Prostate-specific membrane antigen (PSMA) inhibitors as diagnostic and radionuclide therapeutic agents

Abstract

The present disclosure relates to compounds of formula I. These compounds exhibit very good binding affinity to the PSMA binding site. They can be used in combination with radioisotopes or 68 Ga] or [ 177 The radiolabeled compound of formula I comprises a chelating moiety that can be labeled with a radioactive metal, such as [C11, C12, C13, C14, C15, C26, C27, C28, C39, C49, C49, C50, C51, C52, C63, C64, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C95, C96, C97, C98, C9 ...

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is in the field of radionuclide imaging and therapeutic agents. Specifically, derivatives of urea-based prostate-specific membrane antigen (PSMA) inhibitors are disclosed, including derivatives bearing a chelating moiety capable of chelating a radiometal and derivatives bearing a halogenated labeled phenyl. [Background technology]

[0002] Background of the Invention Prostate-specific membrane antigen (PSMA) is a highly specific prostate epithelial cell membrane antigen. Its natural substrates are N-acetyl-aspartylglutamate and folyl-poly-γ-glutamate (prostate-associated PSMA) (Scheme 1). [ka]

[0003] PSMA is highly expressed in a variety of tumors, including prostate cancer. PSMA expression is often increased in aggressive cancers and metastatic disease. High expression of PSMA is observed in the vast majority of angiogenesis in solid tumors, but is absent from the normal vasculature. This makes PSMA an appropriate target for cancer detection and therapy.

[0004] Several small molecule-based PSMA imaging agents have been reported in the literature. Various PSMA-targeting core structures have been used, including 2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentane-1,5-dioic acid (GPI), 2-(3-mercaptopropyl)pentane-dioic acid (2-PMPA), phosphoramidates, and especially urea-Glu groups (Glu-NH-CO-NH-Lys(Ahx)) (Scheme 2). See, for example, US2004054190; Kozikowski AP, et al., J. Med. Chem. 47:1729-38 (2004). Based on these binding core structures, many PSMA inhibitors have been reported to be highly selective and potent. After labeling with various isotopes, they have been disclosed to be useful in in vivo imaging (SPECT or PET) and in radionuclide therapy. [ka]

[0005] SPECT contrast agent: 123 I]MIP-1072, [ 123 I]MIP-1095,[ 99m Tc]MIP-1404, and [ 99m Several potential PSMA-targeted imaging agents using urea-based ligand systems (Glu-NH-CO-NH or Glu-NH-CO-NH-Lys(Ahx)), including [Tc]Tc-MIP-1405 (Scheme 3), have entered clinical trials. Results from phase II clinical studies suggest that these SPECT PSMA imaging agents are suitable for the diagnosis of prostate and other relevant solid tumors. [ka]

[0006] Targeting PSMA 18 F-labeled PET imaging agents have also been reported (Scheme 4). [ka]

[0007] Over the past 20 years, there have been many advances in imaging various tumors. 68 There have been many reports on the use of Ga-labeled small molecules and peptides. 68 Ga]DOTA-TOC,[ 68 Ga]DOTA-TATE, and [ 68 Ga]DOTA-NOC is used as an agent to detect neuroendocrine tumors (NETs) that express somatostatin receptors. 68 Ga-labeled compound [ 68 Ga]PSMA-11 has been well studied (Scheme 4). Clinical data have been generated that demonstrate its ability to detect and monitor prostate cancer [4]. 68 Additional antibodies targeting PSMA binding, including GaPSMA-093 68 A Ga-labeled compound has been reported (Scheme 4) that was reported to have improved tumor targeting properties and pharmacokinetics [5]. See US Patent Application Publication No. 2016 / 0228587.

[0008] Based on targeting PSMA binding sites that are overexpressed in most prostate cancer patients, 177 Lu-labeled PSMA-617 and DOTAGA-(yl)-fk(sub-KuE) (PSMA-I&T) have been reported as PSMA-targeted radionuclide therapies (Scheme 5) (see Discussion [10-13]

[14]

[15] ). 177 Lu]PSMA 617

[16] and [ 177 The results of clinical trials on Lu]PSMA I&T

[17] (Scheme 5) were promising. [ka] One other radionuclide for therapeutic use is 131 I, which emits electrons (beta radiation) with a physical half-life of 8.02 days and emits gamma rays with maximum beta energies of 606 keV (89% abundance) and 364 keV (81% abundance) for treating thyroid cancer. 131There is a long history of using 1I iodide, which is the standard of care for thyroid patients. 131 It has been reported that I-labeled MIP-1095 (Scheme 3) exhibits high PSMA binding affinity (Ki = 4.6 nM) and is an attractive alternative PSMA-targeted radionuclide therapeutic agent [1]. Several radioiodinated imaging and therapeutic agents with structural modifications in the linker region have been reported to have improved tumor targeting properties and pharmacokinetics. See U.S. Patent Application Publication No. 2016 / 0228587. There remains a need for further improving Glu-NH-CO-NH-Lys derivatives as PSMA inhibitors in in vivo imaging and radionuclide therapy. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 2004 / 054190 [Patent Document 2] US Patent Application Publication No. 2016 / 228587 [Non-patent literature]

[0010] [Non-Patent Document 1] Kozikowski AP, et al., J. Med. Chem. 47:1729-38 (2004) Summary of the Invention [Means for solving the problem]

[0011] Summary of the Invention In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is a chelating moiety, or Z 1 : [ka] is a group having the structure where Y 10 is CH or N; L and L a are each independently a bond or a divalent linking moiety containing from 1 to 6 carbon atoms in a chain, ring, or combination thereof, at least one carbon atom of which is optionally O, —NR 3 - or replaced by -C(O)-; R * is a radioactive isotope; R 22 is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; p is an integer from 0 to 4, and when p is greater than 1, each R 22 are the same or different; W is a PSMA targeting ligand; Each T 1 independently, T 11 or T 12 : [ka] having the structure where R 23 Ha-(CH2) a COH, where a is an integer from 0 to 4; Each T 2 independently, T 21 or T 22 : [ka] having the structure where b is an integer from 1 to 6, and G 1 is O, S, or NR 3 and; q is 0, 1, 2, or 3; r is 0, 1, or 2; A 2is a bond or a divalent linking moiety containing from 1 to 20 carbon atoms in a chain, ring, or combination thereof, where one or more carbon atoms are optionally O, —NR 40 - or may be replaced by -C(O)-; B 2 H, [ka] and where c is an integer from 1 to 4; G is O, S, or NR 3 and; X 2 is O, S, or -NR 41 - and; R 3 , R 40 , and R 41 each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl; R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 each is independently hydrogen, alkyl, alkoxyl, or halide; R 37 and R 38 each is independently hydrogen, alkyl, aryl, or alkylaryl; Each R 39 is independently selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; s is 0 or 1; v is an integer from 0 to 4, and if v is greater than 1, then each R 39 are the same or different; where s is 1 and -X 2 -A 2 -B 2 is -OH, r is 0, q is 1, and T 1 T 11 If Z is Z1 or [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which compound is not

[0012] In one embodiment, the present disclosure relates to a method of imaging a subject, comprising administering to the subject a radiolabeled compound disclosed herein; and obtaining an image of the subject or a portion of the subject. In another embodiment, the method for imaging comprises obtaining the image with a device capable of detecting positron emissions.

[0013] Additionally, the present disclosure relates to methods of making compounds of formula I.

[0014] In another embodiment, the present disclosure relates to a method for treating one or more tumors in a subject, comprising administering to the subject an effective amount of a compound or complex disclosed herein.In some embodiments, the tumor is a PSMA-overexpressing tumor.In some embodiments, the tumor is a prostate tumor, a neuroendocrine tumor, or an endocrine tumor.In some embodiments, the tumor is a prostate tumor. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is a chelating moiety, or Z 1 : [ka] is a group having the structure where Y 10 is CH or N; L and L a are each independently a bond or a divalent linking moiety containing from 1 to 6 carbon atoms in a chain, ring, or combination thereof, at least one carbon atom of which is optionally O, —NR 3 - or replaced by -C(O)-; R * is a radioactive isotope; R 22 is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; p is an integer from 0 to 4, and when p is greater than 1, each R 22 are the same or different; W is a PSMA targeting ligand; Each T 1 independently, T 11 or T 12 :

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[0015] [Figure 1]Figure 1 shows the HPLC chromatogram of radiolabeled [68Ga]4. Stationary phase: Eclipse XDB-C18 column 5µ, 4.6 x 150 mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0-8 min A / B 100 / 0-0 / 100; 2 mL / min.

[0016] [Figure 2] Figure 2 shows the HPLC chromatogram of radiolabeled [177Lu]4. Stationary phase: Eclipse XDB-C18 column 5µ, 4.6 x 150 mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0-4 min A / B 85 / 15 to 0 / 100, 4-11 min A / B 85 / 15 to 30 / 70, 11-14 min A / B 30 / 70 to 85 / 15; 1 mL / min.

[0017] [Figure 3] Figure 3 shows HPLC chromatograms of the radiolabeled protected intermediate [I]24, the cold standard 26, and the radioactive trace of the final compound [I]26. Stationary phase: Agilent Porocell 120 EC-C18 column 2.7μ, 4.6 × 50 mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0–1 min A / B 80 / 20, 1–16 min A / B 80 / 20 to 0 / 100, 16–16.5 min A / B 0 / 100 to 80 / 20, 16.5–20 min A / B 80 / 20; 2 mL / min. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention Many different radionuclides and many different precision targets have been reported [8]. Theranostic approaches offer personalized approaches for precision medicine. One suitable isotope is Lu-177 [8, 18, 19]. Lutetium-177 (Lu-177), with a physical half-life of 6.65 days, is a suitable therapeutic radionuclide that emits beta (490 keV), gamma, and X-rays (113 keV (3%), 210 keV (11%)).

[0019] Based on agents targeting PSMA, which is overexpressed in most prostate cancer patients, radiolabeled agents have been prepared for diagnostic imaging and radionuclide therapy. 177 Lu-labeled PSMA-617 and DOTAGA-(yl)-fk(sub-KuE) (PSMA-I&T) have been reported as PSMA-targeted radionuclide therapies (see Discussion [10-13]

[14]

[15] ). The results of clinical trials on PSMA-617

[16] and PSMA-I&T

[17] as radionuclide therapy agents have been very promising.

[0020] Over the past two decades, there have been many reports on the use of radioactive metal-labeled small molecules and peptides to image various tumors. 68 Ga]DOTA-TOC,[ 68 Ga]DOTA-TATE, and [ 68 Ga]DOTA-NOC is a commonly used agent for the detection of neuroendocrine tumors (NETs) that express somatostatin receptors. 68 Ga]PSMA-11 has been reported to be an effective PET imaging agent targeting overexpression of PSMA in prostate cancer patients.

[0021] Additional chelates have been reported for making lutetium (Lu-177) labeled radionuclide therapeutics. Each chelating group has a stability constant (logK dThese include many cyclic and acyclic polyazacarboxylic acids (Scheme 6) with a valence of 15 to 30. These improved chelates, 1,4,7,10-tetraazacyclodocecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), and 1,4,7,10-tetraazacyclodocecane, 1,7-(diglutaric acid)-4,10-diacetic acid (DOTA(GA)2), are stable at room temperature. 177 It has the advantage of forming Lu-labeled complexes (i.e., stable in vitro and in vivo), which simplifies preparation and makes them more suitable for clinical situations.

[0022] Many compounds of the present disclosure include DOTAGA and DOTA(GA)2, both of which: 68 Ga (for diagnostic use) [6] and 177 It can form stable chelated complexes with a variety of radiometals (M), including Lu (for radionuclide therapy) [7] (Scheme 6). [ka]

[0023] The in vivo biodistribution characteristics of the compounds or complexes disclosed herein are improved by specific modifications (e.g., linker changes) to the chemical structure of these compounds, such as iodinated and lutetium-labeled PSMA inhibitors. The structural adjustments resulted in higher tumor uptake and faster renal excretion (reducing non-targeted radiation dose) in PSMA tumor-bearing mice.

[0024] These new agents are valuable in radionuclide therapy when labeled with beta- or alpha-emitting isotopes; however, these agents are also useful as diagnostic agents when labeled with gamma-emitting isotopes.

[0025] Compounds with novel phenoxy linkers have been reported. See U.S. Patent Application Publication No. 2017 / 0189568, incorporated herein by reference in its entirety. This series of PSMA inhibitors, including urea-based PSMA targeting moiety substructures and novel linkers to various chelating groups, yielded stable metal complexes (including Lu-177). These were tested by in vitro binding, tumor cell uptake, and in vivo biodistribution studies. These PSMA inhibitors demonstrated good binding affinity and in vivo targeting ability in prostate tumor-bearing nude mice. For example, novel PSMA inhibitors can have a chelating moiety such as a complex or Compound A; or they can have a: radioactive metal DOTAGA complex, b: radioactive metal DOTA(GA)2 complex, or c: radioactive halogen (Scheme 7). [ka]

[0026] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is a chelating moiety, or Z 1 : [ka] is a group having the structure where Y 10 is CH or N; L and L a are each independently a bond or a divalent linking moiety containing from 1 to 6 carbon atoms in a chain, ring, or combination thereof, at least one carbon atom of which is optionally O, —NR 3 - or replaced by -C(O)-; R * is a radioactive isotope; R 22is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; p is an integer from 0 to 4, and when p is greater than 1, each R 22 are the same or different; W is a PSMA targeting ligand; Each T 1 independently, T 11 or T 12 : [ka] having the structure where R 23 Ha-(CH2) a COH, where a is an integer from 0 to 4; Each T 2 independently, T 21 or T 22 : [ka] having the structure where b is an integer from 1 to 6, and G 1 is O, S, or NR 3 and; q is 0, 1, 2, or 3; r is 0, 1, or 2; A 2 is a bond or a divalent linking moiety containing from 1 to 20 carbon atoms in a chain, ring, or combination thereof, where one or more carbon atoms are optionally O, —NR 40 - or may be replaced by -C(O)-; B 2 H, [ka] and where c is an integer from 1 to 4; G is O, S, or NR 3 and; X 2 is O, S, or -NR 41 - and; R 3 , R 40 , and R 41 each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl; R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 each is independently hydrogen, alkyl, alkoxyl, or halide; R 37 and R 38 each is independently hydrogen, alkyl, aryl, or alkylaryl; Each R 39 is independently selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; s is 0 or 1; v is an integer from 0 to 4, and if v is greater than 1, then each R 39 are the same or different; where s is 1 and -X 2 -A 2 -B 2 is -OH, r is 0, q is 1, and T 1 T 11 If Z is Z 1 or [ka] The present invention relates to a compound, or a pharmaceutically acceptable salt thereof, which compound is not

[0027] In some embodiments, Z is a chelating moiety. Chelating moieties are known in the art and refer to metal-binding groups. In some embodiments, Z is a chelating moiety selected from the group consisting of DOTA, NOTA, NODAGA, DOTAGA, DOTA(GA)2, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-DO3A. These chelating moieties include 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 1,4,7,10-tetraazacyclodosecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA). , and 1,4,7,10-tetraazacyclodosecane, 1,7-(diglutaric acid)-4,10-diacetic acid (DOTA(GA)2), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]penta[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), Deca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) , derived from 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).Useful chelating moieties are disclosed in US 2016 / 0228587, which is incorporated herein by reference in its entirety.

[0028] In some embodiments, Z is [ka] and A 1 is a bond or a divalent linking moiety containing from 1 to 20 carbon atoms in a chain, ring, or combination thereof, where one or more carbon atoms are optionally O, —NR 40 - or may be replaced by -C(O)-; B 1 H, [ka] and where c is an integer from 1 to 4; X 1 is O, S, or -NR 41 - and; D is a divalent chelating group derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0029] In some embodiments, D is [ka] In these divalent chelating groups, the top right binding site is selected from the group consisting of T 1 The bottom binding site is connected to the X 1 connected to the group.

[0030] In some embodiments, D is [ka] is selected from the group consisting of:

[0031] In some embodiments, D is [ka] is selected from the group consisting of:

[0032] In some embodiments, A 1 is a bond or a divalent linking moiety containing 1 to 16 carbon atoms in a chain, ring, or combination thereof, wherein one or more of the carbon atoms is selected from the group consisting of O, -NR 40 In some embodiments, A may be optionally replaced with -, or -C(O)-. 1 is a bond, or -(CH2) n -, -(CH2) n C(O)NH-, -(CH2CH2O) n - or -(CH2CH2O) n (CH2CH2NH) n - and; Each n is independently 1, 2, 3, or 4. In some embodiments, A 1 is the bond, -(CH2) n C(O)NH-, or -(CH2CH2O) n (CH2CH2NH) n -; and n is 1, 2, or 3. In some embodiments, A 1 is a bond, —(CH₂)C(O)NH—, or —(CH₂CH₂O)₂(CH₂CH₂NH)—.

[0033] In some embodiments, B 2 But, H, [ka] where c is an integer from 1 to 3. In some embodiments, c is 3.

[0034] In some embodiments, X 1 is O or —NH—. In some embodiments, X 1 is O and A 1 is a bond, and B 1 is H. In some embodiments, X 1 is -NH-, and A 1is -(CH2)C(O)NH- or -(CH2CH2O)2(CH2CH2NH)-, and B 1 teeth, [ka] is.

[0035] In some embodiments, Z is [ka] is selected from the group consisting of:

[0036] In some embodiments, Z is [ka] is selected from the group consisting of:

[0037] In some embodiments, Z is Z 1 : [ka] is a group having the structure where Y 10 is CH or N; L and L a are each independently a bond or a divalent linking moiety containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, at least one carbon atom of which is optionally O, —NR 3 - or replaced by -C(O)-; R * is a radioactive isotope; R 22 is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; p is an integer from 0 to 4, and when p is greater than 1, each R 22 are the same or different.

[0038] Useful radioisotopes (i.e., radioisotopes) include positron-emitting and photon-emitting isotopes. Radioisotopes are known in the art and include, for example, 11 C. 18 F, 123 I, 124 I, 125 I, 131 I, and 211 It can be As. 124 I can be used for PET imaging. 211 As can be used in radionuclide therapy. In some embodiments, the radioisotope is a radioactive halogen. In some embodiments, the radioisotope emits photons, 123 I and 131 I can be used in SPECT.

[0039] In some embodiments, L is a bond or a divalent linking moiety containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, wherein at least one carbon atom is optionally O, —NR 3 In some embodiments, L is a bond. In other embodiments, L is a divalent linking moiety comprising a C1-C6 alkylene group, where at least one carbon atom is optionally replaced with O, -NR 3 In some embodiments, L is replaced by -, or -C(O)-. n , -(OCH2CH2) n -, -(NHCH2CH2) n - or -C(O)(CH2) n -, where n is 1, 2, or 3. In another embodiment, L is -OCH2CH2-. Other useful examples of divalent linking moieties include -CH2-, -CH2CH2-, -CH2CH2CH2-, -OCH2CH2CH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -COCH2-, -COCH2CH2-, and -COCH2CH2CH2-.

[0040] In some embodiments, L ais a bond or a divalent linking moiety containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, at least one carbon atom optionally being O, —NR 3 In another embodiment, L a is a divalent linking moiety containing a C1-C6 alkylene group, at least one carbon atom of which is optionally O, -NR 3 In some embodiments, L is replaced by -, or -C(O)-. a is -C(O)-.

[0041] In some embodiments, R 22 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxyl, halide, haloC1-C4 alkyl, and CN. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0.

[0042] In some embodiments, Y 10 is CH. In some embodiments, Y 10 is N.

[0043] In some embodiments, Z has the structure: [ka] and where I (iodine) is radioactive. In some embodiments, radioactive iodine is 125 I. In some embodiments, the radioactive iodine 131 I.

[0044] PSMA targeting ligands are known in the art and refer to groups that can bind to PSMA. The PSMA targeting ligand can be the urea-based ligand system discussed herein.

[0045] In some embodiments, the PSMA targeting ligand W has the structure: [ka] and where R 20 and R 21 are each independently an amino acid residue linked to the adjacent —C(O)— group via its amino group.

[0046] In some embodiments, W has the structure: [ka] and where R 2 is hydrogen or a carboxylic acid protecting group, x is an integer from 1 to 6, and y is an integer from 1 to 4. In one embodiment, W is selected from the group consisting of the structure: [ka] It has.

[0047] In certain embodiments, the compounds of the present disclosure are represented by generalized formula I and the attendant definitions:

[0048] Part-[T 1 ] q -[T 2 ] r - represents a linking moiety. 1 independently, T 11 or T 12 Structure: [ka] and where R 23 is -(CH2) a COH, where a is an integer from 0 to 4. In some embodiments, a is 0, 1, or 2. In some embodiments, a is 2.

[0049] In some embodiments, T 12 but, [ka] is.

[0050] In some embodiments, -[T 1 ] q -but, [ka] is.

[0051] In some embodiments, each T 2 independently, T 21 or T 22 : [ka] having the structure where b is an integer from 1 to 6, and G 1 is O, S, or NR 3 In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 3 or 4. In some embodiments, G 1 is O or —NH—. In some embodiments, G 1 is O. In some embodiments, R 31 and R 32 are independently hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, or halide. 31 and R 32 are both hydrogen.

[0052] In some embodiments, -[T 2 ] r -but, [ka] is.

[0053] In some embodiments, A 2 is a bond or a divalent linking moiety containing from 1 to 16 carbon atoms in a chain, ring, or combination thereof, wherein one or more of the carbon atoms are optionally O, —NR 40 In some embodiments, A may be replaced by -, or -C(O)-. 2is a bond, or -(CH2) n -, -(CH2) n C(O)O-, -(CH2) n C(O)NH-, -(CH2CH2O) n - or -(CH2CH2O) n (CH2CH2NH) n -; and each n is independently 1, 2, 3, or 4. In some embodiments, A 2 is a bond or -(CH2) n C(O)NH—; and n is 1, 2, or 3. In some embodiments, A 2 is a bond or —(CH2)C(O)NH—.

[0054] In some embodiments, B 2 But, H, [ka] where c is an integer from 1 to 3. In some embodiments, c is 3.

[0055] In some embodiments, X 2 is O or —NH—. In some embodiments, X 2 is O and A 2 is a bond, and B 2 is H. In some embodiments, X 2 is -NH- and A 2 is a bond or -(CH2)C(O)NH-, and B 2 teeth, [ka] is.

[0056] In some embodiments, R 3 , R 40 , and R 41 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C6 cycloalkyl, heterocycloalkyl, aryl, C1-C4 alkylaryl, and heteroaryl. 3 , R40 , and R 41 Each of these is hydrogen.

[0057] In some embodiments, R 33 , R 34 , R 35 , and R 36 Each of R is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, or halide. 33 , R 34 , R 35 , and R 36 is hydrogen.

[0058] In some embodiments, R 37 and R 38 is independently hydrogen, C1-C4 alkyl, aryl, or C1-C4 alkylaryl. 37 and R 38 is independently hydrogen, phenyl, benzyl, or methylnaphthyl.

[0059] In some embodiments, each R 39 is independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxyl, halide, haloC1-C4 alkyl, and CN. 39 is independently methyl, methoxyl, halomethyl, or halide. In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0.

[0060] In some embodiments, the compound of formula I has formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein R 37a is optionally substituted phenyl or optionally substituted naphthyl.

[0061] In some embodiments, the compound of formula IB has the formula IB: [ka] or a pharmaceutically acceptable salt thereof, wherein R 37a is optionally substituted phenyl or optionally substituted naphthyl.

[0062] In some embodiments, the compound of formula I has the following formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

[0063] In some embodiments, the compound of formula I has the following formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

[0064] In some embodiments, the compound of formula I has formula III-A: [ka] or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound of formula I has formula III-B: [ka] or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound of formula I has formula IV-A or IV-B: [ka] or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, R 37a is aryl. In one embodiment, R 37a is optionally substituted phenyl. In another embodiment, R 37a is optionally substituted naphthyl. In some embodiments, R 37a is phenyl.

[0068] A as described above with respect to Formula I 1 , B 1 , X 1 , A 2 , B 2 , X 2 , T 1 , T 2 The definitions of , q, r, Z, and W apply to any of Formulas IA, IB, II-A, II-B, II-C, II-D, II-AA, II-BB, II-CC, II-DD, III-A, III-B, IV-A, and IV-B.

[0069] In some embodiments, the compound of Formula I has the following structure: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the compound of Formula I has the following structure: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein I (iodine) is radioactive. In some embodiments, the radioactive iodine 125 I. In some embodiments, the radioactive iodine131 I.

[0071] In some embodiments, the present disclosure relates to a complex comprising a compound of formula I as disclosed herein chelated to a metal M, wherein Z is a chelating moiety. In some embodiments, the metal M is 225 Ac, 44 Sc, 47 Sc, 203 / 212 Pb, 67 Ga, 68 Ga, 72 As, 99m Tc, 111 In, 90 Y, 97 Ru, 62 Cu, 64 Cu, 52 Fe, 52m Mn, 140 La, 175 Yb, 153 Sm, 166 Ho, 149 Pm, 177 Lu, 142 Pr, 159 Gd, 213 Bi, 67 Cu, 111 Ag, 199 Au, 161 Tb, and 51 In some embodiments, the metal M is selected from the group consisting of Cr. 68 Ga or 177 In some embodiments, the metal M is 68 In some embodiments, the metal M is Ga. 177 This is Lu.

[0072] An attractive and versatile approach to obtain radiopharmaceuticals for PET / CT is 68 Ga(T 1 / 2 = 68 minutes) to generate PET contrast agents. 68 Ge / 68 The use of Ga generators for PET imaging 68 There are several advantages to using Ga: (1) it is a short-lived positron emitter (half-life 68 min, β + ). (2) 68 Ge / 68The Ga generator is a laboratory device without a nearby cyclotron. 68 Ga is easily produced. (3) Parent 68 Ge has a physical half-life of 270 days, resulting in a useful life of 6 to 12 months. (4) There are several commercial vendors currently supplying this generator for routine clinical practice. (5) The coordination chemistry with Ga(III) is very flexible, and numerous Ga chelates with various stability constants and metal chelation selectivities have been reported; 68 Ga radiopharmaceuticals have been demonstrated to target various tissues or physiological processes for cancer diagnosis.

[0073] In some embodiments, the complex has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , A 1 , A 2 , B 1 , B 2 and M is defined herein. In some embodiments, X 1 is O or -NH-; X 2 is O or -NH-; A 1 is a bond, -(CH2)C(O)NH-, or -(CH2CH2O)2(CH2CH2NH)-; A 2 is a bond or -(CH2)C(O)NH-; B 1 and B 2 Each of the is independently H, [ka] is.

[0074] In some embodiments, the complex has the structure: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment, the present disclosure relates to a method of making a compound of formula I or a complex thereof.

[0076] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or complex disclosed herein. The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically acceptable salt of a compound or complex disclosed herein.

[0077] In one embodiment, the present disclosure provides a method for the preparation of a compound of Formula I or a pharmaceutically acceptable isotonic solution thereof for iv injection, comprising administering to a subject in need of diagnostic imaging (e.g., 68 Ga) and radiation therapy (e.g., 117 and instructions for use of the compound Lu.

[0078] The present disclosure also provides a method for in vivo imaging, comprising administering to a subject an effective amount of a radioactive metal complex or radioactive compound disclosed herein, and detecting a pattern of radioactivity of the complex or compound in the subject. In one embodiment, the present disclosure relates to a method for imaging a subject, comprising administering to a subject a radiolabeled compound disclosed herein; and obtaining an image of the subject or a portion of the subject. In another embodiment, the method for imaging comprises obtaining an image with a device capable of detecting positron emission.

[0079] The present disclosure also provides a method of in vivo imaging comprising administering to a subject an effective amount of a radioactive metal complex or radioactive compound disclosed herein and detecting the pattern of radioactivity of the complex or compound in the subject.

[0080] The present disclosure provides a method for treating one or more tumors in a subject, comprising administering to the subject an effective amount of the radioactive metal complex or radioactive compound disclosed herein.In some embodiments, the tumor is a PSMA-overexpressing tumor.In some embodiments, the tumor is a prostate tumor, a neuroendocrine tumor, or an endocrine tumor.In some embodiments, the tumor is a prostate tumor.

[0081] The typical subject that can be administered the compound of the present disclosure is mammals, particularly primates, especially humans.For veterinary use, various subjects are suitable, for example livestock such as cows, sheep, goats, cattle, pigs, etc.; poultry such as chickens, ducks, geese, turkeys, etc.; pet animals, especially pets such as dogs and cats.For diagnostic or research use, various mammals are suitable subjects, including rodents (for example, mice, rats, hamsters), rabbits, primates and pigs, such as inbred pigs, etc.In addition, for in vitro use, such as in vitro diagnostic and research use, the body fluids and cell samples of the above subjects are suitable for use, such as blood, urine or tissue samples of mammals, particularly primates, such as humans, or blood, urine or tissue samples of animals mentioned in veterinary use.

[0082] The radiopharmaceutical according to the present disclosure may be a positron-emitting gallium-68 complex, 68 Ge / 68 When used in conjunction with a Ga parent / daughter radionuclide generator system, it will enable PET imaging studies and avoid the expense associated with operating an in-house cyclotron for radionuclide production.

[0083] The complexes are formulated into aqueous solutions suitable for intravenous administration using standard techniques for parenteral diagnostic preparations. Aqueous solutions of the complexes can be sterilized, for example, by passage through a commercially available 0.2 micron filter. The complexes are generally administered intravenously in an amount effective to provide a tissue concentration of the radionuclide complex sufficient to obtain the photon (gamma / positron) flux necessary to image the tissue. The dose level of any given complex of the present disclosure to achieve acceptable tissue imaging depends on its specific biodistribution and the sensitivity of the tissue imaging device. Effective dose levels can be determined by routine experimentation. They generally range from about 5 to about 30 millicuries. When the complex is a gallium-68 complex for PET imaging of myocardial tissue, a suitable photon flux can be obtained by intravenous administration of about 5 to about 30 millicuries of the complex.

[0084] The term "amino acid" as used herein includes naturally occurring amino acids and non-naturally occurring amino acids. Naturally occurring amino acids refer to amino acids that are known to be used to form the basic building blocks of proteins, including alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof. Examples of unnatural amino acids include: unnatural analogs of tyrosine amino acid; unnatural analogs of glutamine amino acid; unnatural analogs of phenylalanine amino acid; unnatural analogs of serine amino acid; unnatural analogs of threonine amino acid; alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, ketone, or amino substituted amino acids, or any combination thereof; amino acids with photoactivatable crosslinkers; spin-labeled amino acids; fluorescent amino acids; amino acids with novel functional groups; and amino acids covalently bonded to another molecule. or non-covalently interacting amino acids; metal-binding amino acids; metal-containing amino acids; radioactive amino acids; photocaged and / or photoisomerizable amino acids; biotin or biotin analog-containing amino acids; glycosylated or carbohydrate-modified amino acids; keto-containing amino acids; amino acids containing polyethylene glycol or polyethers; heavy-atom substituted amino acids; chemically cleavable or photocleavable amino acids; amino acids with extended side chains; amino acids containing toxic groups; sugar-substituted amino acids, such as sugar-substituted serine; carbon-linked sugar-containing amino acids; redox-active amino acids; α-hydroxy-containing acids; aminothioacid-containing amino acids; α,α-disubstituted amino acids; β-amino acids; and cyclic amino acids other than proline.

[0085] As used herein, the term "alkanoyl" refers to a group having the following structure: [ka] This refers to R 30 is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl, any of which is optionally substituted. Acyl groups include, for example, C 1~6 It can be alkylcarbonyl (such as acetyl), arylcarbonyl (such as benzoyl), levulinoyl, or pivaloyl. In another embodiment, the acyl group is benzoyl.

[0086] As used herein, the term "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. Preferred alkyl groups are C1-C 10 It is an alkyl group. Typical C 1~10Alkyl groups include, among others, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, isopropyl, sec-butyl, tert-butyl, isobutyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, In one embodiment, useful alkyl groups include linear C alkyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl. 1~6 Alkyl groups and branched chain C 3~6 The alkyl group is selected from the group consisting of C 1~6 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-pentyl, and hexyl. In one embodiment, useful alkyl groups are linear C 2~6 Alkyl groups and branched chain C 3~6 The alkyl group is selected from the group consisting of C 2~6 Alkyl groups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-pentyl, and hexyl. In one embodiment, useful alkyl groups are linear C 1~4 Alkyl groups and branched chain C 3~4 The alkyl group is selected from the group consisting of C 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.

[0087] As used herein, the term "cycloalkyl" includes saturated ring groups having a specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups generally have from 3 to about 12 ring atoms. In one embodiment, a cycloalkyl has one or two rings. In another embodiment, a cycloalkyl is a C3-C8 cycloalkyl. In another embodiment, a cycloalkyl is a C 3~7 In another embodiment, cycloalkyl is C 3~6 Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, and adamantyl.

[0088] As used herein, the term "heterocycloalkyl" refers to a saturated heterocyclic alkyl group.

[0089] As used herein, the term "aryl" refers to a C 6~14 Aryl, especially C 6~10 Contains aryl. Typical C 6~14 Aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups, more preferably phenyl, naphthyl and biphenyl groups.

[0090] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a group having 5 to 14 ring atoms with 6, 10, or 14 pi electrons shared in a cyclic arrangement and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms, or 4 nitrogen atoms. In one embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, and cyclohexane. Examples include doryl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.Typical heteroaryl groups include thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., pyrrol-1-yl, 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl and tetrazol-5-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl), and the like. Examples of heteroaryls include pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). Five-membered heteroaryls can contain up to four heteroatoms. Six-membered heteroaryls can contain up to three heteroatoms. Each heteroatom is independently selected from nitrogen, oxygen, and sulfur.

[0091] Suitable carboxylic acid protecting groups are well known and include, for example, any suitable carboxylic acid protecting group disclosed in Wuts, PGM and Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th Edition, pp. 16-430 (J. Wiley & Sons, 2007), the entire contents of which are incorporated herein by reference. Those skilled in the art are familiar with the selection, attachment, and cleavage of protecting groups, and recognize that many different protecting groups are known to those skilled in the art, and the suitability of one protecting group or another will depend on the particular synthetic scheme planned. Suitable carboxylic acid protecting groups include, for example, methyl esters, t-butyl esters, benzyl esters, and allyl esters. [Example]

[0092] Materials and methods for synthesis general All reagents and solvents were purchased commercially (Aldrich, Acros, or Alfa Inc.) and used without further purification unless otherwise noted. Solvents were dried by a molecular sieve system (Pure Solve Solvent Purification System; Innovative Technology, Inc.). 1 H and 13 C NMR spectra were recorded on a Bruker Avance spectrometer at 400 MHz and 100 MHz, respectively, and referenced to the NMR solvent as indicated. Chemical shifts are reported in ppm (δ) with coupling constants J in Hz. Multiplicities are defined as singlet (s), doublet (d), triplet (t), broad (br), and multiplet (m). High-resolution mass spectrometry (HRMS) data were obtained on an Agilent (Santa Clara, CA) G3250AA LC / MSD TOF system. Thin-layer chromatography (TLC) analyses were performed on Merck (Darmstadt, Germany) silica gel 60 F 254The analysis was carried out using a plate. In general, crude compounds were purified by flash column chromatography (FC) packed with silica gel (Aldrich). High-performance liquid chromatography (HPLC) was carried out on an Agilent 1100 series system. The analysis was carried out in a gamma counter (Cobra II automatic gamma counter, Perkin-Elmer). 68 The Ga radioactivity was measured. The reaction of non-radioactive compounds was confirmed by silica gel 60F. 254 The reaction was monitored by thin layer chromatography (TLC) analysis using precoated plates. 68 an aqueous solution of Ga]GaCl 68 Ge / 68 Ga generator (Radiomedix Inc.) Solid phase extraction cartridges (SEP Pak® Light QMA, Oasis® HLB 3 cc) were obtained from Waters (Milford, MA, USA).

[0093] Compounds 4, 7, 17, 18, 26, 27, 29, 38, 42, and 51, all of which contain a urea-Glu group (Glu-NH-CO-NH-), were prepared as described in the following sections. Note that PSMA-11 and MIP-1095 are known PSMA imaging agents and are presented as positive controls for binding to PSMA.

[0094] The preparation of intermediate compound 2 is based on the following chemical reaction (Scheme 8) and is described in U.S. Patent Application Publication No. 2017 / 0189568, which is incorporated herein by reference in its entirety. [ka]

[0095] The preparation of compound 4 was based on the following chemical reaction (Scheme 9): Compounds 1 and 2 were synthesized according to known methods [5]. [ka]

[0096] The preparation of compound 7 was based on the following chemical reaction (Scheme 10). [ka]

[0097] Example 1 4-(7-(5-((2-(((S)-2-(4-(((4S,11S,15S)-4-benzyl-11,15-bis(tert-butoxycarbonyl)-20,20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl)oxy)phenyl)-1-carboxyethyl)amino)-2-oxoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (3) To a solution of 2 (124 mg, 0.129 mmol) in 5 mL of DMF was added N,N-diisopropylethylamine (DIPEA, 49 mg, 0.38 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 32.7 mg, 0.19 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 37 mg, 0.19 mmol), and 1 (100 mg, 0.129 mmol) at 0 °C. The mixture was stirred at room temperature overnight, after which 30 mL of EtOAc was added to the reaction mixture. It was then washed with HO (10 mL × 2) and brine (10 mL), dried over MgSO, and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH4OH = 90 / 9 / 1) to give 40 mg of 3 as a colorless oil (yield: 17.6%).

[0098] Example 2 (4S,11S,15S)-4-benzyl-1-(4-((2S)-2-(2-(4-(4,10-bis(carboxymethyl)-7-(1,3-dicarboxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4-carboxybutanamido)acetamido)-2-carboxyethyl)phenoxy)-2,5,13-trioxo-3,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylic acid (4) A solution of 3 (20 mg, 0.011 mmol) in 1 mL of TFA was stirred at room temperature for 5 h. The reaction mixture was evaporated in vacuo, and the residue was recrystallized from ether / EtOH. The resulting white solid was dissolved in 1 mL of MeOH and purified by semi-preparative HPLC to give 5 as a yellow oil (yield: 10 mg, 71.3%): 1 HNMR(400 MHz, MeOD) δ: 7.16-7.29(m, 7H), 6.85-6.89(m, 2H), 4.65-4.67(m, 2H), 4.45-4.55(m, 2H), 4.31-4.34(m, 2H), HRMS C 56 H 79 N 10 O 24 (M+H) + Calculated value: 1275.5269; measured value: 1275.5338.

[0099] Example 3 N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(4-iodophenyl)butanamide (5) To a solution of 4-(p-iodophenyl)butyric acid (145 mg, 0.5 mmol) in 5 mL of DCM was added NHS (69 mg, 0.6 mmol) and DCC (125 mg, 0.6 mmol). The reaction was stirred at room temperature for 2 hours. 20 mL of THF was then added to the mixture, followed by ethylene glycol bis(2-aminoethyl) ether (210 mg, 1.5 mmol). The reaction mixture was then stirred at room temperature overnight, the solvent was removed, and the residue was purified by FC (DCM / MeOH / NH4OH = 90 / 9 / 1) to give 120 mg of 5 as a colorless oil (yield: 57.1%). 1 HNMR(400 MHz, MeOD) δ: 7.61(d, 2H, J = 8.0 Hz), 6.96(d, 2H, J = 8.0 Hz), 6.24(br S, 1H), 3.52-3.60(m, 8H), 3.45-3.49(m, 2H), 2.87-2.89(m, 2H), 2.60-2.64(m, 2H), 2.17-2.21(m, 2H), 1.94-1.98(m, 2H).

[0100] Example 4 (2S)-3-(4-(((4S,11S,15S)-4-benzyl-11,15-bis(tert-butoxycarbonyl)-20,20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl)oxy)phenyl)-2-(2-(4-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-7-(22-(4-iodophenyl)-2,2-dimethyl-4,8,19-trioxo-3,12,15-trioxa-9,18-diazadocosan-5-yl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-(tert-butoxy)-5-oxopentanamido)acetamido)propanoic acid (6) To a solution of 3 (10 mg, 0.01 mmol) in 5 mL of DMF, N,N-diisopropylethylamine (DIPEA, 3.9 mg, 0.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 2 mg, 0.015 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 2.9 mg, 0.015 mmol), and 5 (4.2 mg, 0.01 mmol) were added at 0 °C. The mixture was stirred overnight at room temperature, and then 30 mL of EtOAc was added to the reaction mixture. It was then washed with HO (10 mL × 2) and brine (10 mL), dried over MgSO, and filtered. The filtrate was concentrated, and the residue was purified by FC (DCM / MeOH / NHOH = 90 / 9 / 1) to give 20 mg of 6 as a colorless oil (yield: 92%).

[0101] Example 5 (4S,11S,15S)-4-benzyl-1-(4-((2S)-2-carboxy-2-(2-(4-carboxy-4-(7-(1-carboxy-18-(4-iodophenyl)-4,15-dioxo-8,11-dioxa-5,14-diazaoctadecyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)acetamido)ethyl)phenoxy)-2,5,13-trioxo-3,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylic acid (7) A solution of 6 (20 mg, 0.0092 mmol) in 1 mL of TFA was stirred at room temperature for 5 h. The reaction mixture was evaporated in vacuo and the residue was recrystallized from ether / EtOH. The resulting white solid was dissolved in 1 mL of MeOH and purified by semi-preparative HPLC to give 7 as a yellow oil (yield: 12 mg, 77.8%): H NMR (400 MHz, MeOD) δ: 7.62 (d, 2H, J = 7.6 Hz), 7.16-7.29 (m, 7H), 7.01 (d, 2H, J = 7.6 Hz), 6.88 (m, 2H), 4.66-4.67 (m, 2H), 4.45-4.55 (m, 2H), 4.32 (m, 2H), 4.24 (m, 2H), 3.00-3.98 (m, 35H), 2.59-2.67 (m, 8H), 2.43 (m, 2H), 2.20-2.36 (m, 2H), 1.64-2.16 (m, 10H), 1.35-1.54 (m, 4H); HRMS calculated for C72H102IN12O26 (M+H)+, 1677.6073; found 1677.6157.

[0102] The preparation of compounds 17 and 18 was based on the following chemical reaction (Scheme 11). [ka]

[0103] Di-tert-butyl(((S)-6-((S)-2-((S)-2-amino-5-(tert-butoxy)-5-oxopentanamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (11). To a solution of 10 (440 mg, 0.69 mmol) in 10 mL of DMF was added N,N-diisopropylethylamine (DIPEA, 267 mg, 2.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 175 mg, 1 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 191 mg, 1 mmol), and Fmoc-Glu(OtBu)-OH (300 mg, 0.69 mmol) at 0 °C. After stirring overnight at room temperature, 1 mL of piperidine was added to the mixture and maintained at room temperature for 2 h. 50 mL of EtOAc was added to the reaction mixture. It was then washed with HO (20 mL × 2) and brine (20 mL), dried over MgSO, and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH4OH=90 / 9 / 1) to give 366 mg of 11 as a colorless oil (yield: 64.8%). HRMS C 42 H 70 N5O 11 (M+H) + Calculated value: 820.5072; measured value: 820.5103.

[0104] Di-tert-butyl(((S)-6-((S)-2-((S)-2-((S)-2-amino-5-(tert-butoxy)-5-oxopentanamido)-5-(tert-butoxy)-5-oxopentanamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (12). Compound 12 was prepared from 11 (266 mg, 0.32 mmol), N,N-diisopropylethylamine (DIPEA, 123 mg, 0.96 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 81 mg, 0.48 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 91 mg, 0.48 mmol), and Fmoc-Glu(OtBu)-OH (143 mg, 0.32 mmol) according to the same procedure as described for compound 11. Compound 12: 159 mg (yield: 49.4%). HRMS C 51 H 85 NO 14(M+H) + Calculated value: 1005.6124; measured value: 1005.6087.

[0105] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-((S)-5-(tert-butoxy)-5-oxo-2-(4-(tributylstannyl)benzamido)pentanamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (13). To a solution of 11 (43 mg, 0.05 mmol) in 10 mL of DMF, DIPEA (10 mg, 0.08 mmol) and 9 (37 mg, 0.06 mmol) were added at 0 °C. The mixture was stirred at room temperature for 5 h, and the solvent was removed in vacuo. The residue was purified by FC (DCM / MeOH / NH4OH = 95 / 5 / 0.5) to give 17.7 mg of 13 as a colorless oil (yield: 28.1%). 1 HNMR(400 MHz, CDCl3) δ: 8.03(d, 1H, J = 4.4 Hz), 7.76(d, 2H, J = 6.4 Hz), 7.48-7.59(m, 2H), 7.15(s, 4H), 7.09(s, 1H), 6.91-6.97(m, 2H), 5.99(d, 1H, J = 7.6 Hz), 5.79(d, 1H, J = 8.4 Hz), 5.31(s, 1H), 4.53-4.60(m, 2H), 4.29-4.34(m, 2H), 3.06-3.35(m, 4H), 2.30-2.37(m, 4H), 2.04-2.09(m, 3H), 1.79-1.87(m, 1H), 1.53-1.59(m, 6H), 1.42-1.45(m, 40H), 1.29-1.37(m, 6H), 1.08-1.12(m, 6H), 0.88-0.91(m, 9H);HRMS C 61 H 99 N5NaO 12 Sn(M+Na) + Calculated value: 1236.6210; measured value: 1236.6248.

[0106] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-((S)-5-(tert-butoxy)-2-((S)-5-(tert-butoxy)-5-oxo-2-(4-(tributylstannyl)benzamido)pentanamido)-5-oxopentanamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (14). To a solution of 12 (40 mg, 0.04 mmol) in 10 mL of DCM, DIPEA (77 mg, 0.06 mmol) and 9 (24 mg, 0.048 mmol) were added at 0 °C. The mixture was stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was purified by FC (DCM / MeOH / NH4OH = 95 / 5 / 0.5) to give 25.6 mg of 14 as a colorless oil (45.8% yield). 1 HNMR(400 MHz, MeOD) δ: 8.82(d, 1H, J = 3.6 Hz), 8.70(d, 1H, J = 6.4 Hz), 7.92(d, 2H, J = 6.4 Hz), 7.51-7.62(m, 3H), 7.11-7.17(m, 5H), 6.86(s, 1H), 6.36(d, 1H, J = 8.0 Hz), 5.53(d, 1H, J = 7.2 Hz), 4.80-4.84(m, 1H), 4.30-4.45(m, 4H), 3.62-3.65(m, 1H), 3.37-3.39(m, 1H), 3.20-3.25(m, 1H), 2.97-3.03(m, 1H), 2.65-2.69(m, 1H), 2.50-2.57(m, 1H), 2.24-2.30(m, 5H), 2.03-2.08(m, 2H), 1.62-1.85(m, 5H), 1.38-1.56(m, 55H), 1.07-1.11(m, 6H), 0.88-0.91(m, 9H);HRMS C 70 H 114 N6NaO 15 Sn(M+Na) + Calculated value: 1421.7262; measured value: 1421.7242.

[0107] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-((S)-5-(tert-butoxy)-2-(4-iodobenzamido)-5-oxopentanamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (15). Compound 15 was prepared from 12 (37 mg, 0.045 mmol), DIPEA (9 mg, 0.07 mmol), and 8 (19 mg, 0.054 mmol) according to the same procedure as described for compound 13. Compound 15: 24 mg (yield: 50.7%). 1 HNMR(400 MHz, CDCl3) δ: 8.12(d, 1H, J = 5.6 Hz), 7.77(d, 2H, J = 7.6 Hz), 7.57(d, 2H, J = 7.6 Hz), 7.09-7.16(m, 6H), 6.94(s, 1H), 5.99(d, 1H, J = 4.8Hz), 5.83(d, 1H, J = 8.0 Hz), 4.53-4.61(m, 2H), 4.15-4.36(m, 2H), 3.39(d, 1H, J = 7.6 Hz), 3.01-3.22(m, 2H), 2.98-3.04(m, 1Hz), 2.28-2.41(m, 4H), 2.00-2.07(m, 3H), 1.50-1.85(m, 3H), 1.42-1.45(m, 40H);HRMS C 49 H 73 IN5O 12 (M+H) + Calculated value: 1050.4300; measured value: 1050.4326.

[0108] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-((S)-5-(tert-butoxy)-2-((S)-5-(tert-butoxy)-2-(4-iodobenzamido)-5-oxopentanamido)-5-oxopentanamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (16). Compound 16 was prepared from 12 (40 mg, 0.04 mmol), DIPEA (26 mg, 0.048 mmol), and 8 (17 mg, 0.048 mmol) according to the same procedure as described for compound 13. Compound 16: 40 mg (yield: 80.1%). 1 HNMR(400 MHz, MeOD) δ: 8.87(d, 1H, J = 3.6 Hz), 8.81(d, 1H, J = 6.4 Hz), 7.82(d, 2H, J = 8.4 Hz), 7.72(d, 2H, J = 8.4 Hz), 7.50(d, 1H, J = 8.8 Hz), 7.11-7.17(m, 5H), 6.92(s, 1H), 6.31(d, 1H, J = 8.4 Hz), 5.52(d, 1H, J = 7.6 Hz), 4.72-4.83(m, 1H), 4.31-4.42(m, 4H), 3.59-3.63(m, 1H), 3.32-3.40(m, 1H), 3.20-3.25(m, 1H), 2.94-3.01(m, 1H), 2.56-2.65(m, 1H), 2.45-2.50(m, 1H), 2.10-2.32(m, 5H), 2.01-2.08(m, 2H), 1.62-1.88(m, 5H), 1.41-1.56(m, 49H);HRMS C 58 H 88 IN6O 15 (M+H) + Calculated value: 1235.5352; measured value: 1235.5422.

[0109] (((S)-1-Carboxy-5-((S)-2-((S)-4-carboxy-2-(4-iodobenzamido)butanamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (17). Compound 17 was prepared from 15 (17 mg, 0.016 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 17: 8.6 mg (yield: 64.2%). 1HNMR(400 MHz, MeOD) δ: 7.86(d, 2H, J = 7.6 Hz), 7.61(d, 2H, J = 8.0 Hz), 7.18(s, 4H), 7.15(s, 1H), 4.54-4.57(m, 1H), 4.46-4.49(m, 1H), 4.21-4.30(m, 2H), 3.58-3.60(m, 2H), 3.47-3.52(m, 1H), 3.11-3.16(m, 3H), 2.95-3.00(m, 1H), 2.34-2.41(m, 4H), 1.99-2.17(m, 4H), 1.75-1.77(m, 1H), 1.60-1.64(m, 1H), 1.43-1.45(m, 2H), 1.12-1.27(m, 2H);HRMS C 33 H 41 IN5O 12 (M+H) + Calculated value: 826.1796; measured value: 826.1755.

[0110] (((S)-1-Carboxy-5-((S)-2-((S)-4-carboxy-2-((S)-4-carboxy-2-(4-iodobenzamido)butanamido)butanamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (18). Compound 18 was prepared from 16 (38 mg, 0.031 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 18: 10.1 mg (yield: 34.1%). 1HNMR(400 MHz, MeOD) δ: 8.51(d, 1H, J = 6.4 Hz), 7.98(d, 1H, J = 8.4 Hz), 7.86(d, 2H, J = 8.4 Hz), 7.71(s, 1H), 7.66(d, 2H, J = 8.4 Hz), 7.16-7.22(m, 5H), 4.54-4.58(m, 1H), 4.45-4.48(m, 1H), 4.26-4.31(m, 3H), 3.15-3.21(m, 3H), 3.15-3.21(m, 1H), 2.49-2.52(m, 2H), 2.31-2.41(m, HRMS C 38 H 48 IN6O 15 (M+H) + Calculated value: 955.2222; measured value: 955.2273.

[0111] The preparation of compounds 26 and 27 was based on the following chemical reaction (Scheme 12). [ka]

[0112] Di-tert-butyl(((S)-6-((S)-2-(2-(4-((S)-2-((S)-2-amino-5-(tert-butoxy)-5-oxopentanamido)-3-(tert-butoxy)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (20). Compound 20 was prepared from 19 (455 mg, 0.5 mmol), DIPEA (193 mg, 1.5 mmol), HOBt (127 mg, 0.75 mmol), EDC (142 mg, 0.75 mmol), and Fmoc-Glu(OtBu)-OH (221 mg, 0.5 mmol) according to the same procedure as described for compound 11. Compound 20: 361 mg (yield: 65.8%). HRMS C 57 H 89 NO 15 (M+H) + Calculated value: 1097.6386; measured value: 1097.6399.

[0113] Di-tert-butyl(((S)-6-((S)-2-(2-(4-((S)-2-((S)-2-((S)-2-amino-5-(tert-butoxy)-5-oxopentanamido)-5-(tert-butoxy)-5-oxopentanamido)-3-(tert-butoxy)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (21). Compound 21 was prepared from 20 (220 mg, 0.2 mmol), DIPEA (78 mg, 0.6 mmol), HOBt (51 mg, 0.3 mmol), EDC (57 mg, 0.3 mmol), and Fmoc-Glu(OtBu)-OH (88 mg, 0.2 mmol) according to the same procedure as described for compound 11. Compound 21: 156 mg (yield: 60.8%). HRMS C 66 H 104 N7O 18 (M+H) + Calculated value: 1282.7438; measured value: 1282.7511.

[0114] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-(2-(4-((S)-3-(tert-butoxy)-2-((S)-5-(tert-butoxy)-5-oxo-2-(4-(tributylstannyl)benzamido)pentanamido)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (22). Compound 22 was prepared from 20 (76 mg, 0.07 mmol), DIPEA (27 mg, 0.21 mmol), and 9 (69.4 mg, 0.14 mmol) according to the same procedure as described for compound 13. Compound 22: 33.6 mg (yield: 48.0%). 1 HNMR(400 MHz, CD2Cl2) δ: 7.70(d, 2H, J = 6.8 Hz), 7.51(d, 2H, J = 7.2 Hz), 7.38(d, 2H, J = 6.4 Hz), 7.62-7.30(m, 2H), 7.19-7.23(m, 1H), 6.88(d, 2H, J = 7.6 Hz), 6.54(d, 2H, J = 7.6 Hz), 5.55(d, 1H, J = 8.4 Hz), 4.76(s, 1H), 4.48(s, 1H), 4.25(s, 1H), 3.16-3.40(m, 5H), 2.97-3.08(m, 2H), 2.25-2.47(m, 5H), 2.10-2.17 (m, 3H), 1.87-1.95(m, 2H), 1.51-1.57(m, 13H), 1.43(d, 25H, J = 11.2 Hz), 1.27-1.36(m, 18H), 1.12-1.27(m, 7H), 1.08-1.12(m, 6H), 0.87-0.92(m, 9H);HRMS C 76 H 118 N6NaO 16 Sn(M+Na) + Calculated value: 1513.7524; measured value: 1513.7674.

[0115] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-(2-(4-((S)-3-(tert-butoxy)-2-((S)-5-(tert-butoxy)-2-((S)-5-(tert-butoxy)-5-oxo-2-(4-(tributylstannyl)benzamido)pentanamido)-5-oxopentanamido)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (23). Compound 23 was prepared from 21 (50 mg, 0.04 mmol), DIPEA (6 mg, 0.048 mmol), and 9 (13.8 mg, 0.04 mmol) according to the same procedure as described for compound 13. Compound 23: 35 mg (yield: 57.8%). 1 HNMR(400 MHz, CDCl3) δ: 7.81(d, 2H, J = 6.4 Hz), 7.54-7.56(m, 3H), 7.32-7.34(m, 1H), 7.19-7.28(m, 5H), 7.09-7.11(m, 3H), 6.76-6.78(m, 3H), 6.08(s, 1H), 5.69(d, 1H, J = 7.2 Hz), 4.80-4.82(m, 1H), 4.63-4.69(m, 2H), 4.36-4.51(m, 5H), 3.37-3.39(m, 1H), 2.96-3.12(m, 5H), 2.52-2.56(m, 1H), 2.32-2.43(m, 5H), 2.01-2.20(m, 6H), 1.75-1.84(m, 2H), 1.28-1.55(m, 64H), 1.07-1.11(m, 6H), 0.88-0.92(m, 9H); HRMS C 85 H 133 NaNO 19 Sn (M + H) + Calculated value: 1698.8576; measured value: 1698.8774.

[0116] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-(2-(4-((S)-3-(tert-butoxy)-2-((S)-5-(tert-butoxy)-2-(4-iodobenzamido)-5-oxopentanamido)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (24). Compound 24 was prepared from 20 (67 mg, 0.06 mmol), DIPEA (24 mg, 0.19 mmol), and 8 (33 mg, 0.096 mmol) according to the same procedure as described for compound 13. Compound 24: 41.4 mg (yield: 50.6%). 1 HNMR(400 MHz, CD2Cl2) δ: 7.76(d, 2H, J = 8.0 Hz), 7.52(d, 2H, J = 7.6 Hz), 7.22-7.32(m, 5H), 6.91(d, 2H, J = 7.6 Hz), 6.57(d, 2H, J = 7.2 Hz), 5.10-5.18(m, 2H), 4.73(s, 1H), 4.44(s, 1H), 4.21(s, 1H), 4.07(s, 1H), 3.13-3.34(m, 5H), 2.93-3.05(m, 2H), 2.25-2.48(m, 5H), 2.00-2.13 (m, 3H), 1.84-1.90(m, 2H), 1.32-1.49(m, 49H); HRMS C 64 H 92 IN6O 16 (M + H) + Calculated value: 1327.5614; measured value: 1327.5533.

[0117] Di-tert-butyl(((S)-1-(tert-butoxy)-6-((S)-2-(2-(4-((S)-3-(tert-butoxy)-2-((S)-5-(tert-butoxy)-2-((S)-5-(tert-butoxy)-2-(4-iodobenzamido)-5-oxopentanamido)-5-oxopentanamido)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (25). Compound 25 was prepared from 21 (50 mg, 0.04 mmol), DIPEA (6 mg, 0.048 mmol), and 8 (23 mg, 0.04 mmol) according to the same procedure as described for compound 13. Compound 25: 12.5 mg (yield: 18.6%). 1 HNMR(400 MHz, CDCl3) δ: 7.85(d, 2H, J = 8.4 Hz), 7.64-7.70(m, 3H), 7.17-7.26(m, 5H), 6.98-7.09(m, 3H), 6.72(d, 2H, J = 7.6 Hz), 6.28(s, 1H), 5.70(s, 1H), 4.93-4.95(m, 1H), 4.66-4.67(m, 1H), 4.57-4.58(m, 2H), 4.14-4.37(m, 5H), 3.48-3.63(m, 1H), 3.35-3.38(m, 1H), 3.02-3.13 (m, 5H), 2.40-2.52 (m, 2H), 2.26-2.36 (m, 6H), 1.85-2.16 (m, 6H), 1.59-1.69 (m, 2H), 1.41-1.50 (m, 58H) 73 H 107 IN7O 19 (M+H) + Calculated value: 1535.6564; measured value: 1535.6607.

[0118] (((S)-1-Carboxy-5-((S)-2-(2-(4-((S)-2-carboxy-2-((S)-4-carboxy-2-(4-iodobenzamido)butanamido)ethyl)phenoxy)acetamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (26). Compound 26 was prepared from 24 (41 mg, 0.03 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 26: 16.0 mg (yield: 49.4%). 1 HNMR(400 MHz, MeOD) δ: 7.82(d, 2H, J = 7.2 Hz), 7.55(d, 2H, J = 7.6 Hz), 7.13-7.25(m, 7H), 6.74(d, 2H, J = 7.6 Hz), 4.56-4.67(m, 3H), 4.23-4.42 (m, 4H), 3.58-3.63 (m, 2H), 2.93-3.19(m, 7H), 2.39-2.43 (m, 4H), 2.11-2.16(m, 2H), 1.99-2.06(m, 1H), 1.78-1.91(m, 2H), 1.60-1.65(m, 1H), 1.27-1.45(m, 4H); HRMS C 44 H 52 IN6O 16 (M+H) + Calculated value: 1047.2484; measured value: 1047.2558.

[0119] (((S)-1-Carboxy-5-((S)-2-(2-(4-((S)-2-carboxy-2-((S)-4-carboxy-2-((S)-4-carboxy-2-(4-iodobenzamido)butanamido)butanamido)ethyl)phenoxy)acetamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (27). Compound 27 was prepared from 25 (29 mg, 0.019 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 27: 9.7 mg (yield: 41.4%). 1HNMR(400 MHz, MeOD) δ: 8.15(d, 1H, J = 8.4 Hz), 7.84(d, 2H, J = 8.4 Hz), 7.61(d, 2H, J = 8.4 Hz), 7.14-7.28(m, 7H), 6.82(d, 2H, J = 8.4 Hz), 4.62-4.68(m, 2H), 4.39-4.55(m, 4H), 4.31-4.32(m, 1H), 4.23-4.24(m, 1H), 3.06-3.20(m, 4H), 2.92-3.02(m, 2H), 2.33-2.45(m, 6H), HRMS C 73 H 107 IN7O 19 (M+H) + Calculated value: 1535.6564; measured value: 1535.6607.

[0120] The preparation of compound 29 was based on the following chemical reaction (Scheme 13). [ka]

[0121] 4-(7-((5S,8S,11S)-5-(4-(((4S,11S,15S)-4-benzyl-11,15-bis(tert-butoxycarbonyl)-20,20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl)oxy)benzyl)-8,11-bis(3-(tert-butoxy)-3-oxop (2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (28). To a solution of 21 (61 mg, 0.05 mmol) in 3 mL of DMF, DIPEA (39 mg, 0.03 mmol), HOBt (17 mg, 0.1 mmol), EDC (19 mg, 0.1 mmol), and 1 (77 mg, 0.1 mmol) were added at 0 °C. After stirring overnight at room temperature, 20 mL of EtOAc was added to the reaction mixture. It was then washed with HO (10 mL × 2) and brine (10 mL), dried over MgSO, and filtered. The filtrate was concentrated, and the residue was purified by FC (DCM / MeOH / NHOH = 90 / 9 / 1) to give 25 mg of 28 as a colorless oil (yield: 24.6%). HRMS C 104 H 170 N 11 O 29 (M+H) + Calculated value: 2037.2166; measured value: 2037.2224.

[0122] (((1S)-5-((2S)-2-(2-(4-((2S)-2-((2S)-2-((2S)-2-(4-(4,10-bis(carboxymethyl)-7-(1,3-dicarboxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4-carboxybutanamido)-4-carboxybutanamido)-4-carboxybutanamido)-2-carboxyethyl)phenoxy)acetamido)-3-phenylpropanamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid (29). Compound 29 was prepared from 28 (23 mg, 0.011 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 29: 9.7 mg (yield: 59.8%). 1HNMR(400 MHz, DMSO) δ: 8.15(s, 1H), 8.02-8.05(m, 3H), 7.18-7.25(m, 5H), 6.74(d, 2H, J = 7.6 Hz), 6.28-6.33(m, 2H), 4.51-4.54(m, 2H), 4.37-4.41(m, 3H), 4.25-4.29(m, 2H), 4.03-4.10(m, 3H), 3.80(s, 4H), 3.59-3.62(m, 4H), 2.88-3.09(m, 18H), 2.24-2.33(m, 8H), 1.86-1.93(m, HRMS C 64 H 89 N 11 O 29 (M+H) + Calculated value: 1476.5906; measured value: 1476.5995.

[0123] The preparation of compound 38 was based on the following chemical reaction (Scheme 14). [ka]

[0124] Di-tert-butyl(((S)-6-((S)-2-(2-(4-((benzyloxy)carbonyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (31). Compound 31 was prepared from 10 (635 mg, 1 mmol), DIPEA (387 mg, 3 mmol), HOBt (253 mg, 1.5 mmol), EDC (285 mg, 1.5 mmol), and 30 (286 mg, 1 mmol) following the same procedure as described for compound 28. Compound 31: 672 mg (yield: 74.5%). HRMS C 49 H 67 N4O 12 (M+H) +Calculated value: 903.4755, measured value: 903.4789.

[0125] 4-(((4S,11S,15S)-4-benzyl-11,15-bis(tert-butoxycarbonyl)-20,20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl)oxy)benzoic acid (32). A mixture of ester 31 (672 mg, 0.75 mmol) and 10% Pd / C (120 mg) in EtOH (20 mL) was shaken with hydrogen for 3 h. The mixture was then filtered, and the filtrate was concentrated in vacuo to give 578 mg of 32 as a colorless oil (yield: 95%). HRMS C 42 H 61 N4O 12 (M+H) + Calculated value: 813.4286, measured value: 813.4356. tert-Butyl N 6 -((benzyloxy)carbonyl)-N 2 -Glycyl-L-lysinate (34).

[0126] Compound 34 was prepared from H-Lys(Z)-OtBu (746 mg, 2 mmol), DIPEA (780 mg, 6 mmol), HOBt (506 mg, 3 mmol), EDC (570 mg, 3 mmol), piperidine (1 mL), and Fmoc-Gly-OH (594 mg, 2 mmol) according to the same procedure as described for compound 11. Compound 34: 424 mg (yield: 54.3%). HRMS C 20 H 32 N3O5(M+H) + Calculated value: 394.2342, measured value: 394.2392.

[0127] Tri-tert-butyl 2,2',2''-(10-((9S)-9-(tert-butoxycarbonyl)-20,20-dimethyl-3,11,14,18-tetraoxo-1-phenyl-2,19-dioxa-4,10,13-triazahenicosan-17-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (35). Compound 35 was prepared from DOTAGA-tetra(t-Bu ester) (140 mg, 0.2 mmol), DIPEA (78 mg, 0.6 mmol), HOBt (51 mg, 0.3 mmol), EDC (57 mg, 0.3 mmol), and 34 (79 mg, 0.2 mmol) according to the same procedure as described for compound 28. Compound 35: 103 mg (yield: 50.1%). HRMS C 55 H 94 N7O 14 (M+H) + Calculated value: 1076.6859, measured value: 1076.6938.

[0128] Tri-tert-butyl 2,2',2''-(10-((5S)-5-(4-aminobutyl)-2,2,16,16-tetramethyl-4,7,10,14-tetraoxo-3,15-dioxa-6,9-diazaheptadecan-13-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (36). Compound 36 was prepared from 35 (100 mg, 0.1 mmol) and Pd / C (20 mg) according to the same procedure as described for compound 32. Compound 36: 83.7 mg (yield: 89.0%). HRMS C 47 H 88 N7O 12 (M+H) + Calculated value: 942.6491, measured value: 942.6583.

[0129] Di-tert-butyl(((2S)-1-(tert-butoxy)-6-((2S)-2-(2-(4-(((5S)-6-(tert-butoxy)-5-(2-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanamido)acetamido)-6-oxohexyl)carbamoyl)phenoxy)acetamido)-3-phenylpropanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (37). Compound 37 was prepared from 36 (40 mg, 0.042 mmol), DIPEA (16.2 mg, 0.126 mmol), HOBt (11 mg, 0.063 mmol), EDC (12 mg, 0.063 mmol), and 32 (34 mg, 0.2 mmol) following the same procedure as described for compound 28. Compound 37: 21 mg (yield: 28.8%). HRMS C 89 H 146 N 11 O 23 (M+H) + Calculated value: 1737.0593, measured value: 1737.0675. (((1S)-1-carboxy-5-((2S)-2-(2-(4-(((5S)-5-carboxy-5-(2-(4-carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)acetamido)pentyl)carbamoyl)phenoxy)acetamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (38).

[0130] Compound 38 was prepared from 37 (20 mg, 0.011 mmol) in 1 mL of TFA following the same procedure as described for compound 4. Compound 38: 6.8 mg (yield: 48.0%). HRMS C 57 H 82 N 11 O 23 (M+H) + Calculated value: 1288.5585; measured value: 1476.5995.

[0131] The preparation of compound 42 was based on the following chemical reaction (Scheme 15). [ka]

[0132] Benzyl (2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)carbamate (39). Compound 39 was prepared from Z-Gly (209 mg, 1 mmol), DIPEA (387 mg, 3 mmol), HOBt (253 mg, 1.5 mmol), EDC (285 mg, 1.5 mmol), and tetraethyl(aminomethylene)bis(phosphonate) (303 mg, 1 mmol) according to the same procedure as described for compound 28. Compound 39: 150 mg (yield: 30.4%). HRMS C 19 H 33 N2O9P2(M+H) + Calculated value: 495.1661, measured value: 495.1679.

[0133] Tetraethyl((2-aminoacetamido)methylene)bis(phosphonate) (40). Compound 40 was prepared from 39 (1 g, 2 mmol) and Pd / C (200 mg) according to the same procedure as described for compound 32. Compound 40: 525 mg (yield: 72.9%). HRMS C 11 H 27 N2O7P2(M+H) + Calculated value: 361.1293, measured value: 361.1342. Di-tert-butyl(((2S)-6-((2S)-2-(2-(4-((2R)-2-(2-(4-(7-(5-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7, 10-Tetraazacyclododecan-1-yl)-5-(tert-butoxy)-5-oxopentanamido)acetamido)-3-(tert-butoxy)-3-oxopropyl)phenoxy)acetamido)-3-(naphthalen-2-yl)propanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (41).

[0134] Compound 41 was prepared from 40 (13.7 mg, 0.038 mmol), DIPEA (14.7 mg, 0.114 mmol), HOBt (9.6 mg, 0.057 mmol), EDC (10.8 mg, 0.057 mmol), and 3 (65 mg, 0.038 mmol) according to the same procedure as described for compound 28. Compound 41: 44 mg (yield: 56.1%). HRMS C 99 H 167 N 12 O 30 P2(M+H) + The calculated value was 2066.1386, and the measured value was 2066.1480.

[0135] (((1S)-1-Carboxy-5-((2S)-2-(2-(4-((2R)-2-carboxy-2-(2-(4-carboxy-4-(7-(1-carboxy-4-((2-((diphosphonomethyl)amino)-2-oxoethyl)amino)-4-oxobutyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)acetamido)ethyl)phenoxy)acetamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (42). To a solution of 41 (42 mg, 0.02 mmol) in 1 mL of DMF was added 1 mL of TMSBr at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight, and the solvent was removed in vacuo. The residue was treated with 1 mL of TFA. After stirring at room temperature for 5 h, the solvent was removed and the residue was purified by semi-preparative HPLC to give 12 mg of 42 as a white solid (yield: 39.9%). 1 HNMR(400 MHz, DMSO) δ: 7.16-7.24(m, 5H), 7.09(d, 2H, J = 8.4 Hz), 6.73(d, 2H, J = 8.4 Hz), 4.49-4.53(m, 1H), 4.36-4.42(m, 4H), 4.07-4.10(m, 1H), 4.00-4.04(m, 1H), 3.68-3.83(m, 8H), 3.29-3.39(m, 2H), 3.17-3.28(m, 2H), 2.94-3.09(m, 12H), 2.79-2.88(m, 6H), 2.22-2.34(m, 6H), 1.88-1.94(m, 2H), 1.64-1.74(m, 2H), 1.49-1.54(m, 1H), 1.32-1.36(m, 2H), 1.17-1.24(m, 2H);HRMS C 59 H 88 N 12 O 30 P2 (M+2H) 2+ Calculated value: 753.2597, measured value: 753.2769.

[0136] The preparation of compound 51 was based on the following chemical reaction (Scheme 16). [ka]

[0137] Methyl((benzyloxy)carbonyl)glycyl-L-tyrosinate (43). Compound 43 was prepared from Z-Gly (1.045 g, 5 mmol), DIPEA (1.94 g, 15 mmol), HOBt (1.26 g, 7.5 mmol), EDC (1.42 g, 7.5 mmol), and methyl L-tyrosinate (975 mg, 5 mmol) according to the same procedure as described for compound 28. Compound 43: 760 mg (yield: 50.5%). HRMS C 20 H 23 N2O6(M+H) + Calculated value: 387.1556, measured value: 387.1579. Methyl (S)-2-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-(4-(2-(tert-butoxy)-2-oxoethoxy)phenyl)propanoate (44).

[0138] To a solution of 43 (760 mg, 2 mmol) in 20 mL of ACN was added tert-butyl bromoacetate (390 mg, 2 mmol) and K2CO3 (552 mg, 4 mmol). The mixture was then stirred at room temperature for 3 h and filtered. The filtrate was concentrated, and the residue was purified by FC (EtOAc / hexane = 1 / 1) to give 44 as a colorless oil (yield: 770 mg, 77%). HRMS C 26 H 33 N2O8(M+H) + Calculated value: 501.2237, measured value 501.2143.

[0139] (S)-2-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-(4-(2-(tert-butoxy)-2-oxoethoxy)phenyl)propanoic acid (45). A solution of 44 (770 mg, 1.54 mmol) in 20 mL of MeOH / NaOH (1 N) (1 / 1) was stirred at room temperature for 2 h. HCl (1 N) was then added to the reaction mixture to adjust the pH to 4-5. The resulting mixture was extracted with EtOAc (50 mL × 3). The organic layer was then dried over MgSO and filtered. The filtrate was concentrated, and the residue was purified by FC (DCM / MeOH / NHOH = 90 / 9 / 1) to give 45 as a white solid (yield: 560 mg, 74.8%). HRMS C25 H 31 N2O8(M+H) + Calculated value: 487.2080, measured value: 487.1997.

[0140] tert-Butyl (S)-2-(4-(2-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)phenoxy)acetate (46). Compound 46 was prepared from 45 (560 mg, 1.15 mmol), DIPEA (451 mg, 3.5 mmol), HOBt (291 mg, 1.73 mmol), EDC (328 mg, 1.73 mmol), and 40 (400 mg, 1.11 mmol) following the same procedure as described for compound 28. Compound 46: 760 mg (yield: 79.8%). HRMS C 36 H 55 N4O 14 P2(M+H) + Calculated value: 829.3190, measured value: 829.3320.

[0141] (S)-2-(4-(2-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)phenoxy)acetic acid (47). A solution of 46 (760 mg, 0.92 mmol) in 10 mL of TFA was stirred at room temperature for 5 h. The solvent was removed and the residue was purified by FC (EtOAc) to give 47 as a colorless oil (yield: 320 mg, 45.1%). HRMS C 32 H 47 N4O 14 P2(M+H) + Calculated value: 773.2564, measured value 773.2652.

[0142] Di-tert-butyl(((S)-6-((S)-2-(2-(4-((S)-2-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (48). Compound 48 was prepared from 47 (320 mg, 0.415 mmol), DIPEA (155 mg, 1.2 mmol), HOBt (100 mg, 0.6 mmol), EDC (114 mg, 0.6 mmol), and 10 (261 mg, 0.415 mmol) following the same procedure as described for compound 28. Compound 48: 310 mg (yield: 53.8%). HRMS C 65 H 99 N8O 21 P2(M+H) + Calculated value: 1389.6400, measured value: 1389.6318.

[0143] Di-tert-butyl(((S)-6-((S)-2-(2-(4-((S)-2-(2-aminoacetamido)-3-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (49). Compound 49 was prepared from 48 (310 mg, 0.22 mmol) and Pd / C (60 mg) according to the same procedure as described for compound 32. Compound 49: 250 mg (yield: 90.6%). HRMS C 57 H 93 N8O 19 P2(M+H) + Calculated value: 1255.6032, measured value: 1255.6122.

[0144] Di-tert-butyl(((2S)-6-((2S)-2-(2-(4-((2S)-3-((2-((bis(diethoxyphosphoryl)methyl)amino)-2-oxoethyl)amino)-2-(2-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanamido)acetamido)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (50). Compound 50 was prepared from 49 (230 mg, 0.183 mmol), DIPEA (58 mg, 0.45 mmol), HOBt (38 mg, 0.225 mmol), EDC (43 mg, 0.225 mmol), and DOTAGA-tetra(t-Bu ester) (107 mg, 0.152 mmol) following the same procedure as described for compound 28. Compound 50: 58 mg (yield: 19.7%). HRMS C 92 H 155 N 12 O 28 P2(M+H) + Calculated value: 1938.0549, measured value: 1938.0721.

[0145] (((1S)-1-Carboxy-5-((2S)-2-(2-(4-((2S)-2-(2-(4-carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)acetamido)-3-((2-((diphosphonomethyl)amino)-2-oxoethyl)amino)-3-oxopropyl)phenoxy)acetamido)-3-phenylpropanamido)pentyl)carbamoyl)-L-glutamic acid (51). Compound 51 was prepared from 50 (50 mg, 0.026 mmol), TMSBr (1 mL), DMF (1 mL), and TFA (1 mL) according to the same procedure as described for compound 42. Compound 51: 12 mg (yield: 32.2%). 1HNMR(400 MHz, DMSO) δ: 7.13-7.27(m, 5H), 6.74(d, 2H, J = 8.4 Hz), 6.28-6.34(m, 3H), 4.45-4.57(m, 5H), 4.04-4.11(m, 2H), 3.74-3.94(m, 6H), 3.48-3.61(m, 6H), 3.30-3.32(m, 2H), 2.84-3.10(m, 12H), 2.72-2.74(m, 2H), 2.45-2.47(m, 4H), 2.22-2.28(m, 2H), 1.88-1.97(m, 2H), 1.64-1.74(m, 2H), 1.49-1.53(m, 1H), 1.33-1.38(m, 2H), 1.25-1.29(m, 2H);HRMS C 56 H 81 N 12 O 28 P2(MH) - Calculated value: 1431.4764; measured value: 1431.4543.

[0146] (4S,11S,15S)-4-benzyl-1-(4-((2S)-2-(2-(4-(4,10-bis(carboxymethyl)-7-(1,3-dicarboxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4-carboxylate butanamido)acetamido)-2-carboxyethyl)phenoxy)-2,5,13-trioxo-3,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylate gallium([ nat Ga]4). To a solution of compound 4 (30 mg, 0.0235 mmol) in 1 mL of HO was added 60 μL of GaCl solution (1.13 M). The pH was adjusted to 4-5 by adding 1 N HCl, and the mixture was stirred at 80 °C for 1 h, then purified by semi-preparative HPLC. The solvent was removed under vacuum to give 6.8 mg of a white solid. HRMS C 56 H 76 GaN 10 O 24 Calculated for (M+H)+: 1341.4290, found 1341.4325.

[0147] (4S,11S,15S)-4-benzyl-1-(4-((2S)-2-(2-(4-(4,10-bis(carboxymethyl)-7-(1,3-dicarboxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4-carboxylate butanamido)acetamido)-2-carboxyethyl)phenoxy)-2,5,13-trioxo-3,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylate lutetium([ nat Lu]4). A solution of LuCl3 (0.25 M) in 100 μL of 0.1 N HCl was added to compound 4 (20 mg, 15.7 μmol) in 1 mL of HEPES (0.5 M, pH 5). The mixture was stirred at 98 °C for 10 min and then purified by semi-preparative HPLC. The solvent was removed under vacuum to give 15 mg of a white solid. HRMS C 56 H 76 LuN 10 O 24 Calculated for (M+H)+: 1487.4442, found 1487.4527.

[0148] Example 6 PSMA binding affinity - IC50 evaluation In vitro binding assays were performed to determine the PSMA binding affinity of various compounds by incubating PSMA-positive cells with either: 1) 0.2 nM [ 68 Ga]PSMA-11 or [ 125 nonspecific binding was defined with 20 μM 2-PMPA (2-(phosphonomethyl)pentanedioic acid); or 2) different concentrations of test compound (10 -5 ~10 -10 nM, diluted in PBS containing 0.1% bovine serum albumin) in the presence of [ 125Nonspecific binding (NSB) was defined by incubating PC-3 PIP cells with [I]MIP-1095 (0.18 nM, diluted in PBS) and 2 μM of a known PSMA inhibitor, PSMA-617. After 1 h of incubation at 37°C, bound and free fractions were separated by vacuum filtration through GF / B filters using a Brandel M-24R cell harvester. The filters were washed twice with cold Tris-HCl buffer (50 mM, pH 7.4), and the radioactivity on the filters was counted in a gamma counter (Wizard) at 50% efficiency. 2 , Perkin-Elmer). Nonspecific binding was less than 10% of total binding. Data were analyzed using GraphPad Prism 6.0 with a nonlinear regression algorithm to derive half-maximal inhibitory concentrations (IC 50 ) was obtained.

[0149] The binding affinity of test compounds to PSMA was determined by binding either LNCap or PC-3 PIP cell suspensions with a known radioactive tracer, [ 68 Ga]PSMA-11 or [ 125 The IC values ​​of four iodinated compounds, three DOTA-, DOTAG-, and DOTA(GA)2-related compounds, and two known PSMA inhibitors were measured by competitive binding assay using [I]MIP-1095. 50 The values ​​are shown in Table 1. Complexes of compound 4 as well as native Ga and native Lu were also tested. The results showed that all of the compounds claimed in this application exhibited excellent binding affinity, with IC50 values ​​between 1 and 50 nM. After labeling with radioisotopes, they are predicted to bind to tumor tissues that overexpress the PSMA binding site. [Table 1-1] [Table 1-2]

[0150] Example 7 In vitro cellular uptake [ 177 To determine the cellular uptake of [Lu]-labeled ligand, 5 x 10 5 Cells / well were grown in 12-well plates in 1 mL of medium for 48 hours. Cells were washed twice with PBS, and 900 μL of fresh medium was added. Radiolabeled ligand was added, and a PSMA inhibitor (2-PMPA) was applied at a final concentration of 10 μM to determine nonspecific binding. All samples were prepared in triplicate. After incubation at 37°C, cells were washed twice to remove unbound activity and then dissolved in 1 mL of 0.5 M NaOH. Radioactivity was measured in a gamma counter. An aliquot of the solution added to the cells was also measured for calculation of cellular uptake as ID%. 177 All Lu-labeled ligands showed high specific uptake in the PSMA-positive cell line, PIP PC3. 177 Lu]4 and [ 177 Lu]51 is the reference ligand [ 177 Lu]PSMA-617 showed significantly higher uptake than [Lu]PSMA-617, suggesting that they may have superior PSMA binding and retention. Specific binding was not observed in the PSMA-negative cell line, PC3. [Table 2]

[0151] Example 8 [ 68 Ga]4, 177 Biodistribution of Lu-labeled compounds 4 and 7 in tumor-bearing nude mice 68 Ga labeling: 15 nmol of ligand 4 (1 mg / mL DMSO) was mixed with 20 μL of 2.0 N NaOAc and 500 μL of 68A Ga solution (2.25 mCi) was added. The reaction was heated in a 3 mL sealed vial at 90 °C for 10 min in a heating block. After cooling, the sample was analyzed by HPLC (HPLC: Eclise XDB C18 150 × 4.6 mm, gradient, 2 mL / min; A: 0.1% TFA in water; B: 0.1% TFA in ACN: 0-2 min 100% A; 2-4 min: 0% to 100% B; 4-9 min: 100% B; 9-10 min: 100% to 0% B). 68 The radiochemical purity of [Ga]4 was >99% RCP (Figure 1) and the injected dose was stable at 2 hours after formulation.

[0152] For intravenous injection, 150 μL of labeling solution was diluted to 3 mL with saline. Mice were injected with 150 μL of the formulated dose. The injected radioactivity ranged from 19 to 28 μCi, and the amount of PSMA ligand was constant at 0.2 nmol / mouse.

[0153] 177 Lu labeling: To 10 μg of ligand (1 mg / mL DMSO), add 15 μL of 2.0 N NaOAc, 400 μL of 0.05 N HCl, and 20 μL of 177 Lu solution (780 μCi (Capintec instrument 450 (read x 10)) was added. The reaction was heated in a 3 mL sealed vial at 95 °C for 1 h in a heating block. After cooling, the sample was analyzed by HPLC (HPLC: Eclipse XDB-C18 150 x 4.6 mm, gradient, 1 mL / min; A: 0.1% TFA in water; B: 0.1% TFA in ACN: 0-4 min A / B 85 / 15%; 4-11 min: 85 / 15 to 30 / 70%; 11-14 min: 30 / 70% to 85 / 15%). 177 Lu]4 (Figure 2) and [ 177 The radiochemical purity of [Lu]7 was >98% and the injected dose was stable at 48 hours after formulation.

[0154] For iv injection, 150 μL of labeling solution was diluted to 3.75 mL with saline. Mice were injected with 150 μL of the formulated dose. The injected radioactivity was 100 μCi, and the amount of PSMA ligand was constant at 0.72 nmol / mouse. [Table 3a] [Table 3b] [Table 3c]

[0155] [ 68 Ga]4, [ 177 Lu]4, and [ 177 The biodistribution of [Lu] was determined over 192 hours in nude mice bearing PIP PC3 (PSMA-positive) and PC3 (PSMA-negative) tumors on the left and right shoulders, respectively (Tables 3a, 3b, and 3c). Uptake of these radioligands into PC-3 PIP tumors exhibited very different kinetic profiles. 68 Ga]4 showed excellent tumor uptake, suitable for PET imaging. 177 Lu]4 showed rapid tumor accumulation, reaching 22.38±3.50% dose / g at 4 hours pi. 177 For [Lu], such high tumor uptake (35.34 ± 12.11% of the dose / g) was observed at 24 h, reaching the highest uptake at 48 h, with high levels of radioactivity retained in PIP PC3 tumors. 177 Lu]4 and [ 177 The uptake of [Lu]7 in PC3 tumors (PSMA-negative) was significantly lower than that in PC-3 PIP tumors (PSMA-positive). 177 Lu]4 showed rapid clearance of radioactivity from the blood, resulting in 0.02% dose / g after 4 hours pi, whereas [ 177The clearance of [Lu]7 was slow, resulting in 12.06% dose / g at the same time point. By introducing the 4-(p-iodophenyl) moiety as an albumin binder, [ 177 The high blood circulation of [Lu]7 resulted in unprecedented high tumor uptake and retention over time. 177 Lu]4 and [ 177 These results suggest that [Lu]7 may be useful for radionuclide therapy of prostate tumors that overexpress PSMA binding sites.

[0156] Example 9 in tumor-bearing nude mice 177 Biodistribution of Lu-labeled compounds 42 and 51 177 Lu labeling: 10 μg of ligand (42 or 51, 1 mg / mL in DMSO) was diluted with 15 μL of 2.0 N NaOAc, 400 μL of 0.05 N HCl, and 20 μL of 177 Lu solution (780 μCi (Capintec instrument 450) (read x 10)) was added. The reaction was heated in a 3 mL sealed vial at 95 °C in a heating block for 1 h. After cooling, the sample was analyzed by HPLC (HPLC: Eclipse XDB C18 150 x 4.6 mm, gradient, 2 mL / min; A: 0.1% TFA in water; B: 0.1% TFA in ACN: 0-2 min 100% A; 2-4 min: 0% to 100% B; 4-9 min: 100% B; 9-10 min: 100% to 0% B). 177 Lu]42 or [ 177 The radiochemical purity of [Lu]51 was >98%, and the injected dose was found to be stable 24 hours after formulation. For iv injection, 150 μL of labeling solution was diluted to 3.75 mL with saline. Mice were injected with the 150 μL formulated dose. The injected radioactivity was 100 μCi, and the amount of PSMA ligand was constant at 0.72 nmol / mouse. [Table 4a] [Table 4b]

[0157] Similarly, [ 177 Lu]42 and [ 177 The tissue distribution of [Lu]51 was evaluated over 24 hours in mice bearing PIP PC3 (PSMA-positive) and PC3 (PSMA-negative) tumors on the left and right shoulders, respectively (Table 4). Biodistribution data suggested that both agents showed excellent PIP PC3 (PSMA-positive) tumor uptake; in contrast, PC3 (PSMA-negative) tumors showed very low uptake, as expected. 177 Tumor-specific uptake for [Lu]51 177 This finding was novel and unexpected, suggesting that the position of the bisphosphonate group can significantly affect in vivo biodistribution. Both drugs contain a bisphosphonate group and were found to result in high specific uptake in bone. Bone uptake was also observed in [ 177 Lu]51 was consistently higher. 177 Lu]42 and [ 177 The tissue distribution of [Lu]51 suggested that these two agents could co-target PSMA-positive tumors and possibly localize in foci associated with metastatic tumors within the bone. The results of this study support the use of these dual targeting agents for the treatment of metastatic prostate cancer. 177 The use of Lu labeling agents is recommended.

[0158] Example 10 in tumor-bearing nude mice 125 Biodistribution of I-labeled compounds 17, 18, 26, and 27 Radioiodination and purification: 100 μg of any precursor 13, 14, 22, or 23 was dissolved in 100 μL EtOH; 22 μL Na 125I (1033-1118 μCi in 0.1 N NaOH), 100 μL 1 N HCl, and 100 μL 3% H2O2 were added. After 15 minutes at room temperature, the reaction was stopped by adding 150 μL of saturated NaHCO3. The reaction mixture was slowly added to 1.5 mL of saturated NaHCO3. The vial was rinsed with 1000 μL of EtOH, and the mixture was further diluted with 10 mL of water. The active sample was transferred to an activated C4 mini-column. The mixture was forced through and washed twice with 3 mL of water, and the product was eluted with 1 mL of ACN. 100 μL of DMSO was added. The mixture was concentrated to approximately 100 μL and purified by HPLC (Agilent Eclipse XCD C18 150 × 4.6 mm, 5 μm; 4 mL / min, gradient (ACN and water; 0–1 min (20 / 80), 1–16 min (20 / 80 to 100 / 0), 16–16.5 min (100 / 0 to 20 / 80), 16.5–20 min 20 / 80) (collected every minute). The sample was blown to dryness under argon, redissolved in 500 μL CHCl, and 1 mL of TFA was added at room temperature. After 1 h, the solution was blown to dryness and the radioactivity was taken up in 1 mL EtOH (10 μL of saturated ascorbic acid / EtOH was added). 125 The isolated radioactivity for [I]17, 18, 26, and 27 was 197, 189, 600, and 197 μCi, respectively. Representative photographs of the HPLC profiles for the radiolabeled protected (intermediate), cold standard, and radioactive trace of the final compound (Figure 3) are shown in [ 125 I]26 is shown.

[0159] For i.v. injection, 150 μL of labeling solution was diluted to 3.75 mL with saline. Mice were given 2–3 μCi of [ 125 [I] 18, 27, 26, and 18 in 0.15 mL of saline were injected. The injected radioactivity was 2 to 3 μCi. [Table 5] [Table 6] [Table 7] [Table 8]

[0160] In tumor-bearing nude mice 125 Biodistribution studies of [I]18, 27, 26, and 18 evaluated their ability to localize PSMA-positive tumors (Tables 5, 6, 7, and 8). 125 I]26 and [ 125 I]27 is [ 125 I]17 and [ 125 Higher uptake of PIP was observed in tumors, kidneys, and spleen compared to I18. The results suggested that compounds with higher lipophilicity exhibit stronger binding affinity to PSMA in vivo. 125 I]17 and [ 125 I]26 is [ 125 I]18 and [ 125 Compared with [I]27, PIP showed significantly faster washout in tumors, kidneys, and spleen. Observations indicated that lipophilicity and in vivo biodistribution can be manipulated by adding a lipophilic benzene ring or a hydrophilic glutamic acid to the linker. Liver uptake was low, and [I]27 125 I]18, 27, 26, and 18-PSMA compounds show preferential excretion via the renal system rather than the hepatobiliary route. These new agents, when labeled with beta- or alpha-emitting isotopes, are valuable in radionuclide therapy; however, when labeled with gamma-emitting isotopes, these agents also become useful as diagnostic agents.

[0161] While particular embodiments have been illustrated and described, it is to be understood that changes and modifications may be made thereto by those skilled in the art without departing from the technology in its broader aspects as defined in the appended claims.

[0162] This disclosure is not intended to be limited by the specific embodiments described in this application. Modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the present disclosure, in addition to those recited herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the appended claims, along with the full range of equivalents entitled by such claims. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0163] All publications, patent applications, issued patents, or other documents mentioned herein are incorporated by reference herein as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure. Abbreviation: SPECT, single photon emission computed tomography; PET, positron emission tomography HPLC, high-performance liquid chromatography; HRMS, high-resolution mass spectroscopy; PBS, phosphate-buffered saline; SPE, solid phase extraction; TFA, trifluoroacetic acid; GMP: Good manufacturing practice; NET: neuroendocrine tumor FDG, 2-fluoro-2-deoxy-D-glucose DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid DOTA-TOC, DOTA-D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr-ol DOTA-TATE, DOTA-D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr DOTA-NOC, DOTA-D-Phe-c(Cys-Nal-D-Trp-Lys-Thr-Cys)-Thr-ol NOTA: 1,4,7-triazacyclononane-N,N',N''-triacetic acid NODAGA: 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid DOTAGA: 1,4,7,10-tetraazacyclodosecane, 1-(glutaric acid)-4,7,10-triacetic acid DOTA(GA)2: 1,4,7,10-tetraazacyclodosecane, 1,7-(diglutaric acid)-4,10-diacetic acid TRAP: 1,4,7-triazacyclononane- N,N',N''-tris(methylenephosphonic) acid DEDPA: 1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane AAZTA: 6-[bis(hydroxycarbonyl-methyl)amino]-1,4-bis(hydroxycarbonylmethyl)-6-methylperhydro-1,4-diazepine; EDTMP (Ethylene-diamino-N,N,N',N'-tetrakis-methylene-phosphate) bis-(Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC) [ 11 C]-MCG: [ 11 C](S)-2-[3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid, [ 18 F]DCFBC: N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-[ 18 F]-fluorobenzyl-L-cysteine, [ 18 F]DCFPyL: 2-(3-(1-carboxy-5-[(6-[ 18]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid, PSMA-11 Glu-NH-CO-NH-Lys-(Ahx)-(HBED-CC) PSMA-617: 2-[3-(1-carboxy-5-(3-naphthalen-2-yl-2-[(4-([2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl)-acetylamino]-methyl)-cyclohexanecarbonyl)-amino]-propionylamino)-pentyl)-ureido]-pentanedioic acid GPI 2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentane-1,5-dioic acid 2-PMPA 2-(3-mercaptopropyl)pentanedioic acid References [1] Afshar-Oromieh A, Haberkorn U, Zechmann C, Armor T, Mier W, Spohn F, et al. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with (131)I-MIP-1095. Eur. J. Nucl. Med. Mol. Imaging 2017;44:950-9. [2] Reyes DK, Demehri S, Werner RA, Pomper MG, Gorin MA, Rowe SP, et al. PSMA-targeted [(18)F]DCFPyL PET / CT-avid lesions in a patient with prostate cancer: Clinical decision-making informed by the PSMA-RADS interpretive framework. Urol Case Rep 2019;23:72-4. [3] Giesel FL, Knorr K, Spohn F, Will L, Maurer T, Flechsig P, et al. Detection efficacy of [(18)F]PSMA-1007 PET / CT in 251 Patients with biochemical recurrence after radical prostatectomy. J. Nucl. Med. 2018. [4] Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019. [5] Zha Z, Ploessl K, Choi SR, Wu Z, Zhu L, and Kung HF. Synthesis and evaluation of a novel urea-based (68)Ga-complex for imaging PSMA binding in tumor. Nucl. Med. Biol. 2018;59:36-47. [6] Velikyan I. 68Ga-Based Radiopharmaceuticals: Production and Application Relationship. Molecules 2015;20:12913-43. [7] Banerjee S, Pillai MR, and Knapp FF. Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem. Rev. 2015;115:2934-74. [8] Kostelnik TI and Orvig C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 2018. [9] Ballinger JR. Theranostic radiopharmaceuticals: established agents in current use. Br. J. Radiol. 2018;91:20170969.

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[18] Tsionou MI, Knapp CE, Foley CA, Munteanu CR, Cakebread A, Imberti C, et al. Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling. RSC Adv 2017;7:49586-99.

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[27] Waldron BP, Parker D, Burchardt C, Yufit DS, Zimny M, and Roesch F. Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68. Chem. Commun. (Camb.) 2013;49:579-81.

[28] Pomper MG, Musachio JL, Zhang J, Scheffel U, Zhou Y, Hilton J, et al. 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol. Imaging 2002;1:96-101.

[29] Rowe SP, Gage KL, Faraj SF, Macura KJ, Cornish TC, Gonzalez-Roibon N, et al. (1)(8)F-DCFBC PET / CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer. J. Nucl. Med. 2015;56:1003-10.

[30] Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J. Nucl. Med. 2012;53:1883-91.

[31] Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, et al. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin. Cancer Res. 2011;17:7645-53.

[32] Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, et al. Initial Evaluation of [(18)F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol. Imaging Biol. 2015;17:565-74.

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Claims

1. Formula I: 【Chemistry 68】 or a pharmaceutically acceptable salt thereof, During the ceremony, Z is a chelating moiety 【Chemical 74】 and A １ is a bond or a divalent linking moiety containing from 1 to 20 carbon atoms in a chain, ring, or combination thereof, in which one or more carbon atoms are unreplaced or are O, —NR ４０ - or -C(O)-; B １ H, 【Chemistry 75】 and where c is an integer from 1 to 4; X １ is a bond, O, S, or —NR ４１ - and; D is 【Chemistry 75-1】 selected from the group consisting of: W is a PSMA targeting ligand, W is 【Chemistry 80】 where R ２０ and R ２１ are each independently an amino acid residue linked through its amino group to an adjacent —C(O)— group, or 【Chemistry 80】 where R ２ is hydrogen or a carboxylic acid protecting group, x is an integer from 1 to 6, and y is an integer from 1 to 4; the carboxylic acid protecting group is selected from a methyl ester, a t-butyl ester, a benzyl ester, and an allyl ester; Each T １ is independent, T １１ or T １２ : 【Chemistry 70】 The structure is as follows: Here, R ２３ Ha-(CH ２ ) ａ CO ２ H, and a is an integer from 0 to 4; Each T ２ is independent, T ２１ or T ２２ : [Chemical Formula 71] The structure is as follows: where b is an integer from 1 to 6, and G １ is O, S, or NR ３ and q is 0, 1, 2, or 3; r is 0, 1, or 2; A ２ is a bond or a divalent linking moiety containing from 1 to 20 carbon atoms in a chain, ring, or combination thereof, in which one or more carbon atoms are unreplaced or are O, —NR ４０ - or -C(O)-; B ２ H, 【Chemical Formula 72】 and where c is an integer from 1 to 4; G is O, S, or NR ３ and X ２ is O, S, or -NR ４１ - and; R ３ , R ４０ , and R ４１ each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl; R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , and R ３６ each is independently hydrogen, alkyl, alkoxyl, or halogen; R ３７ and R ３８ each is independently hydrogen, alkyl, aryl, or alkylaryl; Each R ３９ is independently selected from the group consisting of alkyl, alkoxyl, halogen, haloalkyl, and CN; s is 1; v is an integer from 0 to 4, and when v is greater than 1, each R ３９ are the same or different compounds, or pharmaceutically acceptable salts thereof.

2. D is, 【Chemical 77】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

3. W has the structure: 【Chemistry 80】 of; R ２０ and R ２１ are each independently an amino acid residue linked to an adjacent —C(O)— group via its amino group, 3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.

4. W has the structure: 【Chemistry 81】 of; R ２ is hydrogen or a carboxylic acid protecting group; the carboxylic acid protecting group is selected from methyl ester, t-butyl ester, benzyl ester and allyl ester; 3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.

5. R ３７ａ is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl, 【Chemistry 82】 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. Formula I-B: 【Chemistry 83】 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof.

7. R ３７ａ is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl; 【Chemistry 84】 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ３７ａ is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl, and q is 1 or 2; 【Chemistry 85】 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

9. Z is 【Hua 88】 and A １ is a bond or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, wherein one or more carbon atoms are unreplaced or replaced with O, —NH—, or —C(O)—; B １ H, 【Chemistry 89】 and where c is 3, X １ is a bond, O, or —NH—; D is 【Chemistry 90】 9. The compound of any one of claims 1 to 8, wherein:

10. R ３７ａ is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl; 【Chemistry 91】 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

11. Formula III-B: 【Chemistry 92】 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

12. Formula IV-A: 【Chemistry 93】 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

13. Formula IV-B: 【Chemistry 94】 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

14. R ３７ａ 12. The compound of any one of claims 5 to 8 and 10 to 11, wherein is unsubstituted or substituted phenyl.

15. X １ The compound according to any one of claims 1 to 11 and 13 to 14, or a pharmaceutically acceptable salt thereof, wherein is O or -NH-.

16. X ２ The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is O or -NH-.

17. A １ and A ２ Each of ２ ) ｎ -, -(CH ２ ) ｎ C(O)O-,-(CH ２ ) ｎ C(O)NH-,-(CH ２ CH ２ O) ｎ - or -(CH ２ CH ２ O) ｎ (CH ２ CH ２ NH) ｎ - and; each n is independently 1, 2, 3, or 4; 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. A １ is a bond, -(CH ２ ) ｎ C(O)NH-, or -(CH ２ CH ２ O) ｎ (CH ２ CH ２ NH) ｎ 18. The compound of claim 17, wherein: -, or a pharmaceutically acceptable salt thereof.

19. A １ is a bond, -(CH ２ )C(O)NH—, or —(CH ２ CH ２ O) ２ (CH ２ CH ２ 19. The compound of claim 18, wherein R is C(CH 2 )-, or a pharmaceutically acceptable salt thereof.

20. A ２ is a bond or -(CH ２ ) ｎ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: C(O)NH-; and n is 1, 2, or 3.

21. A ２ is a bond or -(CH ２ 21. The compound of claim 20, wherein:

22. structure: 【Chemistry 95】 【Chemistry 96】 or 【Chemistry 97】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

23. 23. A complex comprising a compound according to any one of claims 1 to 22 and a metal M chelated to the chelating moiety of said compound, wherein M is ２２５ Ac, ４４ Sc, ４７ Sc, ２０３／２１２ Pb, ６７ Ga, ６８ Ga, ７２ As, ９９ｍ Tc, １１１ In, ９０ Y. ９７ Ru, ６２ Cu, ６４ Cu, ５２ Fe, ５２ｍ Mn, １４０ La, １７５ Yb, １５３ Sm, １６６ Ho, １４９ Pm, １７７ Lu, １４２ Pr, １５９ Gd, ２１３ Bi, ６７ Cu, １１１ Ag, １９９ Au, １６１ Tb, and ５１ Cr.

24. structure: 【Chemistry 100】 24. The complex of claim 23, or a pharmaceutically acceptable salt thereof.

25. X １ is O or —NH—; X ２ is O or —NH—; A １ is a bond, -(CH ２ )C(O)NH—, or —(CH ２ CH ２ O) ２ (CH ２ CH ２ NH)—; A ２ is a bond or -(CH ２ )C(O)NH—; B １ and B ２ each of which is independently H, 【Chemistry 101】 25. The complex of claim 24, wherein:

26. M ６８ Ga or １７７ 26. The complex of any one of claims 23 to 25, wherein Lu is Zn, or a pharmaceutically acceptable salt thereof.

27. structure: 【Chemistry 102】 【Chemistry 103】 24. The complex of claim 23, or a pharmaceutically acceptable salt thereof.

28. 28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or complex of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

29. 28. A composition for use in a method of imaging in a subject, comprising the compound or complex of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, said method comprising administering said composition to said subject; and obtaining an image of said object or a portion of said object; A composition comprising:

30. 30. The composition of claim 29, wherein the method comprises obtaining an image with a device capable of detecting positron emission.

31. 28. A composition for use in a method of in vivo imaging comprising the complex of any one of claims 23 to 27 or a pharmaceutically acceptable salt thereof, the method comprising administering the composition to a subject and detecting a pattern of radioactivity of the complex in the subject.

32. 28. A composition for treating one or more tumors in a subject, comprising a compound or complex according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

33. 23. A kit comprising a sterile container containing an effective amount of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and instructions for therapeutic use.

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