

[0239] Example 15: In human plasma, compound 34 is converted to compound 33 upon addition of L-cysteine. It is possible Human plasma at 34 hours with and without 5 molar equivalents of L-cysteine. The function r1 (1.4T, 37℃) is represented by the black circle and the white circle, respectively. Figure 8). The solid line represents the fit to the data. The addition of L-cysteine ​​is from compound 34. This triggers a rapid conversion to compound 33, which in turn causes a significant increase in r1.

[0240] Several embodiments of the present invention have been described. However, the spirit and scope of the present invention It will be understood that various changes can be made without deviating from the original. The form falls within the scope of the following claims.

Claims

1. Equation (I): 【Chemistry 153】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes chloroalkylene, C ６ ~C １０ arylene, 5- to 10-membered heteroarylene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, Each R ２ and R ３ H, CO ２ H, (C １ ~C ６ Alkyl) CO ２ H, C １ ~C ６ a Lukil, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR ４ R ５ 、CH ２ NHCOR ４ 、C(O)N(OH)R ４ 、C(O)NHSO ２ R ４ 、CH ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ PO ３ R ４ R ５ 、お Independently selected from the group consisting of [L]-[TBM], Each R ４ and R ５ H, C １ ~C ６ Alkyl and [L]-[TBM] group Independently selected from (where alkyl is 1, 2, 3, or 4 independently selected) R Ｘ (Optionally substituted by the base), DG is 【Chemistry 154】 A group consisting of or selected from any structural isomers of formulas IV and V, Each Y is independently CH, CZ, N, O, S, or NR ４ And, Q is CH, CZ, N, O, S, or NR ４ And, Each Z is H, OH, OR ４ CO ２ R ４ , - (C １～６ Alkyl) CO ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl , C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O) NR ４ R ５ 、CH ２ NHCOR ４ 、C(O)N(OH)R ４ 、C(O)NHSO ２ R ４ 、 CH ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ 、PO ３ R ４ R ５ Independently selected from the group consisting of , and -[L]-[TBM] (where alkyl, a Lukenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and hetero Each of the Roaryl units consists of 1, 2, 3, or 4 independently selected R units. Ｘ Based on (Selectively substituted), L is a linker, TBM is the target binding site, and Each R Ｘ is OH, SH, CN, NO ２ , halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ alkynyl, C １ ~C ４ haloalkyl, C １ ~C ４ cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] They are independently selected from the group, However, when Q is CH or CCOOH and all Y are CH, R ２ Also is R ３ (At least one of them is not H) Compounds of or pharmaceutically acceptable salts thereof.

2. DG, 【Chemistry 155】 The compound according to claim 1.

3. The compound according to claim 1 or 2, wherein Q is CH.

4. The compound according to any one of claims 1 to 3, wherein Y is CH.

5. At least one Y is CZ (where Z is CO ２ R ４ , C １ ~C ６ Alkyl, and OR ４ A compound according to any one of claims 1 to 4, which is selected from the group consisting of the following: 。

6. One Y is CZ (where Z is CO ２ R ４ , C １ ~C ６ Alkyl and OR ４ from (selected from the group) and all other Y are CH, any one of claims 1 to 5 A compound as described in item 1.

7. Each R ４ is H or C １ ~C ６ Alkyl (where alkyl is 1, 2, 3, or 4) The following is a claim according to any one of claims 1 to 6, which is optionally substituted by the OH group of compound.

8. R ２ and R ３ A compound according to any one of claims 1 to 7, wherein is H.

9. DG, 【Chemistry 156】 A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. DG, 【Chemistry 157】 The compound according to claim 1.

11. At least one Y is N, O, S, or NR ４ The compound according to claim 10.

12. One Y is NR ４ Any one of claims 10 to 11, wherein the remaining Y is CH. The compounds described above.

13. DG, 【Chemistry 158】 A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

14. DG, 【Chemistry 159】 The compound according to claim 1.

15. At least one Y is N, O, S, or NR ４ The compound according to claim 14.

16. One Y is NR ４ The chemical according to claim 14 or 15, wherein the remaining Y is CH. Compound.

17. DG, [Chemical 160] The compound according to any one of claims 14 to 16.

18. DG, 【Chemistry 161】 The compound according to claim 1.

19. DG, 【Chemistry 162】 The compound according to claim 18.

20. R １ C ３ ~C １０ A cycloalkylene as described in any one of claims 1 to 19. compound.

21. R １ C ６ A compound according to any one of claims 1 to 19, which is a cycloalkylene.

22. R １ but, 【Chemistry 163】 The compound according to any one of claims 1 to 19.

23. R １ C １ ~C ６ The compound according to any one of claims 1 to 19, wherein the compound is alkylene.

24. R １ C ２ The compound according to any one of claims 1 to 19, wherein the compound is alkylene.

25. R １ but, 【Chemistry 164】 The compound according to any one of claims 1 to 19.

26. R ２ The compound according to any one of claims 1 to 25, wherein is H.

27. R ３ The compound according to any one of claims 1 to 26, wherein is H.

28. The aforementioned compound, 【Chemistry 165】 【Chemistry 166】 【Chemistry 167】 The compound according to claim 1, selected from the group consisting of or pharmaceutically acceptable salts thereof thing.

29. Equation (VI): 【Chemical 168】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes Chloalkylene, C ６ ~C １０ Arirene, 5-10 member heteroarirene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, R ２ , R ３ , and R ４ The formula is: 【Chemistry 169】 Independently selected from the group of compounds, R ５ and R ６ H, CO ２ H, (C １ ~C ６ Alkyl) CO ２ H, C １ ~C ６ Al Kill, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR ７ R ８ 、CH ２ NHCOR ７ 、C(O)N(OH)R ７ 、C(O)NHSO ２ R ７ 、CH ２ NHSO ２ R ７ 、N(OH)C(O)R ７ 、P(R ７ )O ２ R ８ 、PO ３ R ７ R ８ 、およ Independently selected from the group consisting of [L]-[TBM], X is CZ, N, O, S, or NR ７ And, Each W is independently CH, CZ, N, O, S, or NR ７ And, Each Z is independently H, OH, OR ４ CO ２ H, -(C １～６ Alkyl) CO ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cyclo Alkyl, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)NR ４ R ５ ,CH ２ NHCCR ４ 、 C (O) N (OH) R ４ 、C(O)NHS ２ R ４ 、CH ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ 、PO ３ R ４ R ５ , and selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. Ｘ Based on the basis, arbitrarily (to be replaced) Each R ７ and R ８ H, C １ ~C ６ Alkyl and -[L]-[TBM] Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R Ｘ (Optionally substituted by the base), DG is 【Chemistry 170】 A group consisting of or selected from any structural isomers of formulas XIII to XIV, Each Y independently controls CH and CZ. １ , N, O, S, or NR ７ And, Q is independent of CH and CZ. １ , N, O, S, or NR ７ And, Each Z １ These are independently H, OH, OR ４ CO ２ H, -(C １～６ Alkyl) CO ２ H , C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Shik Roalkyl, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl 、C(O)NR ４ R ５ 、CH ２ NHCOR ４ 、C(O)N(OH)R ４ 、C(O)NHS O ２ R ４ 、CH ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ 、PO ３ R ４ R ５ , and selected from -[L]-[TBM] (where alkyl, alkenyl) , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Each of the R's is one, two, three, or four independently selected R's. Ｘ Based on the arbitrary selection (to be replaced by) L is a linker, TBM is the target binding site, and Each R Ｘ These are OH, SH, CN, NO ２ Halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] They are independently selected from the group, However, Q is CH or CCOOH, all Y is CH, and R ２ , R ３ , and R ４ When all of them are equation VII, R ５ or R ６ At least one of them is H Furthermore, R ２ , R ３ , or R ４ One of them is equation VIII, and R ５ and R ６ All of H When this is the case, the aromatic ring component of formula VIII (i.e., the ring containing X and W) is DG and They must be different. Compounds of or pharmaceutically acceptable salts thereof.

30. R １ is 1,2-cyclohexylene, and R ２ , R ３ , and R ４ Equation VII is, R ５ and R ６ H is H, DG is equation XI, and one Y is [L] - [TB M] (where [L] is -C(O)- and [TBM] is -NHNH ２ (is) A compound according to claim 29.

31. The aforementioned compound, 【Chemistry 171】 The compound according to claim 29, or a pharmaceutically acceptable salt thereof.

32. Formula (XV): 【Chemistry 172】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes Chloalkylene, C ６ ~C １０ Arirene, 5-10 member heteroarirene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, Each R ２ , R ３ , and R ４ CO ２ H, (C(O)NR ５ R ６ ,CH ２ NHCOR ５ 、C(O)N(OH)R ５ 、C(O)NHSO ２ R ５ 、CH ２ NHSO ２ R ５ 、N(OH ) C(O)R ５ , P(R ５ ) O ２ R ６ , and PO ３ R ５ R ６ And formula: 【Chemistry 173】 Independently selected from the group consisting of the following compounds, X is CZ, N, O, S, or NR ５ And, Each W is independently CH, CZ, N, O, S, or NR ５ And, Each Z is independently H, OH, OR ４ CO ２ H, -(C １～６ Alkyl) CO ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cyclo Alkyl, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)NR ５ R ６ ,CH ２ NHCCR ５ 、 C (O) N (OH) R ５ 、C(O)NHS ２ R ５ 、CH ２ NHSO ２ R ５ 、N(OH)C(O)R ５ 、P(R ５ )O ２ R ６ 、PO ３ R ５ R ６ , and selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. Ｘ Based on the basis, arbitrarily (to be replaced) Each R ５ and R ６ H, C １ ~C ６ Alkyl and -[L]-[TBM] Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R Ｘ (Optionally substituted by the base), L is a linker, TBM is the target binding site, and Each R Ｘ These are OH, SH, CN, NO ２ Halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] (Selected independently from the group) Compounds of or pharmaceutically acceptable salts thereof.

33. R １ is 1,2-ethylene, and R ２ COOH is R ３ Equation XVI (where X (is N and all W are CH) and R ４ It was selected from compound formula XVI. The compound according to claim 32.

34. R ４ but, 【Chemistry 174】 The compound according to claim 33.

35. R ４ but, 【Chemistry 175】 The compound according to claim 33.

36. R ４ but, 【Chemistry 176】 The compound according to claim 33.

37. R ４ but, 【Chemistry 177】 The compound according to claim 33.

38. R １ is 1,2-ethylene, and R ２ COOH is R ３ is COOH and R ４ The compound according to claim 32, wherein is selected from compound formula XVI.

39. R ４ but, 【Chemistry 178】 The compound according to claim 38.

40. R ４ but, 【Chemistry 179】 The compound according to claim 38.

41. R ４ but, 【Chemistry 180】 The compound according to claim 38.

42. R ４ but, 【Chemistry 181】 The compound according to claim 38.

43. The aforementioned compound, 【Chemistry 182】 【Chemistry 183】 The chemical composition according to claim 32, selected from the group consisting of or pharmaceutically acceptable salts thereof. Compound.

44. Formula (XVII): 【Chemistry 184】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes Chloalkylene, C ６ ~C １０ Arirene, 5-10 member heteroarirene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, Each R ２ and R ３ H, CO ２ H, (C １ ~C ６ Alkyl) CO ２ H, C １ ~C ６ a Lukil, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR ４ R ５ 、CH ２ NHCOR ４ 、C(O)N(OH)R ４ 、C(O)NHSO ２ R ４ 、CH ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ PO ３ R ４ R ５ 、お Independently selected from the group consisting of [L]-[TBM], Each R ４ and R ５ H, C １ ~C ６ Alkyl and [L]-[TBM] group Independently selected from (where alkyl is 1, 2, 3, or 4 independently selected) R Ｘ (Optionally substituted by the base), DG is 【Chemistry 185】 A group consisting of or selected from any structural isomers of formulas IV and V, Each Y is independently CH, CZ, N, O, S, or NR ４ And, Q is CH, CZ, N, O, S, or NR ４ And, Each Z is H, OH, OR ４ CO ２ H, -(C １～６ Alkyl) CO ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)N R ４ R ５ 、CH ２ NHCOR ４ 、C(O)N(OH)R ４ 、C(O)NHSO ２ R ４ 、C H ２ NHSO ２ R ４ 、N(OH)C(O)R ４ 、P(R ４ )O ２ R ５ 、PO ３ R ４ R ５ 、 And independently selected from the group consisting of -[L]-[TBM] (where alkyl, aldehyde Kenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and hetero Each aryl consists of 1, 2, 3, or 4 independently selected R Ｘ Arbitrary (Selectively replaced) L is a linker, TBM is the target binding site, Each R Ｘ These are OH, SH, CN, NO ２ Halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I Selected from the group consisting of (II), However, when Q is CH or CCOOH and all Y are CH, R ２ Also is R ３ (At least one of them is not H) Compounds of or pharmaceutically acceptable salts thereof.

45. The aforementioned compound, 【Chemical 186】 【Chemistry 187】 【Chemical 188】 The chemical composition according to claim 44, selected from the group consisting of or pharmaceutically acceptable salts thereof. Compound.

46. Formula (XVIII): 【Chemical 189】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes Chloalkylene, C ６ ~C １０ Arirene, 5-10 member heteroarirene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, R ２ , R ３ , and R ４ The formula is: 【Chemistry 190】 Independently selected from the group of compounds, R ５ and R ６ H, CO ２ H, (C １ ~C ６ Alkyl) CO ２ H, C １ ~C ６ Al Kill, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR ７ R ８ 、CH ２ NHCOR ７ 、C(O)N(OH)R ７ 、C(O)NHSO ２ R ７ 、CH ２ NHSO ２ R ７ 、N(OH)C(O)R ７ 、P(R ７ )O ２ R ８ 、PO ３ R ７ R ８ 、およ Independently selected from the group consisting of [L]-[TBM], X is CZ, N, O, or S or NR ７ And, Each W is independently CH, CZ, N, O, S, or NR ７ And, Each Z is independently H, OH, OR ４ CO ２ H, C １～６ CO ２ H, -(C １～６ a Lukil) CO ２ H, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cycloa Lukil, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C (O)NR ７ R ８ ,CH ２ NHCOR ７ 、C(O)N(OH)R ７ 、C(O)NHSO ２ R ７ 、CH ２ NHSO ２ R ７ 、N(OH)C(O)R ７ 、P(R ７ )O ２ R ８ 、PO ３ R ７ R ８ , and selected from -[L]-[TBM] (where alkyl, alkenyl, a Lukinyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are Each of the following is a selection of 1, 2, 3, or 4 independently chosen Rs. Ｘ The base can be arbitrarily placed (to be exchanged) Each R ７ and R ８ H, C １ ~C ６ Alkyl and -[L]-[TBM] Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R Ｘ (Optionally substituted by the base), DG is 【Chemistry 191】 A group consisting of or selected from any structural isomers of formulas XIII to XIV, Each Y independently controls CH and CZ. １ , N, O, S, or NR ７ And, Q is independent of CH and CZ. １ , N, O, S, or NR ７ And, Each Z １ These are independently H, OH, OR ７ CO ２ H, -(C １～６ Alkyl) CO ２ H , C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Shik Roalkyl, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl 、C(O)NR ７ R ８ 、CH ２ NHCOR ７ 、C(O)N(OH)R ７ 、C(O)NHS O ２ R ７ 、CH ２ NHSO ２ R ７ 、N(OH)C(O)R ７ 、P(R ７ )O ２ R ８ 、PO ３ R ７ R ８ , and selected from -[L]-[TBM] (where alkyl, alkenyl) , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Each of the R's is one, two, three, or four independently selected R's. Ｘ Based on the arbitrary selection (to be replaced by) L is a linker, TBM is the target binding site, Each R Ｘ These are OH, SH, CN, NO ２ Halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I Selected from the group consisting of (II), However, Q is CH or CCOOH, all Y is CH, and R ２ , R ３ , and R ４ When all of them are equation VII, R ５ or R ６ At least one of them is H Furthermore, R ２ , R ３ , or R ４ One of them is equation VIII, and R ５ and R ６ All of H When this is the case, the aromatic ring component of formula VIII (i.e., the ring containing X and W) is DG and They must be different. Compounds of or pharmaceutically acceptable salts thereof.

47. Formula (XIX): 【Chemistry 192】 (In the formula, R １ C ２ ~C ６ Alkylene, C ３ ~C １０ Cycloalkylene, 4-10 member heterozymes Chloalkylene, C ６ ~C １０ Arirene, 5-10 member heteroarirene, (C １ ~C ６ ) Dialkyl (C ６ ~C １０ Arirene), and (C １ ~C ６ ) Dialkyl (5-10 Selected from the group consisting of (heteroarylenes), (where alkylenes, cycloalkylenes) Heterocycloalkylenes, arylenes, and heteroarylenes are, respectively, 1 and 2. , 3 or 4 independently selected R Ｘ (Optionally substituted by the base), and R １ R １ Attached to the adjacent nitrogen via the 1,2 or 1,3 positions above, Each R ２ , R ３ , and R ４ CO ２ H, (C(O)NR ５ R ６ ,CH ２ NHCOR ５ 、C(O)N(OH)R ５ 、C(O)NHSO ２ R ５ 、CH ２ NHSO ２ R ５ 、N(OH ) C(O)R ５ , P(R ５ ) O ２ R ６ , and PO ３ R ５ R ６ And formula: 【Chemistry 193】 Independently selected from the group consisting of the following compounds, X is CZ, N, O, or S or NR ４ And, Each W is independently CH, CZ, N, O, S, or NR ４ And, Each Z is independently H, OH, OR ４ CO ２ H, -(C １～６ Alkyl) CO ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ４ ~C ６ Cyclo Alkyl, C ６ ~C １０ Aryl, 5-6 member heterocyclyl, 5-6 member heteroaryl, C(O)NR ５ R ６ ,CH ２ NHCCR ５ 、 C (O) N (OH) R ５ 、C(O)NHS ２ R ５ 、CH ２ NHSO ２ R ５ 、N(OH)C(O)R ５ 、P(R ５ )O ２ R ６ 、PO ３ R ５ R ６ , and selected from -[L]-[TBM] (where alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl These are 1, 2, 3, or 4 independently selected Rs, respectively. Ｘ Based on the basis, arbitrarily (to be replaced) Each R ５ and R ６ H, C １ ~C ６ Alkyl and -[L]-[TBM] Independently selected from the group (where alkyl is independently selected from 1, 2, 3, or 4 elements) R Ｘ (Optionally substituted by the base), L is a linker, TBM is the target binding site, Each R Ｘ These are OH, SH, CN, NO ２ Halo, pseudohalo, amino, thionyl, sul Finyl, sulfonyl, sulfo, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Cyanoalkyl, C １ ~C ４ hydro Xyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Aminoalkyl, di(C) １ ~C ４ Al Kill) Amino, C １ ~C ４ Alkylamines, phosphinates, phosphinate esters, Phosphonate, phosphonate ester, phosphodiester, C １～４ Alkylphosphodier Stel, C ３ ~C ６ Cycloalkyl, phenyl, 5-6 member heteroaryl, 5-6 member hetero Rocycloalkyl, (C １ ~C ４ Alkyl)phenyl, and -[L]-[TBM] Selected independently from the group, and M is Gd(III), Fe(III), Mn(II), Mn(III), Cr(II) I), Cu(II), Cu(III), Dy(III), Ho(III), Er(III ), Pr(III), Eu(II), Eu(III), Nd(III), La(III) , Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc (V), Re(III), Re(IV), Re(V), Bi(III), and Yb(I (Selected from the group consisting of II) Compounds of or pharmaceutically acceptable salts thereof.

48. The aforementioned compound, 【Chemistry 194】 【Chemistry 195】 【Chemistry 196】 【Chemistry 197】 【Chemistry 198】 From the group consisting of or pharmaceutically acceptable salts thereof or any corresponding stereoisomer The compound according to claim 47, which is selected.

49. Formula (A): (0) １ ) ａ - (8) １ ) ｂ -TBM-(L ２ ) ｃ - (0) ２ ) ｄ (A) (In the formula, TBM is the target binding site, Each D １ This is independently a metal chelate according to any one of claims 44 to 48, Each D ２ This is independently a metal chelate according to any one of claims 44 to 48, L １ It is a linker, L ２ It is a linker, a is an integer between 0 and 4. b is either 0 or 1, However, when a is 0, b is 0, c is either 0 or 1, d is an integer between 0 and 4. However, when d is 0, c is 0, (At least one of a and d is an integer between 1 and 4.) Compounds of or pharmaceutically acceptable salts thereof.

50. [TBM] 【Chemistry 199】 The compound according to claim 49.

51. [TBM] 【Chemistry 200】 The compound according to claim 49.

52. D １ and D ２ The compound described in claim 1 (however, R １ is 1,2-cyclohexylene And R ２ H is R ３ is H, DG is equation II, Q is CH, and Q is The α-position Y is C-[L]-TBM, and all other Y are CH, and L is -C(O The compound according to claim 49, wherein it is (i) - (i).

53. The aforementioned compound, 【Chemical Engineering 201】 A compound according to claim 49, selected from the group consisting of the following.

54. A method for performing magnetic resonance (MR) imaging on a patient, a) An effective amount of the compound according to any one of claims 44 to 53 is administered to the patient. To what extent, b) A step of acquiring an MRI image of the patient, A method that includes this.

55. A method for imaging tumors in patients, a) An effective amount of the compound according to any one of claims 44 to 53 is administered to the patient. To what extent, b) A step of acquiring an MRI image of the tumor in the patient, A method that includes this.

56. A method for imaging blood clots in patients, a) An effective amount of the compound according to any one of claims 44 to 53 is administered to the patient. To what extent, b) A step of obtaining an MRI image of the blood clot in the patient, A method that includes this.

57. A method for imaging brain lesions in patients, a) An effective amount of the compound according to any one of claims 44 to 53 is administered to the patient. To what extent, b) A step of acquiring an MRI image of a brain lesion in the patient, A method that includes this.

58. A method for detecting the presence or absence of a damaged blood-brain barrier in a patient, a) an effective amount of the compound according to any one of claims 44 to 53 (wherein M is Mn(I I) the step of administering to the patient, b) A step of acquiring a first MRI image of the patient's brain, c) A step of acquiring a second MRI image of the patient's brain, d) A step of comparing the images, A method that includes this.

59. A method for detecting the presence or absence of arterial stenosis in a patient, a) an effective amount of the compound according to any one of claims 44 to 53 (wherein M is Mn(I I) the step of administering to the patient, b) A step of acquiring a first MRI image of the patient's artery, c) A step of obtaining a second MRI image of the patient's artery immediately after injection of the compound, d) A step of comparing the images, A method that includes this.

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