Metal / radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy

Abstract

This invention provides compounds useful for imaging, diagnosing, or treating one or more prostate-specific membrane antigen (PSMA) tumors or cells. [Solution] The following compounds or pharmaceutically acceptable salts thereof are used. JPEG2026082844000061.jpg48150 In the formula, Q is H or a protecting group, X1 and X2 are NH or O, and R 1 R is a C1-C4 alkyl group substituted with a halogen-substituted aryl group, 2 and R 4 is H or C1-C4 alkyl, and each R 3 is H, C1-C6 alkyl or C6-C 12 It is an aryl group, W is O or S, Y is, for example, -NH-, L is a linker, and Ch is a chelated moiety that may contain one or more non-radioactive or radioactive metals.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 61 / 989428 and 2014, filed on May 6, 2014. This is a claim for the benefits of application No. 62 / 117603 filed on February 18, 2015, and each document All references are incorporated herein by reference.

[0002] Research or development funded by the federal government This invention was approved by the National Institutes of Health (NIH) as K25CA148901-01A1 and U This was done with government support provided under 54CA1346751. The government provided support for this invention. They have certain rights in that regard. [Background technology]

[0003] Prostate-specific membrane antigen (PSMA) is used for imaging and treatment of prostate and other types of cancer. It is increasingly being recognized as a highly feasible target for this purpose (Ghosh and Heston) ,2004;Milowsky et al.,2007;Olson et al., (2007). PSMA, particularly hormone-resistant, is used in prostate cancer and metastasis. Significantly overexpressed (Ghosh and Heston, 2004; Milowsky) et al., 2007). PSMA is expressed in most solid tumors and neovascular tumors. It is also known as (Haffner et al., 2012; Haffner et al., 2009). Imaging PSMA allows for the study of androgen signaling. Evans et al., 2011) and response to taxane therapy (Hillier Insights can be gained regarding et al., 2011). Previous research has shown that Experimental models of prostate cancer (Schulke et al., 2003; Mease et al.) al., 2013; Banerjee et al., 2010) and clinics (Cho et al.,2012;Kulkarni et al.,2014;Zechma Functionalized cysteine-glutamate or lysine- We are performing radionuclide imaging targeting PSMA using glutamate urea. Large molecular fragments, such as radioactive metals ( 99m Tc, 68 Ga, 111 In, 86 Y, 20 3 Pb, 64 Cu complex (Banerjee, Pullambhatla, Shallal ,et al.,2011;Banerjee,Pullambhatla,Byun, et al., 2011; Banerjee et al., 2008) and nanoparticles ( (Chandran et al., 2008; Kam et al., 2012) To achieve this, a long linker is placed between the large molecule and the target urea, thereby targeting PSMA. The binding was maintained. While not attempting to confine to a specific theory, the ligand-binding site is extracellular. It is estimated that there is a high receptor concentration per cell (approximately 3.2 μM / cell volume). Therefore, PSMA is considered suitable as a biomarker for MR molecular imaging. It was done.

[0004] MR imaging is a clinical technique for performing high-resolution anatomical and functional imaging. It is a non-invasive diagnostic tool related to [the condition]. Molecular MR imaging is used in vivo. Enables visualization of biological markers (Artemov, Mori, Okollie) et al.,2003;Artemov,Mori,Ravi,Bhujwalla ,et al.,2003;Konda et al.,2001;Lanza et al. al., 2004; Huang, et al., 2013). Gd(III) type cont. Last-chain drugs are widely accepted by clinicians because they are easy to administer and also T1-weighted. This is because it allows for positive contrast. The design of high-relaxation contrast agents has advanced. However, sensitivity remains a limiting factor for molecular MR imaging. Regarding its use in imaging applications (specifically, imaging of receptor or protein expression), Gd(III) type contrast agents rarely exceed the detection limit (Artem ov,Mori,Okollie et al.,2003;Artemov,Mori ,Ravi,Bhujwalla,et al.,2003;Konda et al. ,2001;Lanza et al.,2004;Huang et al.,201 3) By using signal amplification methods, MR complements radionuclide-based techniques, specifically molecular MRI. This may be a highly sensitive modality for imaging (Aime et al.) .,2004;Major et al.,2009;Song et al.,200 8; Artemov, 2003). Even if the sensitivity of the target substance can be improved by amplification, simple The shift from low molecular weight compounds to larger complexes alters the pharmacokinetic profile of substances. There is a possibility that it will change significantly (Artemov, Mori, Okollie e t al.,2003;Artemov,Mori,Ravi,Bhujwalla,e t al.,2003;Konda et al.,2001;Lanza et al. .,2004; Huang, et al.,2013). Sherry et al. found it to be extremely high Binding affinity (K d ) has the ability to minimize the amount of substance required for detection by MR. We addressed the sensitivity problem by creating a contrast agent that works (Hanaoka et al., 2008; De Leon-Rodriguez et al., 2010) As one solution to enable MR-based receptor imaging, It was devised to combine a body-specific high-affinity ligand with the detection polymer Gd(III). (Wu et al. 2012).

[0005] An example of this approach is using a multimer Gd-dendron with a high longitudinal relaxation (r1) value. This includes molecular imaging of VEGFR2 through preparation (De Leon-Ro (driguez et al., 2010). In other polymeric materials, at higher magnetic field strengths... Improved r1 values ​​have been reported, but this is because MR is in both experimental and clinical settings. This is because the magnetic field at Meising is getting stronger (Masterone 2011). By optimizing the degree of relaxation in the field, a larger signal-to-noise ratio and contrast-to-noise ratio can be achieved. This offers advantages such as a higher signal-to-noise ratio (SNR / CNR), higher spatial resolution, and shorter gaps. It also comes with the benefit of free time (Rooney 2007). The combination, that is, using the high-affinity target portion together with a highly sensitive multimer contrast agent. This involves targeting MR imaging of cells and tissues expressing prostate-specific membrane antigen (PSMA). This provides a logical basis for investigating the issue.

[0006] Furthermore, urea-based substances may also be used for radiotherapy of lesions containing PSMA using radionuclides. It is thought that this might be possible. In fact, 131 I] MIP1095 ((S)-2- (3-((S)-1-carboxy-5-(3-(4- 131 I] iodophenyl)ureido)phenyl)ureido)pentaanedioic acid) (Zechmann et al., 2014 ) and and 177 Lu-labeled PSMA targeting substances (Kulkarni et al., 2014) clinical studies using that approach are in progress for the treatment of castration-resistant prostate cancer. This approach is similar to radioimmunotherapy (RIT), which has been proven to be extremely effective in the treatment of lymphoma with two commercially available products routinely incorporated into clinical practice. However, due to the use of radiolabeled antibodies for imaging, RIT is associated with difficulties, including a long circulation time, unpredictable biological effects, and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy. and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy. and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy. and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy. and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy. and in some cases the need for a pretargeting method. Furthermore, antibodies may be less accessible to tumors than pharmacologically manipulable low-molecular-weight substances. Therefore, low-molecular-weight compounds with high binding affinity for PSMA are still needed for tumor imaging and radiotherapy.

[0007] Positron-emitting radionuclides 86 Y (half-life [t 1 / 2 = 14.74 hours, β + = 33%, E β+ = 664 keV) is an attractive isotope for molecular imaging (Nayak and Brechbiel, 2011). Yttrium-86 is 86Sr(p,n) 86 It can be easily prepared using a small medical cyclotron with the Y nuclear reaction (Yoo e (t al., 2005). High-energy β - Radiator 90 Y(t 1 / 2 = 64.06 hours, β - = 72%, E β- (=2.288 MeV) is widely used in internal radiation therapy (Wi Tzig et al., 2003; Bodei et al., 2004), 86 Y is 90 It is ideal for dose estimation of Y-labeled radiotherapy (Helisch et al. .,2004). 86 Antibodies and peptides radiolabeled with Y are 90 Same properties as those labeled with Y Because it has the properties of radiation therapy, 90 It is possible to accurately estimate the absorbed dose for Y. (Nayak and Brechbiel, 2011; Palm et al., 2 003). 177 Lu 90 Beta particle range shorter than Y (t 1 / 2 =6.7 days, E β- = 0.5 MeV ) has similar chelating properties, 90 Not only those that are radially labeled with Y, but also , potential 177 Suitable imaging alternatives for investigating Lu-based radiotherapy and as 86 Y is proposed. A similar theoretical basis is found in the radioactive nucleus of neuroendocrine target peptide receptors. It is also applied to substances used for various therapeutic purposes (Chen et al., 2012). Using this approach, potential matched pair images suitable for SPECT imaging Radioactive isotopes 203Pb (half-life, 51.9 hours, E β- =279-keV gamma rays, 81% ) are therapeutic radionuclides for alpha particle therapy. 212 Can be used with Pb (Chappe ll,et al.2000;Yong,et al.2011;Yong,et al. 2012; Yong, et al. 2013). 212 The Pb collapse scheme includes 212 Bi It contains alpha particles, two beta particles, and some gamma rays when it decays. Alpha particle emitters are local Due to local high-density ionization and other high linear energy transfer characteristics (to an irreparable degree of D (This results in disruption of NA double strands and cytotoxicity that is independent of tissue oxygen content or dose rate), It is particularly attractive for targeted radiotherapy (McDevitt, et al, 1998). 212 Pb and 212 Both Bi possess radiochemical properties that have been well discussed regarding antibody binding. It is a promising source of alpha particles for the future, and 224 It can be easily obtained with an Ra generator.

[0008] Similarly, radiohalogens that showed high binding affinity to PSMA in vitro. Carbamate-based PSMA inhibitors have also been developed and are radiolabeled with the positron emitter F-18. When this occurs, high uptake and normal in PSMA-positive mouse tumor xenografts It showed rapid clearance from tissue. The pharmacokinetic profile of this class of compounds is favorable. Because it has little nonspecific binding (that is, it is not metabolized in vivo), (With a reasonable tumor residence time), imaging research extends to molecular radiotherapy. Carbamate inhibitors utilize linker functionality similar to urea-based metal / radioactive metal substances. By using this method to couple with metal chelating materials, PSMA achieves high binding affinity. It can maintain metal or radioactive metal conjugate carbamates Caffolds can also be used for imaging and therapy of PSMA-expressing cells and tissues. [Overview of the project]

[0009] In some embodiments, the subject matter of this disclosure is formula (I):

[0010] [ka] (I)

[0011] The present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein Z is tetrazole or CO2Q Q is H or a protecting group, X1 and X2 are independently NH or O, and a c is an integer selected from the group consisting of 1, 2, 3, and 4, and c is 0, 1, 2, 3, and 4. An integer selected from the group consisting of R, where each R 1 , R 2 and R 4 These are independently H or C1-C4 Kills, each round 3 These are independently H, C1-C6 alkyl, or C2-C 12 It is Ariel, and W is Independently, O or S, Y is -NH- and can be present or absent, and L is a linker —and the linker,

[0012] [ka]

[0013] Selected from the group consisting of , where m is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8. The integer to be selected, and each R 5 H or each R6 These are independently H or C1-C6 Kill - COOR 6 And n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. An integer selected from the group consisting of the following, where Ch may contain one or more metals or radioactive metals. This is the chelated portion.

[0014] In other embodiments, the subject matter of this disclosure is one or more prostate-specific membrane antigen (PSMA) tumors. Or provides a method for imaging or treating cells, the method for one or more tumors or This involves contacting cells with an effective amount of the compound of formula (I) to form an image.

[0015] Regarding specific aspects of the subject matter of this disclosure that have been addressed in whole or in part by the subject matter of this disclosure As described above, the accompanying embodiments and drawings, which will be explained in more detail later, will be further explained. As time goes on, other aspects will become clear. Therefore, having given a general overview of the subject matter of this disclosure, please refer now to the attached drawings. The drawings are not necessarily to scale. [Brief explanation of the drawing]

[0016] [Figure 1A] (A) The structures of Gdl, Gd2, and Gd3, and (B) the IC50 curve. [Figure 1B] (A) The structures of Gdl, Gd2, and Gd3, and (B) the IC50 curve. [Figure 2] The concentrations of Gdl to Gd3 in PC3 PSMA-flu (blue) and PC3 PSMA+PIP (red) cell pellets are shown. Data were obtained from ICP-MS analysis. [Figure 3]This shows the percentage (%ID) of the internally transferred and cell surface-bound incubation doses (incubated dose) for Gd1 and Gd2. Data were obtained from ICP-MS analysis. [Figure 4A] This study shows Gd3-induced T1 contrast enhancement in isogenic human PC3 prostate cancer cell pairs, PSMA+PIP, and PSMA-flu cells. (A) Color-coded T1 maps of PIP and flu cells. Relaxation rate was determined at 25°C and 9.4T. (B) Quantification of T1 change (ΔT1) in PIP and flu cells following Gd3 treatment (n=4, P<0.05). (C) Cell uptake of Gd3 in RIP and flu cells. The amount of Gd(III) associated with PIP cell pellets was significantly higher than in flu cell pellets. Gd3 accumulation in PIP cells was blocked by prior incubation with ZJ43 (n=4, P<0.05). [Figure 4B] This study shows Gd3-induced T1 contrast enhancement in isogenic human PC3 prostate cancer cell pairs, PSMA+PIP, and PSMA-flu cells. (A) Color-coded T1 maps of PIP and flu cells. Relaxation rate was determined at 25°C and 9.4T. (B) Quantification of T1 change (ΔT1) in PIP and flu cells following Gd3 treatment (n=4, P<0.05). (C) Cell uptake of Gd3 in RIP and flu cells. The amount of Gd(III) associated with PIP cell pellets was significantly higher than in flu cell pellets. Gd3 accumulation in PIP cells was blocked by prior incubation with ZJ43 (n=4, P<0.05). [Figure 4C]This study shows Gd3-induced T1 contrast enhancement in isogenic human PC3 prostate cancer cell pairs, PSMA+PIP, and PSMA-flu cells. (A) Color-coded T1 maps of PIP and flu cells. Relaxation rate was determined at 25°C and 9.4T. (B) Quantification of T1 change (ΔT1) in PIP and flu cells following Gd3 treatment (n=4, P<0.05). (C) Cell uptake of Gd3 in RIP and flu cells. The amount of Gd(III) associated with PIP cell pellets was significantly higher than in flu cell pellets. Gd3 accumulation in PIP cells was blocked by prior incubation with ZJ43 (n=4, P<0.05). [Figure 5A] (A) Fluorescence imaging shows the cellular uptake and internal translocation of Gd1-Rh. PSMA+PC3 PIP and PSMA-PC3 flu cells were incubated with serially diluted Gdl-Rh (4 μM to 4 nM) solutions at 37°C for 30 minutes, followed by removal of excess contrast agent with cold PBS. Magnified views of PC3 PIP (B) and PC3 flu (C) at a contrast agent concentration of 4 nM. Rhodamine fluorescence is shown in red, and nuclei counterstained with DAPI are shown in blue. (D) Structure of Gd1-Rh. [Figure 5B] (A) Fluorescence imaging shows the cellular uptake and internal translocation of Gd1-Rh. PSMA+PC3 PIP and PSMA-PC3 flu cells were incubated with serially diluted Gdl-Rh (4 μM to 4 nM) solutions at 37°C for 30 minutes, followed by removal of excess contrast agent with cold PBS. Magnified views of PC3 PIP (B) and PC3 flu (C) at a contrast agent concentration of 4 nM. Rhodamine fluorescence is shown in red, and nuclei counterstained with DAPI are shown in blue. (D) Structure of Gd1-Rh. [Figure 5C](A) Fluorescence imaging shows the cellular uptake and internal translocation of Gd1-Rh. PSMA+PC3 PIP and PSMA-PC3 flu cells were incubated with serially diluted Gdl-Rh (4 μM to 4 nM) solutions at 37°C for 30 minutes, followed by removal of excess contrast agent with cold PBS. Magnified views of PC3 PIP (B) and PC3 flu (C) at a contrast agent concentration of 4 nM. Rhodamine fluorescence is shown in red, and nuclei counterstained with DAPI are shown in blue. (D) Structure of Gd1-Rh. [Figure 5D] (A) Fluorescence imaging shows the cellular uptake and internal translocation of Gd1-Rh. PSMA+PC3 PIP and PSMA-PC3 flu cells were incubated with serially diluted Gdl-Rh (4 μM to 4 nM) solutions at 37°C for 30 minutes, followed by removal of excess contrast agent with cold PBS. Magnified views of PC3 PIP (B) and PC3 flu (C) at a contrast agent concentration of 4 nM. Rhodamine fluorescence is shown in red, and nuclei counterstained with DAPI are shown in blue. (D) Structure of Gd1-Rh. [Figure 6A] The %IDs shown are (A) Gd3 bound to the cell surface and (B) Gd3 translocated internally after 1, 4, and 24 hours. [Figure 6B] The %IDs shown are (A) Gd3 bound to the cell surface and (B) Gd3 translocated internally after 1, 4, and 24 hours. [Figure 7] This study describes the viability of PSMA-PC3 flu cells incubated with Gd1, Gd2, Gd3, and ProHANS. Cells were incubated with contrast agents at various Gd concentrations at 37°C for 24 hours, and viability was measured using the MTS assay. Viability measurements were normalized to match cells grown in the absence of the contrast agent. [Figure 8] This study describes the viability of PSMA+PC3 PIP cells incubated with Gd1, Gd2, Gd3, and ProHANS (Gd-DOTA). Cells were incubated with contrast agents at various Gd concentrations at 37°C for 24 hours, and viability was measured using the MTS assay. The viability measurements were normalized to match cells grown in the absence of the contrast agent. [Figure 9A-B]This image shows Gd3 MR imaging of human PC3 prostate cancer PSMA+PIP and PSMA-flu tumor xenografts in male NOD / SCID mice. (A) Enhancement (ΔR1%) maps in PSMA+PC3 PIP and PSMA-PC3 flu tumors are overlaid on T2-weighted images at 40, 80, 120, and 160 minutes after a single bolus injection of Gd3 into the tail vein. (B) ΔR1% maps of a trimer Gd contrast agent without a PSMA target region in PSMA+ and PSMA- tumors at 40, 80, 120, and 160 minutes after a single bolus injection of Gd3 into the tail vein. [Figure 10A] (A) T1 time course calculated for the total volume of each tumor between 1 and 1600 minutes after injection, and (B) the area of ​​expansion over time from 0 to 200 minutes. Highly specific and sustained enhancement in PSMA+PC3 PIP tumors was noted. [Figure 10B] (A) T1 time course calculated for the total volume of each tumor between 1 and 1600 minutes after injection, and (B) the area of ​​expansion over time from 0 to 200 minutes. Highly specific and sustained enhancement in PSMA+PC3 PIP tumors was noted. [Figure 11] The percentage change in relaxation (%ΔR1) in mice after injection of Gd3 at a dose of 0.05 mmol / Kg (n=3) is shown (p<0.03, PIP:flu). [Figure 12] This shows the time-dependent in vivo changes in T1 values ​​of a tumor (n=1) before and after injection of 1x PBS (phosphate-buffered saline). [Figure 13A-B] (A) Selected MR image shown in Figure 11, (B) Structure of Gd3. [Figure 14] The structure of the 86Y-labeled inhibitor of PSMA is shown. [Figure 15A] The preparative HPLC chromatogram for [86Y]4 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 18.6 min is for unchelated 4 at λ=254 nm. [Figure 15B]The preparative HPLC chromatogram for [86Y]4 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 18.6 min is for unchelated 4 at λ=254 nm. [Figure 16A] The preparative HPLC chromatogram for [86Y]5 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 34 min is for unchelated 5 at λ=254 nm. [Figure 16B] The preparative HPLC chromatogram for [86Y]5 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 34 min is for unchelated 5 at λ=254 nm. [Figure 17A] The preparative HPLC chromatogram for [86Y]6 is shown. (A) Radioactive HPLC peaks, (B) UV peak at 15.8 min is for unchelated 6 at λ=220 nm. (C) HPLC chromatogram for pure [86Y]6. [Figure 17B] The preparative HPLC chromatogram for [86Y]6 is shown. (A) Radioactive HPLC peaks, (B) UV peak at 15.8 min is for unchelated 6 at λ=220 nm. (C) HPLC chromatogram for pure [86Y]6. [Figure 17C] The preparative HPLC chromatogram for [86Y]6 is shown. (A) Radioactive HPLC peaks, (B) UV peak at 15.8 min is for unchelated 6 at λ=220 nm. (C) HPLC chromatogram for pure [86Y]6. [Figure 18A-C] The images show whole-body PET-CT imaging of mice with PSMA+PC3 PIP and PSMA-PC3 flu tumors (A)86Y-4, (B)86Y-5, and (C)86Y-6, 2 hours after injection. Approximately 3.3 mBq (90 μCi) of radioactive tracer was intravenously (IV) injected into the mice. PSMA+PC3 PIP (solid arrows), PSMA-PC3 flu (white arrows), K=kidney, GB=gallbladder, GI=gastrointestinal tract, L=left, R=right. Images have been decay-corrected and adjusted to the same maximum value. [Figure 19A-C]PET-CT imaging of [86Y]-4 in mice with PSMA+PC3 PIP and PSMA-PC3 flu tumors is shown. Images were obtained with (A) no PSMA blockade and (B) PSMA blockade using ZJ43, a potent and selective PSMA inhibitor, as a blocker (50 mg / kg). PSMA-specific binding was further checked by the reduction in uptake of the radiotrace in both the tumor and the kidney (another PSMA+ site) when treated with ZJ43. Mice were intravenously injected with approximately 6.2 MBq (168 μCi) of the radiotrace. PSMA+PC3 PIP (solid arrow), PSMA-PC3 flu (white arrow). K=kidney, B=bladder, L=left, R=right. Images have been decay-corrected and adjusted to the same maximum value. Figure 19C shows the structure of the potent and selective PSMA inhibitor ZJ43. [Figure 20A-C] (A) 0.5 hours after injection, (B) 2 hours after injection, and (C) 12 hours after injection are shown PET-CT images of 86Y-6 in mice with PSMA+PC3 PIP and PSMA-PC3 flu tumors. Approximately 6.2 MBq (160 μCi) of radioactive tracer was intravenously injected into the mice. PSMA+PC3 PIP (solid arrow), PSMA-PC3 flu (white arrow), K=kidney, L=left, R=right. Images have been attenuated and adjusted to the same maximum value. [Figure 21A-B] (A) shows 3D time-course MIP (Maximum Projection) screens of 86Y-6PET in baboons 1–2 hours after injection and (B) shows 2–3.5 hours after injection. To enhance visualization, bladder radioactivity was semi-automatically partitioned and subsequently removed using a thresholding method. MIP 3D rendering was used to survey the distribution of radioactive tracers throughout the body. Radioactive tracers were not observed in most normal tissues, except in the bladder (not shown) and kidney (K). Catheters were inserted into rats for this study. Mild uptake in the lacrimal gland, parotid gland, and salivary gland was noted (short arrow, long arrow, and white arrow, respectively). [Figure 22] The structures of 177Lu-SRV171 and related proposed substances for further improving in vivo pharmacokinetics are shown. [Figure 23] The percentage of incubation dose (ID) for 177Lu-SRV171 (0.01-10 μCi / 1 million cells) of PSMA+PIP and PSMA-flu cells at 37°C after 2 hours is shown. Uptake specificity was further checked by co-incubation with 10 μM ZJ43. [Figure 24] This study shows the internal migration of 177Lu-SRV171 (1μCi) for up to 24 hours. [Figure 25A-C] SPECT images of male mice with PIP and flu tumors treated with 177Lu-SRV171 (500 μCi) at (A) 2 hours after injection, (B) 24 hours after injection, and (C) 96 hours after injection are shown. Low uptake was observed in the kidney (K), bladder (B), and flu tumors. [Figure 26] The intracellular distribution of 177Lu-SRV171 in different organs 3, 24, 48, 72, and 96 hours after injection is shown. [Figure 27] The structures of 203Pb-SR-IX-II and 203Pb-SRV171 are shown. [Figure 28A] (A) SPECT-CT images of male mice with PIP and flu tumors treated with 203Pb-SRV171 (left) and 203Pb-SR-IX-II (right) at 60 minutes, 120 minutes, and 240 minutes after injection are shown. [Figure 28B] (A) SPECT-CT images of male mice with PIP and flu tumors treated with 203Pb-SRV171 (left) and 203Pb-SR-IX-II (right) at 60 minutes, 120 minutes, and 240 minutes after injection are shown. [Figure 28C] (A) SPECT-CT images of male mice with PIP and flu tumors treated with 203Pb-SRV171 (left) and 203Pb-SR-IX-II (right) at 60 minutes, 120 minutes, and 240 minutes after injection are shown. [Figure 29]Two lysine-carbamate scaffolds used in the design of the subject matter compounds of this disclosure are shown: oxypentanediic acid (OPA), corresponding to the carbamate scaffold, and aminopentanediic acid (NPA), corresponding to the "reverse" carbamate scaffold. [Figure 30] The HPLC chromatogram of ZCP-01 is shown. [Figure 31] The electrospray ionization mass spectrometry (ESI-MS) results for low-temperature [In]ZPC-01 are shown. [Figure 32] The HPLC chromatogram of low-temperature [In]ZCP-01 is shown. [Figure 33A] [In] The preparative HPLC chromatogram of ZCP-01 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 32 minutes is for unchelated ZCP-01 at λ=200 nm. [Figure 33B] [In] The preparative HPLC chromatogram of ZCP-01 is shown. (A) Radioactive HPLC peaks. (B) The UV peak at 32 minutes is for unchelated ZCP-01 at λ=200 nm. [Figure 34A-C] The uptake of [111In]ZCP-01 in mice with PSMA+PC3 Pip and PSMA-PC flu tumor xenografts at (A) 2 hours, (B) 4 hours, and (C) 24 hours after injection is shown. [Modes for carrying out the invention]

[0017] The subject matter of this disclosure will now be described in more detail with reference to the accompanying embodiments and drawings. This is to clarify that these are illustrative examples of, but not all, embodiments of the subject matter of this disclosure. The subject matter of the disclosure can be embodied in numerous different forms and is not limited to the embodiments described herein. It should not be interpreted that way. Rather, these embodiments do not fulfill the legal requirements to which this disclosure applies. It is presented to satisfy this. In fact, a person skilled in the art in which the subject matter of this disclosure relates would know this. The teachings presented in this specification, as described and related examples and drawings, have merit. Numerous modifications and other embodiments of the subject matter of this disclosure can be conceived. The subject matter is not limited to the specific embodiments of the disclosure, nor does it include modifications and other embodiments. Please understand that this is included within the scope of the attached claims.

[0018] I. Metal / radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy Harmful agents Because it can obtain anatomical, functional, and molecular information simultaneously, magnetic resonance (MR) imaging The approach is advantageous. MR molecular imaging is an established and widely used clinical method. Combining modalities and their high spatial resolution with molecular profiling in vivo It is possible to do so. However, because the sensitivity of MR is inherently low, recognizable MR devices High local concentrations of biological targets are required to generate trusts.

[0019] While I don't want to be bound by any particular theory, PSM is relevant to MR molecular imaging agents. A was considered a good target because it had a high target concentration per cell (approximately 3 μM / cell body). This is because the ligand binding site is located extracellularly. The approach described herein is for MR detection To reduce the amount of agent required for extraction, contrast against specific molecules or cellular targets Binding affinity of the drug (minimum K d The purpose is to improve ). Therefore, the app of this disclosure Roach considers high binding parent as one possible solution for MR-based molecular imaging. A harmonious receptor-specific ligand is combined with a multimeric Gd(III) substance.

[0020] To date, PET based on radioactive metals (64 cu) and SPECT( 111 In addition Beauty 99m Tc) Imaging in mice using radiolabeled urea-based PSMA inhibitors This has been successfully carried out using (i) the PSMA target portion, and (ii) pharmacological adjustments. (iii) a linker and a 3-molecule solution containing a chelating agent that enables the attachment of radionuclides. A strategy has been developed. This strategy is for PET imaging and is compatible with ru 90 It serves as a model for radiotherapy using Y-labeled materials. 86 Y sign DOTAcon It contained a jugate substance. DOTA is a powerful chelating agent for many metals. The same DOTA conjugate can be used with other radioactive radionuclides for radiotherapy, such as Lu-177, A c-225, Bi-213, Bi-212, Pb-212, Cu-67 and Sc-47 It can be used. In the subject matter of this disclosure, the same urea linker construct can be used. By using this method and increasing the number of Gd chelates (monomer, dimer, and trimer Gd), a high-field counter-field is used. By optimizing the relaxation time measurement behavior or MR sensitivity as a binding agent, and its binding affinity, We systematically investigated the potential of PCa-based PSMA-based MR imaging.

[0021] A. Compounds of formula (I) In some embodiments, the subject matter of this disclosure is formula (I):

[0022] [ka] (I)

[0023] The present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein Z is tetrazole or CO2Q Q is H or a protecting group, X1 and X2 are independently NH or O, and a c is an integer selected from the group consisting of 1, 2, 3, and 4, and c is 0, 1, 2, 3, and 4. An integer selected from the group consisting of R, where each R 1 , R 2 and R 4 These are independently H or C1-C4 Kills, each round 3 These are independently H, C1-C6 alkyl, or C2-C 12 It is Ariel, and W is Independently, O or S, Y is -NH- and can be present or absent, L is

[0024] [ka]

[0025] A linker selected from the group consisting of, where m is 1, 2, 3, 4, 5, 6, 7 and An integer selected from a group consisting of 8, and each R 5 H or each R 6 H is independent The C1-C6 alkyl group is C1-C6 alkyl -COOR 6 And n is 1, 2, 3, 4, 5, 6, 7, 8 An integer selected from the group consisting of 9, 10, 11, and 12, where p is 1, 2, 3, 4, An integer selected from the group consisting of 5, 6, 7, and 8, where Ch is one or more metals or radiation. This is a chelated portion that may contain a metallic acid.

[0026] Formula (I) is from International Publication No. 2009 / 002529 and International Publication No. 2010 / 10812. It does not contain the compounds disclosed in Brochure No. 5 and International Publication No. 2013 / 082338. In particular, the following compounds are explicitly excluded from the composition claims in this application.

[0027] [ka]

[0028] Furthermore, in certain embodiments, the chelated portion is

[0029] [ka]

[0030] Selected from the group consisting of , where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8. This is the integer to be selected.

[0031] Furthermore, in certain embodiments, the compound of formula (I) is

[0032] [ka] JPEG2026082844000008.jpg146163

[0033] (In the formula, x is selected from the group consisting of 2 and 3, and M is a metal or radioactive metal.) It is selected from the group, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the metal is Gd, Lu, Ac, Bi, Pb, Cu, In, S Selected from the group consisting of c and Y. In certain embodiments, the metal or radioactive metal is Gd-157, Lu-177, Ac-225, Bi-212, Bi-213, Pb-20 3 / Pb-212, Cu-67, In-111, Sc-44 / Sc-47 and Y-90 Selected from the group consisting of the above. Furthermore, in certain embodiments, for MRI applications, non-radioactive The metal is Gd-157 (stable isotope). For radiotherapy applications, the radioactive metal is L u-177, Ac-225, Bi-203, Pb-210, Cu-67, In-111, Selected from the group consisting of Sc-47 and Y-90. In the case of PET imaging, radioactive The metal is selected from the group consisting of Y-86 and Sc-44. Also, in the case of SPECT applications In addition, the radioactive metal is selected from the group consisting of Lu-177 and In-111.

[0035] B. Formula (I) for MR imaging and / or therapy of PSMA-expressing tumors or cells How to use the blend In some embodiments, the subject of this disclosure is one or more prostate-specific membrane antigens (PSM). A) Provide a method for imaging or treating tumors or cells, wherein the method comprises one or more The process involves contacting tumors or cells with an effective amount of the compound of formula (I) to form an image. The compound of formula (I) is

[0036] [ka] (I)

[0037] (In the formula, Z is tetrazole or CO2Q, Q is H or a protecting group, and X1 and X2 are Each is independently NH or O, and a is selected from the group consisting of 1, 2, 3, and 4. It is a number, where c is an integer selected from the group consisting of 0, 1, 2, 3, and 4, and each R 1 , R 2 , R 3 and R 4 is independently H or C1-C4 alkyl, and W is independently O or S. Y is -NH- and can be present or absent, and L is

[0038] [ka]

[0039] A linker selected from the group consisting of, where m is 1, 2, 3, 4, 5, 6, 7 and An integer selected from a group consisting of 8, and each R 5 H or each R 6 H is independent The C1-C6 alkyl group is C1-C6 alkyl -COOR 6 And n is 1, 2, 3, 4, 5, 6, 7, 8 An integer selected from the group consisting of 9, 10, 11, and 12, where p is 1, 2, 3, 4, An integer selected from the group consisting of 5, 6, 7, and 8, where Ch is one or more metals or radiation. It contains a chelated portion that may contain a metallic acid, or a pharmaceutically acceptable salt thereof.

[0040] "Contact" means that at least one compound containing the imaging agent of the subject matter of this disclosure is present in small quantities. This refers to any action that results in physical contact with a PSMA-expressing tumor or cell. Contact involves a compound with cells or tumors, and at least one compound with at least one cell or This may include exposure to an amount sufficient to cause contact with the tumor. This method involves the compound and Cells or tumors are introduced, preferably mixed, under controlled conditions (e.g., in a culture dish or test tube). This method can be performed in vitro or ex vivo. o can be performed, in which case contact means at least one cell or tumor in the subject. This means exposure to at least one compound of the subject matter of the disclosure, for example, to the test subject of the compound. This is administration via any appropriate route. In the subject matter of this disclosure, contact is the contact of the compound. The subject is introduced or exposed to the cells at a location far from the cells, affecting the subject's bodily functions or natural bodily fluids (for example, Contact between the compound and cells or tumors by diffusion or artificial movement (e.g., stirring). This may include causing the tumor or cells to be subjected to in vitro It can be observed in vivo or ex vivo.

[0041] "Image formation" refers to using magnetic resonance (MR) as a basis (in water molecules within tissue). A magnet that generates a detectable signal by polarizing and exciting hydrogen nuclei. Cells, tissues, tumors This means generating images of tumors, body parts, etc.

[0042] Formula (I) is from International Publication No. 2009 / 002529 and International Publication No. 2010 / 10812. It does not contain the compounds disclosed in Brochure No. 5 and International Publication No. 2013 / 082338, Therefore, the following compounds are explicitly excluded from the imaging claims in this application.

[0043] [ka]

[0044] Furthermore, in certain embodiments, the chelated portion is

[0045] [ka]

[0046] Selected from the group consisting of , where q is the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8. These are integers selected from the list.

[0047] Furthermore, in certain embodiments, the compound

[0048] [ka] JPEG2026082844000014.jpg43150JPEG2026082844000015.jpg44150JPEG2026082844000016.jpg70150JPEG2026082844000017.jpg145160

[0049] (where x is selected from the group consisting of 2 and 3, and M is a metal or a radioactive metal) selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc and Y. In certain embodiments, the metal or radioactive metal is Gd-157, Lu-177, Ac-225, Bi-203, Pb-210, Cu-67 , In-111, 44Sc- / 47Sc and Y-90. Further in certain embodiments, for MRI applications, the non-radioactive metal is Gd-157 (stable isotope) . For radiotherapy applications, the radioactive metal is Lu-177, Ac-225, Bi -203, Pb-210, Cu-67, In-111, Sc-47 and Y-90 selected from the group consisting of. For PET imaging, the radioactive metal is Y-86 and Sc-44 . For SPECT applications, the radioactive metal is Lu-177 and In-111 selected from the group consisting of.

[0051] In certain embodiments, one or more PSMA-expressing tumors or cells are prostate tumors or cells , metastatic prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma,[[]] pancreatic tumors or cells, bladder tumors or cells, sarcoma, melanoma, breast tumors or cells, colon tumors or This includes cells, germ cells, pheochromocytoma, esophageal tumors or cells, gastric tumors or cells, and combinations thereof. Selected from the group consisting of a batch. Furthermore, in a particular embodiment, one or more PSMA The present tumor or cells are prostate tumors or cells.

[0052] In some embodiments, one or more PSMA-expressing tumors or cells are in vitro , in vivo or ex vivo. In certain embodiments, one or more PS MA-expressing tumors or cells are present in the subject.

[0053] In some embodiments, tumors or cells are observed in the subject. The subjects treated by the methods of this disclosure in the embodiments are preferably human subjects. However, The methods described herein are effective for all vertebrate species included in the term "subject". It should be understood that: Therefore, the "subject" is a medical subject, for example, in an existing condition or Human treatment is the treatment of a disease or the preventive treatment to prevent the onset of a certain condition or disease. This may include test subjects or animals (other than humans) used for medical, veterinary, or development purposes. Suitable animal subjects include, but are not limited to, mammals, primates, for example. Humans, monkeys, apes, cattle (e.g., livestock cattle, bulls), sheep (e.g., sheep), goats Species such as goats, pigs such as piglets and adult pigs, horses such as horses and donkeys, Zebras, cats (including wildcats and domestic cats), dogs (including dogs), rabbits (Including rabbits, hares, etc.), and rodents (including mice, rats, etc.). The animal is a tiger. It can become an insulatory animal. In some embodiments, the subject is human, and the following Subjects include, but are not limited to, fetuses, newborns, infants, adolescents, and adults. Furthermore, a "subject" is someone who is suffering from or suspected of suffering from a certain condition or disease. This may include patients (animals) that are affected. Therefore, the terms "subject" and "patient (animal)" are used here. They are used interchangeably. In some embodiments, the subject is human. Other embodiments Morphologically, the subjects are non-human.

[0054] In some embodiments, a detectably effective amount of imaging of the method of the present disclosure The agent is administered to the subject. In the subject matter of this disclosure, the image of "a detectably effective amount" A zing agent is sufficient to obtain an acceptable image using equipment available for clinical use. This is defined as a quantity. A detectable, effective amount of imaging agent is administered by two or more injections. It is possible to administer this detectably effective amount of imaging agent, depending on the degree of susceptibility of the individual. Factors such as the individual's age, sex, and weight, the individual's idiosyncratic response, and dose measurement. Furthermore, it may vary depending on the equipment and film-related factors. Optimization of such factors is It is well within the skill level of a person skilled in the art.

[0055] It is preferable that the compounds of the subject matter of this disclosure are rapidly eliminated from the body's tissues. Typically The compounds of the subject matter of this disclosure are eliminated from the body in less than approximately 24 hours. More preferably, The compounds of the subject matter of the disclosure were found to be present in the body at approximately 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, and 2 hours. They will be eliminated if they are within 90 minutes or less than 60 minutes.

[0056] In some embodiments, the method disclosed herein relates to a subject of a compound containing an imaging agent. Includes clearance from tumors or cells. At least one advantage of the methods of the present disclosure is that, in some embodiments, the clearance of a compound containing an imaging agent from the kidney occurs more rapidly than the clearance from the tumor of the subject.

[0057] In some embodiments, the methods of the present disclosure use compounds that are stable in vivo, so that substantially all, e.g., about 50%, 60%, 70%, 80% or more preferably more than 90% of the injected compound, is not metabolized by the body before being excreted. In other embodiments, the compounds containing an imaging agent are stable in vivo.

[0058] C. Definitions i. Chemical definitions Although those skilled in the art will be able to fully understand the following terms regarding the compounds of formula (I), the following definitions are provided to facilitate the description of the subject matter of the present disclosure. These definitions are intended to supplement and exemplify definitions that will be apparent to those skilled in the art upon consideration of the present disclosure and are not intended to exclude them.

[0059] Whether or not preceded by the term "optionally", as used herein, the terms "substituted" and "substituent" refer to the ability, as understood by those skilled in the art, to change one functional group for another as long as the valence of all atoms is maintained. Where a given structure may be substituted with two or more substituents selected from two or more specified groups, the substituents may be the same or different at each position. Substituents may be further substituted (e.g., an aryl group substituent may have another substituent near it, e.g., another aryl group, and this aryl group may be further substituted at one or more positions, e.g., with fluorine).

[0060] ​​When specifying substituents or linking groups in their conventional chemical formulas written from left to right, These groups are identical and contain the same chemically identical substituents that result from writing the structure from right to left. Including, for example, CH2O- is equivalent to -OCH2-, and -C(=O)O- is equivalent to -OC(=O). - is equivalent to -OC(=O)NR-, and -NRC(=O)O- is equivalent to -NRC(=O)O-, etc.

[0061] In this specification, when a bond is located next to an internal substituent (for example, -NRC(O)-), The order of atoms is fixed, the orientation of the groups is not reversed, and they are inserted into the structure in the presented orientation. In other words, -NRC(O)- is different from -C(O)NR-. In this specification, the term C (O) (for example, -NRC(O)-) is used to indicate a carbonyl (C=O) group. Oxygen is bonded to carbon by a double bond.

[0062] When using the expression "independently selected," the substituents mentioned (e.g., the group) The R groups (such as R1, R2, etc., or variables such as "m" and "n") can be the same or different. For example. Both R1 and R2 can be substituted alkyl groups, or R1 can be hydrogen and R2 can be substituted alkyl groups. For example, it can become a substitute alkyl group.

[0063] This specification indicates the singular form (a, an, a(n)) used when referring to substituent groups. The word means at least one thing. For example, a compound is an alkyl or a When substituted in a reel, this compound optionally contains at least one alkyl and / or fewer alkyl groups. Both are substituted with one aryl substituent. Furthermore, if a part is substituted with an R substituent, this The base can be described as "R-substituted." When a part is R-substituted, this part is less It is substituted with at least one R substituent, and each R substituent is arbitrarily different.

[0064] Unless otherwise specified, named "R" or base generally corresponds to the base that bears that name. Then it has a structure recognized in that field. For explanation purposes, the above specific representative "R" The base is defined below.

[0065] The description of the compounds in this disclosure is limited by the principles of chemical bonding known to those skilled in the art. If a group can be substituted with one or more substituents, such substitution is a chemical bond. In accordance with the principles and not inherently unstable and / or under ambient conditions (e.g., aqueous, neutralized and A compound that will be easily destabilized under several known physiological conditions (as will be apparent to those skilled in the art) A substance is selected to obtain the desired product. For example, a heterocycloalkyl or heteroaryl is selected. By bonding to the rest of the molecule via a ring heteroatom, in accordance with the principles of chemical bonding known to those skilled in the art. This avoids compounds that are inherently unstable.

[0066] In this specification, the term "hydrocarbon" refers to all chemical groups, including hydrogen and carbon. Hydrogen can be substituted or unsubstituted. As those skilled in the art will know, when substitution is performed, all hydrogen The valency must be met. Hydrocarbons can be unsaturated, saturated, branched, unbranched, cyclic, or polycyclic. Alternatively, it can be a heterocyclic compound. Examples of hydrocarbons will be defined in detail later, but for example... Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino This includes, etc.

[0067] The term "alkyl," whether by itself or as part of another substituent, unless otherwise specified, Linear (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon group or these It means combination, and can be completely saturated, monovalent or polyunsaturated, and divalent and polyvalent It may contain a group and have a specified number of carbon atoms (i.e., C1-C 10 is 1 to 10 carbon (Meaning) In certain embodiments, the term "alkyl" means the removal of one hydrogen atom. C derived from hydrocarbon moieties containing 1 to 20 carbon atoms 1-20 Comprehensive linear ( That is, "linear", branched or cyclic saturated or at least partially, and possibly completely saturated. This refers to unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals.

[0068] Typical saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, and n- Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, s ec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl and the same This includes group and isomers.

[0069] "Branching" refers to the linking of lower alkyl groups such as methyl, ethyl, or propyl to a linear alkyl chain. It refers to the alkyl group that is combined. A "lower alkyl" is a group with 1 to about 8 carbon atoms, for example. For example, an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. That is, C 1-8 Alkyl). "Higher alkyl" refers to a group with approximately 10 to 20 carbon atoms, for example. For example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms This refers to an alkyl group having parent atoms. In certain embodiments, "alkyl" specifically refers to... C 1-8 This refers to a linear alkyl group. In other embodiments, "alkyl" specifically refers to C 1-8 This refers to branched-chain alkyl groups.

[0070] In certain embodiments, the alkyl group is a C1-C6 alkyl group or a C1-C4 alkyl group. Yes. In this specification, the term "C1-C6 alkyl" means a completely saturated linear, branched, or ring-linked alkyl group. C1-C6 hydrocarbons and their hybrids, such as (cycloalkyl)alkyls It has a taste. Examples of C1-C6 alkyl substituents include methyl (Me), ethyl (Et), and propyl (n-propyl(n-Pr, n Pr), isopropyl (i-Pr, 1 Pr) and Cyclop Ropil (c-Pr, 0 Pr) including), butyl (n-butyl (n-Bu, n Bu), Iso- Butyl (i-Bu, 1 Bu), sec-butyl (s-Bu, s Bu), tert-butyl ( t-Bu, 1 Bu) or cyclobutyl (c-Bu, 0 This includes (including Bu), etc.

[0071] The alkyl group is optional and can be substituted with one or more alkyl substituents, which may be the same or different. (Substituting alkyl). The term "alkyl substituent" is not limited to the following, Alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxy Sil, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylth This includes o, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be inserted along the kill chain. And this nitrogen substituent is hydrogen, lower alkyl (referred to herein as "alkylaminoalkyl") It is also called "Lu" or "Aryl."

[0072] Therefore, in this specification, the term "substituted alkyl" is defined as such. It contains an alkyl group, and one or more atoms or functional groups of the alkyl group are, for example, alkyl, substituted. Alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, Another, containing aminos, alkylaminos, dialkylaminos, sulfates and mercaptos Substituted with an atom or a functional group.

[0073] The term "heteroalkyl" is defined by itself or in combination with other terms as otherwise provided. Unless otherwise specified, select from the group consisting of at least one carbon atom and O, N, P, Si, and S. A stable linear, branched, or cyclic carbonized chain consisting of at least one heteroatom. This refers to hydrogen groups or combinations thereof, and nitrogen, phosphorus, and sulfur atoms are optionally oxidized. Furthermore, nitrogen heteroatoms can be optionally quaternized. Heteroatoms O, N, P, S and Si are he Substitution at any internal position of the teloalkyl group or at a position where the alkyl group is bonded to the rest of the molecule. This is possible. Examples include, but are not limited to, -CH2-CH2-O-CH3, -C H2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2 -CH3, -CH2-CH 25 -S(O)-CH3, -CH2-CH2-S(O)2-CH3, - CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=C This includes HN(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2- It is O-Si(CH3)3.

[0074] As described above, heteroalkyl groups in this specification have a heteroatom that connects the molecule The remaining groups to which the other groups can be attached are -C(O)R', -C(O)NR', ​​-NR'R'', -OR'. Includes -SR and / or -SO2R'. Described as "heteroalkyl," and specific he When followed by a teloalkyl group, such as -NR'R, the terms heteroalkyl and -NR'R” are used. It can be seen that they are neither redundant nor mutually exclusive. Rather, specific heteroalkyl This becomes clear by describing the group. Therefore, in this specification, the term "heteroalkyl" Shouldn't we interpret "ru" as excluding certain heteroalkyl groups, such as "-NR'R"? do not have.

[0075] In the term "(cycloalkyl)alkyl," cycloalkyl and alkyl are defined above. As stated, the bond point is on an alkyl group. This term is not limited to the following: However, it does not contain cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl. The alkyl group may be substituted or unsubstituted.

[0076] "Cyclic" and "cycloalkyl" refer to a group of carbon atoms consisting of approximately 3 to 10 carbon atoms, for example, 3, 4, 5. A cyclocyclic monocyclic or polycyclic system consisting of 6, 7, 8, 9, or 10 carbon atoms. Alkyl alkyl groups can optionally be partially unsaturated. Also, cycloalkyl groups can optionally be partially unsaturated. The ring may be substituted with alkyl group substituents, oxo and / or alkylenes as defined in the details. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms are inserted along the alkyl chain. The nitrogen substituent may be hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl. Therefore, heterocyclic groups are obtained. Typical monocyclic cycloalkyl rings include cyclopropyl and cycloalkyl rings. It contains clobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0077] Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, and kan. Fur, camphane, and noadamantyl, as well as fused ring systems, such as dihydro- and tetra- It contains hydronaphthalene, etc.

[0078] The terms "cycloheteroalkyl" or "heterocycloalkyl" may be the same or different. Selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si). Non-aromatic ring systems, unsaturated or partially unsaturated ring systems containing one or more selected heteroatoms, for example This refers to 3- to 10-membered substituted or unsubstituted cycloalkyl ring systems, and optionally one or more double bonds. It may include.

[0079] The cycloheteralkyl ring may optionally be another cycloheteralkyl ring and / or a non-aromatic carbon. It can be condensed or otherwise bonded to the hydrogen ring. The heterocycle can be independently selected from oxygen, sulfur, and nitrogen. It includes elements having 1 to 3 selected heteroatoms, and nitrogen and sulfur heteroatoms are optional. The nitrogen heteroatom may be oxidized and optionally quaternized. In certain embodiments, the term A "heterocyclic ring" is a ring atom in which at least one ring atom is a heteroatom selected from O, S, and N. This refers to a non-aromatic 5, 6, or 7-membered ring or polycyclic group (the nitrogen and sulfur heteroatoms are optionally oxidized). (may include), but is not limited to, two-cyclic or three-cyclic groups, oxygen, sulfur and comprises a fused 6-membered ring having 1 to 3 heteroatoms independently selected from nitrogen, (i Each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 2 double bonds. The ring has 0 to 3 double bonds, and (ii) the nitrogen and sulfur heteroatoms can be optionally oxidized. (iii) The nitrogen heteroatom can be optionally quaternized, and (iv) any of the above heterocycles It can condense into an aryl or heteroaryl ring. Typical cycloheteralkyl ring systems include , but not limited to the following, pyrrolidinil, pyrrolidinil, imidazolidinil, imi Dazolinil, pyrazolidinil, pyrazolinil, piperidyl, piperazinil, indolinil , quinuclidinyl, morpholinil, thiomorpholinil, thiadiadinyl, tetrahydro It contains furanyl, etc.

[0080] The terms "cycloalkyl" and "heterocycloalkyl" can be used either by themselves or in combination with other terms. When combined, unless otherwise specified, they are referred to as "alkyl" and "heteroalkyl," respectively. This represents the cyclic version. In addition, in the case of heterocycloalkyl, the heteroatom is the remainder of the heterocycle in the molecule. It can occupy a bonding position. Examples of cycloalkyls are not limited to the following, but cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cy This includes chloroheptyl, etc. Examples of heterocycloalkyls are not limited to the following. However, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperi Dinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran -2-yl, tetrahydrofuran-3-yl, tetrahydrothiene-2-yl, tetrahydro This includes dorothien-3-yl, 1-piperazinyl, 2-piperazinyl, etc. (Term: "Cyc") "Roalkylene" and "heterocycloalkylene" are cycloalkyl and heterocycloalkylene, respectively. This refers to divalent derivatives of cycloalkyl groups.

[0081] In this specification, the term "cycloalkylalkyl" refers to cycloalkylalkyl as defined above. This refers to the kill group, which is bonded to the parent molecule via an alkyl group as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. It includes.

[0082] An unsaturated alkyl group is one that has one or more double or triple bonds. Examples of the lukyl group include, but are not limited to, vinyl, 2-propenyl, and clotyl. , 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4 -pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher congenerates This includes isomers and admixtures. Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl." It can be done.

[0083] In particular, the term "alkenyl" as used herein means that by removing one hydrogen atom, a small amount is obtained. C has at least one carbon-carbon double bond 1-20 Induced from the integral linear or branched hydrocarbon portion This refers to the monovalent group that is derived. Examples of alkenyl groups include ethenyl (i.e., vinyl), p Lopenyl, Butenyl, 1-methyl-2-buten-1-yl, Pentenyl, Hexenyl, O This includes ctenyl and butadienyl.

[0084] In this specification, the term "cycloalkenyl" means a compound containing at least one carbon-carbon double bond. This refers to cyclic hydrocarbons having a cycloalkenyl group. Examples of cycloalkenyl groups include cyclopropenyl and cyclo Butenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclo It contains hexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. It can be done.

[0085] In this specification, the term "alkynyl" refers to a compound having at least one carbon-carbon triple bond. A specified number of carbon atoms in a straight or branched chain. 1-20 This refers to a monovalent group derived from hydrocarbons. Examples of "alkynyl" include ethinyl, 2-propynyl (propargyl), 1-propynyl, This includes pentynyl, hexynyl, heptynyl, and allenyl groups, among others.

[0086] The term "alkylene" refers to a molecule with 1 to about 20 carbon atoms, either by itself or as part of another substituent. Atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 Straight lines derived from alkyl groups having 5, 16, 17, 18, 19, or 20 carbon atoms This refers to a chain or branched divalent aliphatic hydrocarbon group. Alkylene groups can be linear, branched, or cyclic. Furthermore, the alkylene group may optionally be unsaturated and / or have one or more alkyl group substitutions. It can be substituted with a group. Along the alkylene group, one or more oxygen atoms, sulfur atoms, or substituted or unsubstituted atoms may be present. Nitrogen atoms may be optionally inserted (also referred to as "alkylaminoalkyl" in this specification), As mentioned above, the nitrogen substituent is alkyl. An example of an alkylene group is methylene(- CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclo(CH2) Xylene (-C6H 10-); -CH=CH-CH=CH-; -CH=CH-CH2-; -C H2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2C H2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r -(q and each of q and r is independently an integer from 0 to about 20, such as 0, 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or lower alkyl); methylenedioxyl (-O-CH2-O-) and ethylene dioxyl (-O-(CH2)2-O-) are included. The alkylene group can have from about 2 to about 3 carbon atoms and can further have from 6 to 20 carbons. Typically, an alkyl ( or alkylene) group has from 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group and generally has 8 or fewer carbon atoms.

[0087] The term "heteroalkylene" means a divalent group derived from heteroalkyl, either by itself or as part of another substituent, such as -CH2-CH2-S-CH2-CH2- and -C H2-S-CH2-CH2-NH-CH2-, but is not limited thereto. For heteroalkylene groups, the heteroatom can also occupy one or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Further, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. For example, the formula: -C(O)OR'- is -C(O)OR' - and -R'OC(O) - represents both.

[0088] The term "aryl" refers to a monocyclic or polycyclic compound formed by condensation or covalent bonding, unless otherwise specified. This refers to aromatic hydrocarbon substituents that can form a ring (for example, 1-3 rings).

[0089] The term "heteroaryl" refers to a polycyclic compound consisting of 1 to 4 heteroatoms selected from N, O, and S. In this case, it refers to an aryl group (or ring) having nitrogen and sulfur in a different ring. The atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group is carbon or he It can be bonded to the rest of the molecule via the telo atom. Non-restrictive aryl and heteroaryl groups. Examples include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2 -Pyrrolyl, 3-Pyrrolyl, 3-Pyrazolyl, 2-Imidazolyl, 4-Imidazolyl, P Rajinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5 -Oxazolyl, 3-Isoxazolyl, 4-Isoxazolyl, 5-Isoxazolyl , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thi Enyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-Pyrimidyl, 5-Benzothiazolyl, Prinyl, 2-Benzimidazolyl, 5-In Drill, indazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5 -Includes quinoxalinyl, 3-quinolyl, and 6-quinolyl. The aryl and mentioned above. The substituents for each heteroaryl ring system are selected from the group of acceptable substituents described later. Selected. The terms "arylene" and "heteroarylene" refer to aryl and heteroarylene, respectively. This refers to the divalent form of terroraryl.

[0090] For brevity, the term "aryl" is used in combination with other terms (for example) (aryl oxo, aryl thioxo, aryl alkyl) are as defined above. It includes both reel and heteroaryl rings. Hence the term "arylalkyl". And "heteroarylalkyl" refers to a group in which the aryl or heteroaryl group is a carbon atom (for example) For example, an alkyl group in which a methylene group is substituted with an oxygen atom (e.g., phenoxymethyl Alkyl alkyl groups (including 2-pyridyloxymethyl and 3-(1-naphthyloxy)propyl) A group bonded to a group (for example, benzyl, phenethyl, pyridylmethyl, furylmethyl, etc.) This shall include. However, the term "haloaryl" as used herein means one or more The range shall include only aryls substituted with halogens.

[0091] A heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (for example, When including "3-7 members," the term "member" refers to a carbon or heteroatom.

[0092] In this specification, the term "alkylaryl" is defined as an aryl group as defined above. It includes alkyl groups as defined after substitution. The aryl group can be at any position on the alkyl group. It can be combined with. (Terminology C4-C) 16 Alkylaryls are compounds that have an alkyl group and an aryl group on the carbon It contains alkylaryl groups that have a total of 4 to 16 carbon atoms when counting the elementary atoms together. Examples of alkylaryl groups include, but are not limited to, benzyl(phenylmethylammonium It contains methyl(Tyl), phenylethyl and naphthylmethyl. The alkylaryl group is substituted or It can be unsubstituted. Unless the total number of atoms in the substituent is greater than that of the alkylaryl group, the substituent will not be substituted. These atoms are not counted in the total number of atoms in the alkylaryl group.

[0093] Furthermore, the formulas used herein:

[0094] [ka]

[0095] The structure generally represented is a ring structure, for example, but is not limited to the following, 3-carbon, 4 -Aliphatic and / or aromatic cyclic compounds such as carbon, 5-carbon, 6-carbon, 7-carbon (saturated ring This refers to structures (including partially saturated ring structures and unsaturated ring structures), and includes R groups as substituents. The R group may or may not be present, and if present, one or more R groups each constitute one of the ring structures. It can be substituted on more than one available carbon atom. The presence or absence of R groups and the number of R groups are variables. Determined by the value of "n", where n generally ranges from 0 to the number of substituteable carbon atoms on the ring. It is an integer. If there are two or more, each R group is on an available carbon in the ring structure rather than on another R group. Substitutions occur on the primes. For example, the above structure where n is 0 to 2 is:

[0096] [ka]

[0097] This includes, but is not limited to, compound groups such as compound groups.

[0098] The dashed lines representing bonds in a ring structure indicate that bonds may or may not be present within the ring. In other words, the dashed lines representing bonds in a ring structure indicate that the ring structure is a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure. This indicates that the selection is made from a group consisting of saturated ring structures.

[0099] Substituents with broken bonds, as shown in the example below, directly affect the molecule at the position indicated by the substituent. This signifies bonding. It does not imply the presence of additional methylene (CH2) groups. Symbol

[0100] JPEG2026082844000020.jpg8170

[0101] This indicates the bonding point of the portion of the molecule to the rest of the molecule.

[0102] [ka]

[0103] In substituents with two broken bonds, as shown in the example below, the orientation of the atoms is written from left to right. This means that it should be as shown, and should be inserted into the molecule in the direction shown in the diagram. Unless otherwise specified. As long as this is not the case, no additional methylene (CH2) groups are implied.

[0104] [ka]

[0105] If an atom named as an aromatic ring or heteroaromatic ring is defined as "absent," then this The atoms that are named can be replaced by direct bonds.

[0106] Each of the above terms (for example, "alkyl", "heteroalkyl", "cycloalkyl") "Lu", "heterocycloalkyl", "aryl", "heteroaryl", "phosphonate" " and "sulfonates" and their divalent derivatives) are subject to the substitution and non-substitution of the indicated group. This includes both substitution forms. Any substituents for each type of group are listed below.

[0107] Alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl monovalent and divalent derivatives Body groups (alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cy Chloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl Substituents for the group that is often referred to as such (including the group) are not limited to the following, but - OR', =O, =NR', =N-OR', -NR'R'', -SR', -Halogen, -Si R'R"R'", -OC(O)R', -C(O)R', -CO2R', -C(O)NR' R”, ​​-OC(O)NR'R', -NR"C(O)R', -NR'-C(O)NR"R' ", -NR"C(O)OR', -NR-C(NR'R")=NR'", -S(O)R', Select from -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, and -NO2. m' can be one or more of the diverse bases of the number 0 to (2m'+l) that are selected, and m' is such This is the total number of carbon atoms in the group. R', R'', R''', and R'''' each independently contain hydrogen. Substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero Cycloalkyl, substituted or unsubstituted aryl (e.g., aryls substituted with 1 to 3 halogens) (Alkyl), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or This may refer to an alkoxyalkyl group. In this specification, the "alkoxy" group is a molecule via divalent oxygen. The rest is an alkyl group bonded to the remainder. If the compound of this disclosure contains, for example, two or more R groups, Each R group is selected independently, and if there are two or more, each R', R'', R''' and R'''' It is similar to the group. When R' and R'' are bonded to the same nitrogen atom, they combine the nitrogen atom. They can combine to form 4-, 5-, 6-, or 7-membered rings. For example, -NR'R'' is as follows: While not limited to these, the term should include 1-pyrrolidinil and 4-morpholinil. From the above discussion on alkyl groups, those skilled in the art will know that the term "alkyl" is formed when a group other than a hydrogen group is bonded to it. Groups containing carbon atoms, such as haloalkyl groups (e.g., -CF3 and -CH2CF3) and A Contains sills (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.) It can be understood that this is the case.

[0108] Similar to the substituents described above for alkyl groups, aryl and heteroaryl groups (and Examples of substituents for these divalent derivatives are diverse, including zero to empty valence atoms in aromatic ring systems. The total number of open valences, for example, halogen, -OR', -NR'R” -SR', -Halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R' , -NR'-C(O)NR"R'", -NR"C(O)OR', -NR-C(NR'R" R'”)=NR””, -NR-C(NR’R”)=NR’”-S(O)R’, -S(O) 2R', -S(O)2NR'R'', -NRSO2R', -CN and -NO2, -R', -N3 -CH(Ph)2, fluoro(C1-C4)alkoxo and fluoro(C1-C4)al Selected from the kill, R', R'', R'''' and R'''' are independently hydrogen, substituted or unsubstituted aluminum. Kill, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted From heterocycloalkyls, substituted or unsubstituted aryls and substituted or unsubstituted heteroaryls If the compounds of this disclosure contain, for example, two or more R groups, each R group may be independently selected. If selected, and there are two or more, each R', R'', R''' and R'''' group is treated the same.

[0109] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring are of any formula - TC(O)-(CRR') q -U- can form a ring, and T and U can independently form -NR-, It is an -O-, -CRR'-, or single bond, where q is an integer from 0 to 3. Alternatively, Ally Two of the substituents on adjacent atoms of the heteroaryl ring are of any two of the formula -A-(CH2 ) r -B- can be substituted with a substituent, and A and B are independently -CRR'-, -O-, -NR- , -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or single bond, r The integer is between 1 and 4.

[0110] In this way, one of the single bonds in the newly formed ring can be optionally replaced with a double bond. To obtain. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring are Optionally, use the formula -(CRR') s -X'-(C”R'”) d - can be substituted with substituents, and s and d are They are independent integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S The substituents are (O)2- or -S(O)2NR'-. The substituents R, R', R'' and R''' are independent of each other. Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero Select from cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. obtain.

[0111] In this specification, the term "acyl" means a carboxyl group in which the -OH group is substituted with another substituent. It also refers to an organic acid group having the general formula RC(=O)-, where R is as defined herein. It is a lukyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group. Therefore, the term "acyl" specifically refers to arylacyl groups, such as acetylfuran and It contains a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.

[0112] The terms "alkoxyl" and "alkoxy" are used interchangeably in this specification. Also, saturated (i.e., alkyl-O-) or unsaturated (i.e., alkyl-O-) molecules bonded to the parent molecule via an oxygen atom. This refers to saturated (i.e., alkenyl-O- and alkynyl-O-) groups, and the term "alkyl" is used. As mentioned above, "Alkenil" and "Alkinil" are C 1-20 Comprehensive linear, branched or It may contain a cyclic saturated or unsaturated oxo-hydrocarbon chain, for example, methoxyl, ethoxyl , propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, t-butoxyl This includes sil, n-pentoxyl, neopentoxyl, n-hexoxyl, etc.

[0113] In this specification, the term "alkoxyalkyl" refers to alkyl-O-alkyl ethers. This refers to, for example, a methoxyethyl or ethoxymethyl group.

[0114] "Aryloxyl" refers to the aryl group, including substituted aryl groups, as described above. It refers to a certain aryl-O- group. In this specification, the term "aryloxyl" refers to a certain aryl-O-group. Phenyloxyl or hexyloxyl and alkyl, substituted alkyl, halo or alkoxy This may refer to substituted phenyloxyl or hexyloxyl.

[0115] "Aralkyl" refers to a compound where aryl and alkyl are as described above and also substituted. This refers to aryl-alkyl groups, including aryl and substituted alkyl groups. Exemplary aralkyl groups It contains benzyl, phenylethyl, and naphthylmethyl.

[0116] "Aralkyloxyl" refers to a substance in which the aralkyl group is as described above. This refers to an O-group. An example of an aralkyloxyl group is benzyloxyl.

[0117] "Alkoxycarbonyl" refers to an alkyl-O-CO- group. An example is... The coxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, and butyloxycarbonyl. It contains bonyl and t-butyloxycarbonyl.

[0118] "Aryloxycarbonyl" refers to the aryl-O-CO- group. Examples: The aryloxycarbonyl group includes phenoxy- and naphthoxy-carbonyl groups. .

[0119] "Aralkyl-O-CO- group" refers to the aralkyl-O-CO- group. The aralkoxycarbonyl group is benzyloxycarbonyl.

[0120] "Carbamoyl" refers to the amide group of formula -CONH2. "Alkylcarbamoyl" refers to the R'RN-CO- group, where one of R and R' is hydrogen, and R and R The other side is an alkyl and / or substituted alkyl as described above. "Rubamoyl" refers to the R'RN-CO- group, where R and R' are independently of the aforementioned group. These are alkyl and / or substituted alkyl groups.

[0121] In this specification, the term "carbonyldioxyl" refers to the carbonyldioxyl of the formula: -O-CO-OR. It refers to a tetraactive group.

[0122] "Acyl-oxy" refers to an acyl - O - group, where acyl is as described above.

[0123] The term "amino" refers to an - NH2 group and also refers to nitrogen - containing groups known in the art that are derived from ammonia by replacement of one or more hydrogen radicals by organic radicals. For example, the terms " acylamino" and "alkylamino" refer to specific N - substituted organic radicals having acyl and alkyl substituents respectively.

[0124] "Aminoalkyl" as used herein refers to an amino group covalently bonded to an alkylene linker. In particular, the terms alkylamino, dialkylamino and trialkylamino as used herein refer to one, two or three alkyl groups respectively, bonded to the parent molecular moiety through a nitrogen atom as defined above. The term alkylamino refers to a group having the structure - NHR', where R' is an alkyl group as defined above. The term dialkylamino refers to a group having the structure - N R'R", where R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure - NR'R"R"', where R', R" and R'" are each independently selected from the group consisting of alkyl groups. Additionally, R', R" and / or R'" can together optionally be - (CH2) k - such that k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino and propylamino.

[0125] The amino group is -NR'R'', where R' and R'' are typically hydrogen, substituted or unsubstituted. Alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, Substitute or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or Selected from unsubstituted heteroaryls.

[0126] The terms alkylthioether and thioalkoxyl refer to molecules bonded to the parent molecule via a sulfur atom. Combined saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and This refers to the alkynyl-S- group. Examples of the thioalkoxyl moiety are not limited to the following: However, there are methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, etc. It includes.

[0127] "Acylamino" refers to the acyl-NH- group, and acyl is as described above. Yes. "Aroylamino" refers to the aroyl-NH- group, and aroyl is as described above. It is a member of the group.

[0128] The term "carbonyl" refers to the -(C=O)- group.

[0129] The term "carboxyl" refers to the -COOH group. In this specification, such a group is referred to as "calc." It is also referred to as the "bon acid" portion.

[0130] In this specification, the terms "halo," "halogenated product," or "halogen" refer to fluoro, chloroform, and chloroform. This refers to the rolo, bromo, and iodine groups. In addition, terms such as "haloalkyl" refer to monohaloalkyl groups. This includes chlorite and polyhaloalkyl compounds. For example, the term "halo(C1-C4)alkyl" " is not limited to the following, but includes trifluoromethyl, 2,2,2-trifluoro This includes ethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0131] The term "hydroxyl" refers to the -OH group.

[0132] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0133] The term "mercapto" refers to the -SH group.

[0134] In this specification, the term "oxo" refers to an oxygen atom double-bonded to a carbon atom or another element. It means child.

[0135] The term "nitro" refers to the -NO2 group.

[0136] The term "thio" refers to the aforementioned compounds in which a carbon or oxygen atom is replaced by a sulfur atom.

[0137] The term "sulfate" refers to the -SO4 group.

[0138] In this specification, the terms thiohydroxyl or thiol refer to the group of formula:-SH.

[0139] The term ureid refers to the urea group of the formula -NH-CO-NH2.

[0140] Unless otherwise explicitly defined, “substituent” in this specification refers to one of the following parts The functional groups include one or more selected functional groups, which are defined herein as follows: ru. (A)-OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, non-potent Substituting alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl aryl, unsubstituted aryl, unsubstituted heteroaryl and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and biheteraryl. The group B is, (i) Oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, non-potent Substituting alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl aryl, unsubstituted aryl, unsubstituted heteroaryl and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Substituted with at least one substituent selected from, the group of (ii) is (a) Oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, non-potent Substituting alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl aryl, unsubstituted aryl, unsubstituted heteroaryl and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or is heteroaryl Substituted with at least one substituent selected from, and the group of (b) is oxo, -OH, - NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted hetero Alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl and non It is substituted with at least one substituent selected from substituted heteroaryl compounds.

[0141] In this specification, "lower substitution" or "lower substituent" refers to the same term as "substituent" as described above. This refers to a group selected from all substitution groups, and each substituted or unsubstituted alkyl group is substituted or unsubstituted C1 -C8 alkyl, and each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 member heteroalkyl It is a cycloalkyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl. It is a cyclic heterocycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7 member heterocycloalkyl. It is a cycloalkyl group.

[0142] In this specification, "size-limited substitution" or "size-limited substituent" refers to a "substituent" This means a group selected from all of the substituents mentioned above, and each substituted or unsubstituted alkyl is substituted or is unsubstituted C1-C 20 It is an alkyl group, and each substituted or unsubstituted heteroalkyl group is substituted or unsubstituted. It is a 2-20 member heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is substituted or unsubstituted C It is a 4-C8 cycloalkyl group, and each substituted or unsubstituted heterocycloalkyl group is either substituted or unsubstituted. It is a 4- to 8-membered heterocycloalkyl group.

[0143] Throughout the specification and claims, any chemical formula or name refers to all tautomers, homologues, etc. Furthermore, optical and stereoisomers, and racemic mixtures in which such isomers and mixtures exist. To include.

[0144] It will be obvious to those skilled in the art that certain compounds of this disclosure may exist in tautomer forms, and All such tautomer forms of a substance are within the scope of this disclosure. "Tautomers" are organisms that exist in equilibrium and rapidly transform from one isomer to the other. It refers to one of two or more structural isomers.

[0145] Unless otherwise specified, the structures described herein refer to all stereochemical forms of those structures. This includes the configurations of R and S stereochemistry with respect to each chiral center. The single stereoisomers of the compound, as well as mixtures of enantiomers and diastereomers, are This falls within the scope of this disclosure.

[0146] The specific compounds of this disclosure have an asymmetric carbon atom (optical or chiral center) or a double bond. Enantiomer, racemic compound, diastereomer, tautomer, geometric isomer, absolute stereochemistry From a chemical standpoint, (R)- or (S)-, or in the case of amino acids, (D)- or (L). Stereoisomers and individual isomers that can be defined as such are included within the scope of this disclosure. Compounds are not those known in the art to be too unstable to be synthesized and / or isolated. i. This disclosure shall include racemic and optically pure forms of compounds. Optically active (R)- and (S)- or (D)- and (L)-isomers are chiral synthons or chiral It can be prepared using reagents or divided using conventional techniques as described herein. If a compound contains an olefin bond or other geometrically asymmetric center, unless otherwise specified, The compound shall contain both E and Z geometric isomers.

[0147] The methods for preparing optically active forms are well known in the field, for example, racemic mixtures. This involves the resolution, asymmetric synthesis, or synthesis from optically active starting materials of (racemic compounds). The resolving of the compound can be achieved, for example, by crystallization in the presence of a resolving agent or by using a chiral HPLC column. This can be achieved by conventional methods such as chromatography using olefins, C=N double bonds. Numerous geometric isomers, such as those described herein, may also exist in the compounds, and such stable All isomers are assumed in the subject matter of this disclosure. Cis and trans isomers of the compounds in the subject matter of this disclosure. Geometric isomers are explained, either as a mixture of isomers or as separate isomers. It can be isolated. Unless a specific stereochemistry or isomer form is specifically indicated, all chiral ( Enantiomer and diastereomer and racemic forms, as well as all the geometry of a certain structure Isomer forms are intended.

[0148] The compounds described herein may have one or more charged atoms. For example, a compound may have zwitter ions. It can become neutral, but the overall pH can be neutral. Other embodiments depend on pH and other factors. In these embodiments, the compound may have one or more charged groups. It can associate with . How to prepare the salt or exchange counterions is well known in the field. Yes. Generally, such salts contain a stoichiometric amount of the appropriate base for these compounds in their free acid form. (For example, react with Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.) Alternatively, these compounds in their free base form can be prepared by reacting them with a stoichiometric amount of the appropriate acid. It can be prepared. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. The counterion can be changed, for example, by ion exchange techniques such as ion exchange chromatography. It is possible. Unless a counterion or salt is specifically indicated, all zwitterions, salts, and counterions are Intended. In certain embodiments, the salt or counterion is administered to the subject by a medical professional. It may become pharmacopoeially acceptable. Pharmacopoeially acceptable salts will be discussed later.

[0149] In this specification, "protecting group" attacks a regenerated functional group or another functional group in a molecule. It is a chemical substituent that can be selectively removed with readily available reagents. The appropriate protecting group is It is publicly known in the field and is still being developed. Suitable protecting groups include, for example, Wutz et al. l.(”Greene's Protective Groups in Organi c Synthesis,Fourth Edition,”Wiley-Inters This can be found in Science, 2007. Wutz et al. (pp. 533-6) Protecting groups for protecting the carboxyl group, as described in 43), in certain embodiments It is used in the following manner. In some embodiments, the protecting group can be removed by acid treatment. Specific examples of protective groups include, but are not limited to, benzyl, p-methoxybenzyl ( PMB), tertiary butyl ( t Bu), Methoxymethyl (MOM), Methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranil (THP), tetra Hydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TM) S), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and tri It contains phenylmethyl(trityl, Tr). Those skilled in the art will know the appropriate form for which a protecting group is needed. It can recognize the situation and select a protective element suitable for use in a specific environment.

[0150] Unless otherwise specified, the structures described herein are in the presence of one or more isotope-enriched atoms. This also includes compounds that differ only in their properties. For example, hydrogen may be replaced with deuterium or tritium. , or carbon 13 C- or 14 Compounds having this structure except for those substituted with carbon-enriched carbon are: It is within the scope of disclosure.

[0151] The compounds of this disclosure have an unnatural proportion of atoms in one or more of the atoms constituting such compounds. It may also contain isotopes. For example, a compound may contain radioactive isotopes, such as tritium. 3 H), Yo Element-125( 125 I) or carbon-14 ( 14C) can be radiolabeled. All compounds in this disclosure Isotope variations of are included in the scope of this disclosure, whether radioactive or not.

[0152] ii. Medicinal salts The compounds disclosed herein may exist as pharmaceutically acceptable salts. "Salts" are relatively toxic depending on the specific substitution moieties found on the compounds described herein. It shall contain salts of active compounds prepared with an acid or base. Medicinally acceptable salts are Generally well known to those skilled in the art, and given only as examples, not as an limitation, acetates, benzenes Lufonates, besilates, benzoates, bicarbonates, bicarbonates, bicarbonates, bromides, calcium edetate Cium, carnsylate, carbonate, citrate, EDTA, Edicylate, estolate, esylate, f Marates, gluceptates, glucons, glutamates, glycolyl arsanilates Hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate Alkaline, iodide, isethionate, lactate, lactobionate, malate, maleic acid Salt, mandelate, mesylate, mucinate, napsylate, nitrate Salts, pamoates (embonates), pantothenates, phosphates / diphosphates, polygalac Turonate, salicylate, stearate, basic acetate, succinate, sulfate, tan Sulfates, tartrates (e.g., (+)-tartrate, (-)-tartrate, or racemic mixtures) These mixtures may include (or the teoclates). These salts are prepared by methods known to those skilled in the art. It can be prepared by [method]. Other pharmaceutically acceptable salts are, for example, Remington: The Science and Practice of Pharmacy(20th ed. .) Seen in Lippincott, Williams & Wilkins (2000). .

[0153] Base addition salts, such as sodium, potassium, calcium, ammonium, and organic amino acids. This also includes magnesium salts or similar salts. The compounds of this disclosure have a relatively basic functionality. If the group is present, the acid addition salt will convert the neutral form of such compound into a pure or suitable inert solvent. It is obtained by contacting it with a sufficient amount of the desired acid. Examples of acceptable acid addition salts include inorganic Acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonic acid, phosphoric acid, monohydrogen-phosphate, dihydrogen Derived from phosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, and organic compounds. Acids, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolyl This includes salts derived from sulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.

[0154] Salts of amino acids such as arginate and glucuronic acid or galactus This also includes salts of organic acids such as hydroxy acids, for example, Berge et al., "Pharmaceuticals utical Salts”, Journal of Pharmaceutical See Science, 1977, 66, 1-19). Certain compounds in this disclosure This allows for the conversion of compounds into base or acid addition salts, providing both basic and acidic functionality. It has a group. The neutral form of the compound is obtained by contacting the salt with a base or acid and the parent compound in a conventional manner. It can be regenerated by isolation. The parent form of the compound has specific physical properties, for example, in polar solvents. Its solubility differs from that of various salt forms.

[0155] The specific compounds of this disclosure exist in both non-solvated and solvated forms (including hydrated forms). Generally, the solvated form is equivalent to the non-solvated form and is included within the scope of this disclosure. The specific compounds disclosed may exist in various crystalline or amorphous forms. Generally speaking, the present invention assumes... All physical forms are equivalent for the intended use and fall within the scope of this disclosure.

[0156] iii. General definition Although specific terms are used in this specification, they are used in a general and descriptive sense. This is merely a description and not intended to be restrictive. For clarity, a specific definition is given here. Note: Unless otherwise defined, all technical and scientific terms used herein are as defined herein. The terms described in the detailed document have the same meaning as those generally understood by those skilled in the art in the field to which the subject matter pertains. do.

[0157] In animals, "cancer" refers to the characteristic of cancer-causing cells, such as uncontrolled growth. Proliferation, loss of specialized function, immortality, remarkable metastatic ability, remarkable improvement in anti-apoptotic activity , fast growth and proliferation rate, and specific characteristic morphology and cellular markers This refers to the presence of cells. Depending on the circumstances, cancer cells may take the form of a tumor, and such cells They can exist locally within an animal's body, or circulate in the bloodstream as independent cells.

[0158] "Control" means a standard or baseline condition.

[0159] "Disease" is defined as a condition that impairs or interferes with the normal function of cells, tissues, organs, organisms, or subjects. It means any state or malfunction.

[0160] The "effective amount" of a substance is the amount that, compared to a control, elicits a desired biological response or It refers to the amount of the substance sufficient to produce a measurable difference. As those skilled in the art will understand. The absolute amount of a specific substance that is effective in treating a disease, disorder, condition, or injury is the amount of the substance delivered. Quality, dosage form, subject's age, weight and overall health, desired biological endpoint, location The dosage may vary depending on factors such as the desired therapeutic effect. Ultimately, the appropriate amount and dosage will depend on the attending clinician. Determine the regimen. For example, the "effective amount" of a substance is used to determine how to use that compound in imaging. A sufficient amount of the compound to produce a measurable image when used, or to treat the substance It may be a sufficient amount to improve the symptoms of the disease when used. A person skilled in the art will know the effective amount It is also possible to understand whether a certain substance can be administered in a single dose or whether it can be achieved through multiple divided doses. ru.

[0161] In this specification, the term "administration" means bringing a subject into contact with the substance of this disclosure.

[0162] In accordance with long-standing patent law conventions, the singular indefinite article is used in this application, including in the claims. The definite article indicates "one or more." Therefore, for example, in the phrase "a certain subject," Unless it is clear from the context that this is not the case (for example, multiple subjects), multiple subjects This includes test subjects, and the same applies to others.

[0163] Throughout this specification and the claims, the term “comprise” means: Unless the context makes it clear otherwise, it is used in a non-exclusive sense. Therefore, the term "include" and its grammatical variations are considered non-restrictive. Listing items in a list means that the items listed can be substituted or added to them. This does not exclude other similar items.

[0164] For the purposes of this specification and the appended claims, unless otherwise specified, quantity, size, dimensions, All sequences of numbers representing proportions, shapes, blending ratios, parameters, percentages, parameters, quantities, and characteristics. Other numerical values ​​used in the specification and claims are those where the term "about" is specifically attached to a value, quantity or range. Even if not explicitly stated, please understand that in all cases the term is modified by "approximately". Therefore, unless otherwise specified, the numerical parameters described in the following specification and attached claims shall not apply. The meter is not, and does not need to be, precise, and does not represent the desired result sought in the subject matter of this disclosure. Depending on the properties, the approximate value and / or may be larger or smaller as needed, Tolerances, customary factors, rounding, measurement errors, and other factors known to those skilled in the art should be reflected. For example, the term "about" when referring to a certain value means that in some embodiments of a specified quantity... ±100%, ±50% in some embodiments, ±20% in some embodiments In some embodiments, ±10%, in some embodiments, ±5%, in some embodiments In some embodiments, ±1%, ±0.5%, and in some embodiments This may include fluctuations of ±0.1%. This is because such fluctuations may occur if the disclosure method is performed. This is because it is suitable for doing so, or for using the disclosed composition.

[0165] Furthermore, when using the term "approximately" in relation to one or more numbers or numerical ranges, within a certain range It should be understood that this refers to all such numbers, including all numbers of the same kind, and this term is also written The range is adjusted by widening the boundary above and below the listed value. The numerical range is set at the endpoint. By listing them, all numbers, for example, integers (including fractions) within that range (for example) For example, if it says 1-5, it means 1, 2, 3, 4 and 5, and their fractions, for example 1.5, 2 This includes 0.25, 3.75, 4.1, etc., and any range within that range. [Examples]

[0166] This disclosure is intended to guide those skilled in the art in practicing typical embodiments of the subject matter of this disclosure. The following embodiments are included. Given the present disclosure and the general level of the art, Those skilled in the art will know that the following examples are for illustrative purposes only, and numerous changes, modifications, and revisions have been made. It can be seen that positives can be added without departing from the subject matter of this disclosure. Regarding the synthesis described later... The descriptions and specific examples provided are for illustrative purposes only, and the disclosed compounds can be produced by any other method. In doing so, it should not be interpreted as being limited in any way.

[0167] Example 1 Synthesis and evaluation of gadolinium (Gd)-based contrast agents overview Because it can obtain anatomical, functional, and molecular information simultaneously, magnetic resonance (MR) imaging The approach is advantageous. MR molecular imaging is an established and widely used clinical method. Combining modalities and their high spatial resolution with molecular profiling in vivo It is possible to do so. However, because the sensitivity of MR is inherently low, recognizable MR devices To generate trust, a high local concentration of a biological target is required. The inventors have identified that target High concentrations in target cells, limited expression in non-target tissues, and access on the cell surface. Due to its properties, prostate-specific cancer is an attractive target for imaging and treatment of prostate cancer. Membrane antigens (PSMAs) are suitable biomarkers for MR-based molecular imaging. We hypothesized that it could fulfill the role of [this function]. To achieve this, we used 1 to 3 Gd per molecule. Three types of high-affinity, low-molecular-weight gases are graded as Gd1, Gd2, and Gd3 based on their chelate properties. A dolinium (Gd)(III)-based PSMA-targeted contrast agent was synthesized (Figure 1A). The purpose of this research is to evaluate the PSMA binding affinity and longitudinal relaxation degree (r1) of the synthesized material. This was the case. PSMA-expressing cells (isogenic) and non-expressing control cells. Cellular uptake of substances is evaluated using radiofrequency inductively coupled plasma mass spectrometry (ICP-MS). Finally, the ability of that substance to distinguish PSMA-expressing cells from control cells was investigated. Evaluation was performed using MR imaging in both vitro and in vivo conditions.

[0168] Materials and methods (21S,25S)-8,15,23-Trioxo-1-((4-((1,4,7,10 -Tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-2 -Iyl(methyl)phenyl)amino)-1-thioxo-2,7,16,22,24-phenyl) Taazaheptacosan-21,25,27-tricarboxylic acid, Gd1 Compound Gd1 was prepared according to recent reports. Compound 1 was prepared in the following three steps. Prepared with commercially available N-Boc-1,4-diaminobutane (68 mg, 0.36 mmol, (in 0.5 ml of DMSO) 1,4,7,10-tetraazacyclododecane-1,4,7 ,10-tetraacetic acid, 2-[(4-isothiocyanatophenyl)methyl](p-SCN- Bn-DOTA) (192 mg, 0.28 mmol, in 2.5 mL of DMSO) and DI It was mixed with EA (132 μl, 0.75 mmol) and stirred at 40°C for 4 hours. The solvent is evaporated, and the solid residue is reversed C 18 Flash chromatography (5.5g, Agi) Using lent SF10) with water and acetonitrile (0.1% TFA each) Upon purification, Boc-protected 7 was obtained after lyophilization. Yield: 146 mg, approximately 55%. SI-MS 740[M+H] + The compound obtained in that step is then ice-cold TFA / C The sample was treated with an H2Cl2 (1 / 1) solution and stirred at ambient temperature for 2 hours. The solvent was then evaporated. The residue was then dried under vacuum and subjected to reverse-phase flash chromatography (5.5g, Agil). When purified with ent SF10, 7 was obtained in a reasonable yield. The solvent was evaporated, and the residue was... Dry under vacuum and perform reverse-phase flash chromatography (5.5g, Agilent SF 10) Purification yielded product 7. Yield approximately 104 mg, 40%. 1 1H NMR (DMSO -d6)δ:8.80-8.64(m, 1H), 8.12-7.90(m, 2H), 7. 75-7.10(bm, 4H), 4.65-4.63(m, 1H), 4.17-2.59 (m, 27H), 2.40-1.11(m, 6H). ESI-MS:640[M+1] + 7. Solution (110 mg, 0.17 mmol, in 3 mL of distilled water) Gd2(CO3)3( It was added to a solution of 85 mg (0.17 mmol) and stirred at 60°C for 14 hours. ESI-MS:C 48 H 77 N 10 O 17 Theoretical value for S: 797.5183 [M+H] + , Measurement value: 797.5212. Next, the compound was purified by HPLC. Method 1: Solvent A (0. 1% TFA (in water) and solvent B (0.1% TFA in acetonitrile), flow rate 8 mL / min The elution gradient is 100% A and 0% B at 5 minutes, and 100% A to 8% at 5-25 minutes. 0%A, 0%B~20%B, 80%A~20%A and 20%B~80%B in 25~30 minutes That was the case.

[0169] (30S,34S)-2,9,17,24,32-Pentaoxo-1-(4,7,10- Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl )-8-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-teto Laazacyclododecane-1-yl acetamide)-3,10,16,25,31,33 -Hexazahexatriacontane-11,30,34,36-tetracarboxylic acid, niga Dolinium(III) salt, Gd2 The compound was prepared according to Scheme 2. N-bis-Boc-L-lysine NHS(3 Fmoc-Lys(Boc)-O in a solution of gm, 6.7 mmol, in 10 mL of DMF Add H (2.49 g, 6.7 mmol) and leave the solution at room temperature for 1 hour until clear. The solution was subjected to ultrasonic treatment until the desired result was obtained. The solution was stirred at room temperature for 4 hours, and the solvent was removed under vacuum. Compound 4 was obtained in nearly quantitative yield after removal. Compound 4 was further analyzed using a silica gel column at a yield of 3 / 9 7. Purification was performed using MeOH / CH2Cl2 as an eluent. 1 1H NMR (CDCl3) δ:8.01(d, 2H), 7.89(m, 2H), 7.78-7.44(m, 4H), 6.82(m, 1H), 6.15(m, 1H), 5.58(m, 1H), 5.01-4. 03(m, 5H), 3.75-3.32(m, 6H), 2.22-1.31(m, 30H ) ESMS m / Z:696[M+H] + Compound 4 (2g, 2.9 mmol) is divided into 10 units. The mixture was dissolved in 1 / 1 mL of 1 / 1 TFA / CH2Cl2 solution and stirred at room temperature for 2 hours. After solvent evaporation, wash the solid residue with 3 x 3 mL of diethyl ether and dry under vacuum. Compound 5 was obtained as a TFA salt. Compound 5 was obtained in quantitative yield and after freeze-drying, It was used without refining. 1 H NMR(D2O)δ:8.01(d,2H), 7.8 9(m, 2H), 7.78-7.44(m, 4H), 4.78-4.75(m, 2H), 4.32(m, 1H), 4.11-4.09(m, 1H), 4.01-3.98(t, 1 H), 3.50-3.11(m, 3H), 3.10-2.99(m, 2H), 2.01- 1.01(m, 12H). DOTA-NHS (100mg, 0.13mmol, 0.5m 5.2 TFA (32 mg, 0.04 mmol) and DIEA (in DMSO) are added to a solution of L. (0.78 mmol, 136 μL) was added gradually over 45 minutes at room temperature. Next, the solution was added. The mixture was stirred for another two hours, and the completion of the reaction was monitored using HPLC. The reaction product was purified by HPLC to obtain compound 6. Compound 6 was then mixed with a 20% piperidine solution. Process for the moc group, C 18 Flash chromatography reveals 90 / 10 H2O / The samples were purified using CH3CN (each containing 0.1% TFA) solutions and then freeze-dried. ESIM S:1046[M+H] + The freeze-dried compound (50 mg, 0.047 mmol) Dissolve ) in distilled water (2 mL), and Gd2(CO3)3 (0.26 mmol, 3 mL in water) Compound 7 was added to the solution of ) and stirred at 60°C for 12 hours. 18 Flash Chromatography shows a gradient of 90 / 10 to 80 / 20 H2O / CH3CN (and Each was purified using a 0.1% TFA solution and then freeze-dried. Solution of 3 in DMSO ( 25 mg (0.004 mmol) to 7 (40 mg, 0.003 mmol) slowly 3 times The mixture was added over 0 minutes and stirred at room temperature for approximately 2 hours until the reaction was complete. The completion of the reaction was monitored by HPLC. After completion, the reaction mixture was subsequently purified by HPLC, and the product was collected. It was freeze-dried. ESI-MS:1813.08[M+H] + Measured value: 1813.0 8. Next, the compound was purified by HPLC. Method 1: C 64 H 103 Gd2N 15 O 26 About The theoretical value is 1813.5681[M] + Measured value 1813.5681 [M+1]. Solvent A (0.1% TFA, in water) and solvent B (0.1% TFA, in acetonitrile), flow rate 8 m L / min. The elution gradient is 100% A and 0% B at 5 minutes, and 100% A to 8% at 5-25 minutes. 0%A and 0%B to 20%B, 80%A to 20%A and 20%B to 80% in 25-30 minutes B.

[0170] (3S,7S)-5,13,20,28-Tetraoxo-32-(2,4,6-Tris( 1-(2-hydroxy-3-(4,7,10-tris(carboxymethyl)-1,4,7 ,10-Tetraazacyclododecane-1-yl)propyl)-1H-1,2,3-Tria Zole-4-yl)phenoxy)-4,6,12,21,27-pentaazadotriacone Tan-1,3,7,22-tetracarboxylic acid, trigadolinium(III) salt, Gd3 Gd3 was prepared by the multi-step synthesis shown in Scheme 3. Compound 8 was previously reported. That's how I prepared it.

[0171] 2,5-Dioxopyrrolidine-1-yl5-(2,4,6-triethinylphenoxy) Ntanoet, 9 Add TSTU (440 ml) to solution 8 (300 mg, 1.13 mmol, in 5 mL of DMF) (g, 1.47 mmol) and TEA (541 μL, 3.39 mmol) were added, and the result was obtained. The solution was stirred at room temperature for 4 hours until the reaction was complete, and monitored by TLC. The medium is removed under high vacuum, the residue is dissolved in CH2Cl2, and then filtered by silica gel column at 40°C / The product was purified using a 60-50 / 50 acetone / hexane solution as an eluent. When the fractions containing the substance were combined and evaporated, the desired product was obtained as a colorless solid. Yield approximately 310mg. NMR(CDCl3): δ7.56(s, 2H), 4.26(t, 2 H), 3.39(s, 2H), 3.04(s, 1H), 2.78(s, 4H)2.48( t, 2H), 2.01-1.80(m, 4H).

[0172] (3S,7S)-26-amino-5,13,20-trioxo-4,6,12,21-the Traazahexacosan-1,3,7,22-tetracarboxylic acid 2,2,2-trifluoro Acetate, 10 Compound 10 was prepared according to previous reports. Briefly, it is tris-t-Bu In the solution of Protection 3 (100 mg 0.135 mmol in 1.35 ml of DMF), HL ys(Boc)(Ot-Bu) (59.5 mg, 0.175 mmol), followed by DIE A (70.7 μL, 0.135) was added, and the clear solution was stirred at room temperature overnight. Next, The solution was concentrated under vacuum until it became a clear, oily residue. The residue was divided into a 2:1 MeCN / When dissolved in water (6 mL) and freeze-dried, a clear, foamy product was obtained. Yield: [Yield not specified]. Production: [Product not specified]. The substance was used without further purification. Yield: 117 mg, 0.126 mmol, 93% ESI-MS:928[M+H] + The compound is placed in a 2 ml ice-cold solution of TFA / CH2Cl2. It was dissolved in [a solution], and then TES (278 μL, 1.7 mmol) was added dropwise. A clear solution was obtained in 5 [units of measurement]. The mixture was stirred over time and concentrated under vacuum. The residue was dissolved in 5 mL of water and reversed-phase flushed. The product was purified by saturation chromatography. The product was then mixed with 80 / 20 water / CH3CN (each). Elution was performed using 0.1% TFA. ESI-MS: 603[M+H] + .

[0173] (3S,7S)-5,13,20,28-Tetraoxo-32-(2,4,6-Triethi Nylphenoxy)-4,6,12,21,27-pentaazadotricontane-1,3, 7,22-tetracarboxylic acid, 11 Compound 9 (132 mg, 0.362 mmol) was (3S,7S)-26-amino-5 ,13,20-Trioxo-4,6,12,21-Tetraazahexacosan-1,3,7 ,22-tetracarboxylic acid 2,2,2-trifluoroacetic acid (260 mg, 0.362 mm) (ol), triethylamine (0.202 mL, 1.44 mmol) and DMF (3.62 The mixture was added in one dose to a solution containing (mL). The mixture was stirred at room temperature for 4 hours until it turned yellowish-brown. The solution was concentrated until a colored residue remained. The residue was dissolved in 1 / 1 water / acetonitrile (3 mL). Let C 18 Reverse-phase flash chromatography was used to determine the composition of 100% water, 0.1% TFA, followed by... The solution consists of 80 / 20 and 60 / 40 water / acetonitrile (each containing 0.1% TFA). Purification was performed using a step gradient. Each gradient step involved approximately 144 mL of solvent volume. Success. The flow rate was 40 mL / min. The fraction containing the desired product was extracted until it became a residue. When concentrated and freeze-dried, it becomes (3S,7S)-5,13,20,28-tetraoxo-3 2-(2,4,6-triethinylphenoxy)-4,6,12,21,27-pentaza Dotriacontane-1,3,7,22-tetracarboxylic acid was obtained as a white solid. 169 mg, yield 54%. ESI-MS, C 43 H 57 N5O 13 [M+H] + Theory about Value: 852.4, Measured value: 851.9. 1 1H NMR (400MHz, DMSO-d6) 12 .12(bs, 4H)8.01(d, 1H), 7.76(m, 2H), 7.57(s, 2 H), 6.33(m, 2H), 4.47(s, 2H), 4.28(s, 1H), 4.09 -4.15(m, 4H), 3.00(m, 4H), 2.21-2.27(m, 2H), 2 .10(m, 4H), 2.02(t, 2H), 1.89-1.94(m, 1H), 1.2 2-1.69 (m, 24H). 13 ¹³C NMR (100 MHz, DMSO-d6) δ175 .0, 174.6, 174.3, 174.1, 172.8, 172.3, 172.1, 1 62.1, 158.9, 158.5, 157.7, 137.6, 118.0, 117.5 , 86.6, 82.0, 81.5, 78.6, 74.1, 52.7, 52.1, 38.7 38.6, 35.8, 35.5, 32.2, 31.1, 30.3, 29.7, 29.3 , 29.2, 28.9, 28.8, 27.9, 25.7, 25.6, 23.3, 23.0 , 22.1.

[0174] Gd3 (3S,7S)-5,13,20,28-Tetraoxo-32-(2,4,6-Trie Tinylphenoxy)-4,6,12,21,27 Pentaazadotriacontane-1,3, 7,22-tetracarboxylic acid (12 mg, 0.14 mmol), compound 002 (28 mg) A mixture containing water (0.046 mmol) and t-butanol (0.1 mL) is added. 0.5 mL), followed by TBTA (0.15 mg, 0.3 μmol) and tetrakissin (acetone). Nitrile copper(I) hexafluorophosphate (0.11 mg, 0.3 μmol) is added. The mixture was stirred at 65°C for 18 hours. 2.5 mL of the reaction mixture was added to 0. The solution was dissolved in 1% sodium bicarbonate and filtered. The resulting solution was then subjected to HPLC. For Phenomenex, Luna, 10 micron, 10x250 mm column and 0-9 The desired solution was purified over 20 minutes using a gradient consisting of 5% acetonitrile and water. Product (003) was eluted in 6.1 to 7.1 minutes. The fractions containing 003 were combined and concentrated. Shrinkage and freeze-drying yielded a white solid. 13 mg, yield 34%. ESI-MS C 94 H 141 Gd3N 26 O 34 [MH] -The theoretical value for this is 2650.7, and the measured value is 2648. 9.

[0175] Scheme 1

[0176] [ka]

[0177] Scheme 2

[0178] [ka]

[0179] Scheme 3

[0180] [ka]

[0181] result Representative PSMA contrast agents containing Lys-Glu urea as the target moiety: monomers The structures of the dimer and trimer Gd (Gd1, Gd2, and Gd3) are shown in Figure 1A. Multi-step liquid The target compound was prepared by devising a phase synthesis method. This method is briefly described in Schemes 1-3. .

[0182] For all three compounds, the chelating agent DOTA was used. Thermodynamic and kinetic stability This is because it can form complexes with high qualitative properties. To obtain a high degree of relaxation, Gd1 is DOTA-B It contains n-SCN. The structure of Gd1 is based on positron emission tomography (PET) data reported in recent years. It is based on a lead-86Y labeled imaging agent for preclinical use, and this imaging agent is preclinical Highly specific tumor accumulation has been demonstrated in Dell (Banerjee, et al.). (2015). Gd2, both the ∝- and ε-amines of lysine, and condyloma. The peptides were prepared by galvanizing and using a solution-based peptide synthesis method. Under the same conditions, the reaction When the reaction was performed in a room-temperature ultrasonic bath, the yield of the coupling reaction was significantly improved. Gd3 is M As previously reported by astarone et al., rigid triathromycin can be used with click chemistry. The phenol core, to which three Gd(III)-DOTA molecules are bound via zole bonds It includes conjugating a PSMA target functional group to its core via the oxygen of phenol. Gd3 exhibits relatively high relaxation as a result of the triazole linker portion becoming more rigid. The degree was shown. The compound was purified by reverse-phase HPLC and characterized by LC-MS. The Gd(III) content of the substance potentially has a negative effect on the probe's binding affinity. To confirm whether or not it has Gd1, a fluorescence-based PSMA inhibition assay was used. The PSMA inhibition constants (Ki) for Gd2 and Gd3 were determined and are shown in Table 1.

[0183] [Table 1]

[0184] A known high-affinity PSMA inhibitor: N-[[[(S)-1-carboxy-3-methylbutyl [Amino]carbonyl]-L-glutamic acid (ZJ43) (Olszewski et al.) (al., 2004) was used as the reference ligand. As expected, all compounds showed high binding. It showed affinity, with Gd1 (0.45 nM) having the highest Ki value, followed by Gd3 (7.19 nM). Next, Gd2 (18.18 nM) was the lowest. Imaging was performed at 9.4 T and 25°C. In that case, the solution phantom will be 3.0-6.2 mM. -1 s-1 (Gd(III)), 3.0~1 2.5mM -1 s -1 The degree of r1 relaxation in PBS varied between (contrast agents). Table 1). As expected, at 25°C, Gd1 had the lowest degree of relaxation, followed by Gd2 and Gd3. To confirm the selectivity and specificity of the substance, a large amount of PSMA (PC3 PIP) was expressed. Genetically modified human prostate cancer cells and their corresponding wild-type PSMA-free cells Existing cells (PC3 flu) were selected as a negative control (Banerjee (Angew, 2001). After incubation with Gd1 or Gd2, pellet form PSMA+PC3 PIP and PSMA-PC3 flu cells are T1-weighted MR contraceptives. No changes were observed in either the stroma or R1. Conversely, both the stroma incubated with Gd3 showed no changes. T1-weighted images of the cell line show unlabeled cells and PSMA-PC3 flu cells. Compared to Rett, as shown in Figure 4A, PSMA+PC3 PIP cells exhibit a significant difference. MR contrast enhancement was observed. Cellular palpation was performed in the presence and absence of 50 μM Gd3. Rett's MRI enhancement and T1 measurement are performed by washing the cell line with standard medium. After Gd3 removal, Gd3-treated flu cells were compared with control flu cells. Therefore, high enhancement and T between Gd3-treated PIP cells and control PIP cells The difference at one relaxation rate, ΔR 1 This was shown (Figures 4B and 4C).

[0185] Selective blockade experiments by performing co-incubation of Gd3 and ZJ43 were actually conducted. It showed significant blockade of 1 enhancement. Cells incubated with Gd3 in the presence of ZJ43. The cells showed only slight changes in T1 values ​​in both types of cells. This indicates that ZJ43 was able to specifically block the binding of Gd3. These results suggest that Gd3 It showed receptor-specific cell binding to PSMA+PC3 PIP cells, and PSMA-mediated control This demonstrates the presence of last-stage enhancement and proves the concept of receptor-mediated endocytosis. In fact, ICP-MS analysis of cells after post-image analysis shows that PC3 flu cells Only a small amount of Gd(III) was associated with the cellular pellet, but PC3 PIP cell pellets The results showed that the net had a high Gd content (Figures 2 and 3). PSMA+PC3 PIP details The cellular pellet contained approximately 22.82 μM of Gd3, followed by Gd2 and Gd1. They had estimated intracellular Gd(III) concentrations of approximately 12.5 μM and 7.2 μM, respectively (Figure 2). Therefore, the difference between ΔR1 in PIP cells and that of flu cells is P in PIP cells. This reflects the changes caused by specific Gd3 binding to SMA.

[0186] Cellular intracellular translocation assays revealed that PSMA+PC3 PIP cells were finely divided between Gd1 and Gd2. The percentage of incubated volume (%ID) that underwent internal migration within the cell after 4 hours of incubation. After the test, the values ​​were found to be 9.06±0.31 and 21.63±3.51, respectively. At that time, only 2.42±0.11 and 3.51±1.32%ID were associated with the cell surface. (Figure 3) Furthermore, slightly higher nonspecific uptake was observed in PSMA-PC3 f It is associated with Gd2 in lunus cells, and this is lower than Gd1's K i Related to the value It is thought that... To further investigate cellular uptake and internal translocation, Rhod amine-Red TM-X-labeled dual-modality Gd monomer contrast agent We prepared and confirmed the PSMA-mediated internal transfer of this class of contrast agent (Figure 5D). As expected, this substance is only found in PSMA+PC3 PIP cells (Figures 5A-5C). It showed specific and high accumulation. These results suggest that the cell receptor expressed at this level... This demonstrates that these simple target substances can be detected by MRI.

[0187] Time-dependent internal transition studies were conducted at 1, 4, and 24 hours after incubation to Gd3. The cells followed (Figures 6A and 6B). Intracellular uptake after 1 hour and 4 hours was high and specific. Yes, in PSMA+PC3 PIP cells, the values ​​were 28.30±0.47 and 39, respectively. The ID was 92±3.59%, and 24 hours after incubation, it was approximately 89.69± 3.90% ID was observed. A similar amount of Gd (approximately 33-37% ID) was observed at the same time point. These results were linked to the cell membrane in PSMA+PC3 PIP cell pellets. Gd3 detectable T1-weighted enhancement in PIP cells and Gd in PSMA+PIP cells It shows a strong correlation with the highly specific accumulation of 3.

[0188] Prior to evaluating Gd3 in the case of imaging live mice, its biocompatibility should be assessed. The cell proliferation assay was used to investigate the effects of various concentrations of Gd3 in PSMA+PC3 PIP and PSMA-PC3 flu cells were incubated with Gd3 for 24 hours. Gd(III) concentration up to 1 mM did not have a significant effect on the survival rate of SMA-flu cells. (i.e., a survival rate of approximately 90%) (Figure 7). However, the Gd(III) concentration >1 mM The degree of PS affected the viability of PSMA+PC3 PIP cells (Figure 8). Observed levels of PS MA+PC3 PIP cell death is characterized by high intracellular translocation of Gd3, and the long incubation period used. This is thought to be due to the 24-hour interval.

[0189] In vivo MR imaging was performed using subcutaneous implantation in the right and left lower flanks of the PS. Male N with MA+PC3 PIP (right) and PSMA-PC3 flu (left) tumors. In OD / SCID mice, intravenous administration of Gd3 (0.05 mmol / kg dose) at a dose of 9.4 tablets was performed. It was performed after the injection. During the first 20 minutes after the injection, in both PIP and flu tumors, non No specific uptake occurred. A sharp decrease in T1 levels was observed in all tissues, and P SMA flu had the highest response time at 0.63 seconds, followed by PIP tumors at 0.57 seconds and muscle at 0.2 seconds. This lasted 61 seconds. Importantly, it allowed for rapid clearing of contrast agents from muscle and flu tumors. Lance was observed. Contrast enhancement in PIP tumors was most pronounced 40 minutes after injection. The percentage was also high at 36%, and remained high at 30% until 1.5 hours after injection. At 3 hours, muscle Furthermore, it was confirmed that the T1 values ​​of flu tumors returned to their initial values, and the T1 values ​​of PIP tumors showed no significant change. It did not show any transformation.

[0190] In vivo MR imaging of Gd3 was performed, and the images were subcutaneously implanted in the right and left lower flanks, respectively. Patients with PSMA+PC3 PIP and PSMA-PC3 flu tumor xenografts The procedure was also performed after a single bolus intravenous injection (0.06 mmol / kg) in Uss. Figure 9A shows: Quantitative contrast imaging of 1 mm sections of both tumors 40–160 minutes after injection. Hans mapping is shown (ΔR1). Contrast enhancement is PSMA + PC3 PI. It remained constant within the P tumor for at least 3 hours, but PSMA-PC3 fl In tumors and muscle tissue, the levels decreased rapidly. PSMA+PC3 PIP tumor (Figure) The change in T1 value in Figures 10A and 10B) is lowest at 1819± during the first 40-60 minutes. It reached 76ms (mean ± SD, mean 36% enhancement in R1 value, n=4), and 90 It remained constant at 29% until 190 minutes after injection, and then slowly decreased to 24%. In the case of PSMA-PC3 flu tumors, the highest contrast enhancement is achieved from 2 injections. At 0 minutes, it was approximately 24%, and then the contrast enhancement rapidly decayed (at 40 minutes, ΔR1 < 20%. These results were obtained 80 and 120 minutes after injection of PSMA + PC3 This demonstrates specific contrast enhancement (P ≤ 0.05) for PIP tumors. As shown in Figure 9B, these results were obtained using the same trimer Gd probe that does not have a target region. Other mice administered using the same method (no tumor enhancement was observed) (Mastaron) A direct comparison was made with e, 2011.

[0191] Under the same experimental conditions, a control study using physiological saline (PBS) showed PIP and f No change in T1 levels was observed for lu tumors (Figure 12).

[0192] While not intended to confine to any particular theory, when combined with PSMA, the rotational correlation of Gd3 is observed. The time increased compared to the unbonded state. Bonding also altered the hydration number and water exchange rate for each substance. The relaxation level changed from what was expected based on the relaxation level of the free contrast agent. This is possible (Caravan et al., 2007). Also, rotation in a high magnetic field. Extending the correlation time slightly reduces the degree of relaxation due to the interaction between the contrast agent and cellular components. (Caravan, P., et al. 2009; De Leon-Rodrig uez,LM,et al.2010;Geninatti-Crich,S.20 11) Highly sensitive multimer Gd(III) in combination with established PSMA target small molecules By enhancing the complex, PSMA-targeted MR can be achieved in vitro and in vivo. Molecular imaging was performed.

[0193] In summary, the Gd-based contrast agent Gd3 was used in in vitro studies using mouse xenografts. It could be used for PSMA-specific MR imaging in vo. Prostate cancer and other Optimization of the construct is underway for translational use in cancer.

[0194] Example 2 PSMA receptor concentration Number of receptors per cell (NRC) = 4.9 x 10 6 , r 細胞 = 8.75 μm

[0195]

number

[0196]

number

[0197] Therefore, 0.05 seconds -1 Changes in organization (organization t 0 (Assuming 1 = 2 seconds, this represents an enhancement of approximately 10%) To observe this, a degree of relaxation is necessary (if the receptor:contrast ratio is 1:1).

[0198]

number

[0199] Example 3 Prostate-specific membrane antigens for dose measurement estimation 86 Preclinical evaluation of Y-labeled inhibitors overview 86 Y (Half-life = 14.74 hours, 33%β) + ) is a long-term image of a biological process. It is included in the new positron-emitting isotopes with relatively long physical half-lives that enable this process. Three low molecular weight molecules in rodent experimental models. 86 Y-labeled PSMA-conjugated urea (Figure 14) Production and in-vivo distribution surveys, and corresponding 90 Y- and 177 Preparation for clinical trials with Lu-labeled substances Imaging of the most pharmacokinetically favored substances in non-human primates for radiation dose measurement. This has been reported.

[0200] [ 86 Multi-step synthesis was used for the preparation of Y]-4~6. Evaluated by Ssey. In vivo characteristics using male mice with tumors [ ] 86 Regarding Y]-4~6, and also 24 hours after injection at [ 86 Y]-4 and [ 86 This was conducted by studying the in vivo distribution of Y-6 using quantitative whole-body PET scans. By recording the chant, we can learn about the dynamics of 14 organs in male baboons. 86 Y]-6 It was measured using [a specific method / tool].

[0201] Compound [ 86 Y]-4~6 was obtained with high radiochemical yield and purity, and its specific activity was 83.92 G. The concentration exceeded Bq / μmol. PSMA1 / 2 positive PC-3 PIP and PSMA negative. PET imaging and in vivo distribution studies using mice with tive PC-3 flu tumors. From research, [ 86 Y]-4~6 in PSMA-positive PC-3 PIP tumors, by injection or It showed high site-specific uptake starting 20 minutes later, and remained high after 24 hours. It was found that the compound [ 86 Y]-6 shows the highest tumor uptake and retention, 5 32.17±7.99% and 15.79±6.44% doses per hour and 24 hours, respectively. The value was g(%ID / g). Low radioactivity concentrations were found in blood and other tissues that express PSMA, excluding the kidneys. It was associated with normal organs. PET imaging in baboons showed that all organs were associated with normal organs. It was revealed that there are two phases (rapid and slow) of clearance, and in 25 minutes the kidneys... The uptake was highest (8% ID / g). Using individual absolute uptake kinetics, OL The radiation dose was calculated using INDA / EXM software. The highest average absorbed dose was measured in the renal dermis. Recognized for its quality, 1.9 mGy / MBq[ 86 The result was Y]-6.

[0202] Materials and methods Solvents and chemicals obtained from commercial sources are of analytical grade or higher, and further purified... It was used without any issues. 9-Fluorenylmethyloxycarbonyl (Fmoc) protected amino Acid (containing Fmoc-Lys(Boc)-Wang resin), 1-hydroxybenzotrione Zol monohydrate and 2-(1H-benzotriazol-1-yl)-1,1,3 ,3-tetramethyluronium hexafluorophosphate (HBTU) is all Chem Impex International Inc. (Wooddale, Illinois) I bought it. Carrierless [ 86 Y](NO3)3 is National Cancer Institute tute of the National Institutes of Healt Obtained from h (Bethesda). DOTA-tris(t-butyl ester)-monoacid and p- SCN-Bn-DOTA(B-205) is a licensed product of Macrocyclics, Inc. (Dallas). Purchased from Texas. Yttrium(III) nitrate, triethylsilane (Et3 SiH), diisopropylethylamine (DIEA) and triethylamine (TEA) are Purchased from Sigma-Aldrich (St. Louis, Missouri, USA). Other chemicals All scientific materials, unless otherwise specified, are Thermo Fisher Scientific. Purchased from IC (Pittsburgh, Pennsylvania). Analytical thin-layer chromatography ( Aldrich aluminum backing 0.2mm silica gel Z19, 329- The procedure was performed using one plate, under ultraviolet light (254 nm), and using I2 and 1% ninhydr in EtOH. Visualized with phosphorus. Flash chromatography was performed using Bodman (Aston, Pencil). I used silica gel MP SiliTech 32-63 D60A purchased from Vanilla. The experiments were conducted using the following methods. Reproducibility was ensured by performing all experiments in duplicate or triple replication. 1 1H NMR The spectrum is displayed on the Bruker Ultrashield. TM The data was recorded using a 400MHz spectrometer. The chemical shift (δ) is the incomplete deuteration of the NMR solvent. The proton resonances resulting from the ration are reported in ppm and downfield. Low-resolution ESI mass spectra are obtained from Bruker Daltonics Esquire. Obtained from a 3000 Plus spectrometer (Billerica, Massachusetts). High-resolution mass. The spectrum was obtained from the University of Notre Dame Mass Spe Proteometry & Proteomics Facility (Notre Dame, India) From Iana State, using ESI, direct injection with Bruker micrOTOF-II, Alternatively, C connected to Bruker micrOTOF-Q II 18 Ultra-high with column It was obtained by LC elution using a pressure-controlled Dionex RSLC system.

[0203] High-performance liquid chromatography (HPLC) can be used to determine 4-6 and [ 89 Purification of Y4-6, W A Phenomenex installed on an Aters 600E Delta LC system C 18 Luna 10x250mm 2 The column is a Waters 486 tunable wavelength UV / Vi column. This is done using the s detection device together with Empower software (Waters C Controlled at the facility (Milford, Massachusetts) (Figure 15A and (Figures 15B, 16A and 16B, 17A, 17B and 17C). HPLC is performed as follows: By this method, solvent A (0.1% TFA, in water) and solvent B (0.1% TFA, aceton The procedure was performed using (during trilling). Method 1: The elution gradient was 75%A and 25%B (5 mins). ), 75%A~60%A and 25%B~40%B (5~25 minutes), 60%A~75%A and The concentration was 40% to 25% (25 to 30 minutes), and the flow rate was 8 mL / min. Method 2: Flow rate 8 mL / min. Elution gradients are 100% A and 0% B (0-5 min), 100% A-45 min. The values ​​were %A and 0%B to 55%B (5 to 45 minutes). 86 HPLC purification of Y4-6 Varian Prostar system with Model 490 UV absorbance detector (Paroa (California, California) and Bioscan Flow-count System (Bio Bioscan NaI scintillator (connected to scan, Washington D.C., USA) This was done using a suction detector. 86 For HPLC purification of Y4-6, see Waters No. vapak C 18 150 x 3.9 mm 2 A column was used. HPLC was performed using the following method. Using solvent A (0.1% TFA in water) and solvent B (0.1% TFA in CH3CN) The procedure was performed with a flow rate of 1 mL / min. A 25-minute gradient test was conducted using 85%A and 15%B (iso). cratic) method [ 86 Used for the purification of Y4. Gradient method (0-5 minutes: 78% A and (22%B, 5-25 minutes are 78%A-58%A and 22%B-42%B) 86 Y]5 The gradient method was used (0-5 minutes: 88% A and 12% B, 5-25 minutes: 88% A-6 8%A and 12%B~32%B) 86 It was used in the purification of Y]6. The specific activity was determined by UV absorption. Retention time of the product during preparative HPLC purification, divided by the mass corresponding to the area under the curve. The radioactivity eluted was calculated. When all final compounds were measured by HPLC, > It was obtained with a radiochemical purity of 95%. Compound 1 was prepared according to a previous report (Ba nerjee, Pullambhatla, Byun, et al., 2011). combination Regarding items 4 and 5, 4 was previously reported (Banerjee et al., 2010) ) Furthermore, item 5 was prepared using the same general method, which will be briefly described later.

[0204] Synthesis and Radiochemistry (13S,27S,31S)-4,7,10-Trivenzyl-2,5,8,11,18, 21,29-heptaoxo-1-(4,7,10-tris(carboxymethyl)-1,4 ,7,10-tetraazacyclododecane-1-yl)-3,6,9,12,17,22, 28,30-Octazatriacontane-13,27,31,33-tetracarbon Acid, 5 Compound 5 was prepared according to the prior report outlined in Scheme 4 ((Banerj ee et al., 2010). Compounds 3 and 4 were prepared according to the solid-phase peptide method. Fmoc-Lys(Boc)-Wang resin (100 mg, 0.43 mM) was used in CH2 The solution was swollen with Cl2 (3 mL), followed by DMF (3 mL). A 0% piperidine solution is added to the resin, and then it is mixed in a mechanical shaker for 30 minutes. The resin was gently shaken at ambient temperature. The resin was then mixed with DMF (3 x 3 mL) and CH2Cl2 (3 x 3 mL). Washed with [method]. The generation of free amines was tested using the Kaiser test (Kaiser et al., 197). Evaluated at 0). After swelling the resin with DMF, Fmoc-Phe-OH(3 Solutions of HBTU (3 eq), HOBt (3 eq), and DIPEA (4.0 eq) The mixture was added and gently shaken for 2 hours. Next, the resin was mixed with DMF (3x3 mL) and Washed with CH2Cl2 (3 x 3 mL). Coupling efficiency was evaluated by the Kaiser test. The sequence described above is Fmoc-Phe-OH and DOTA-(t-butyl ester) The coupling step was repeated two more times with 3-CO2H. The final compound was, When TFA / CH2Cl2(1 / 1) is used to cleave the resin and concentrate it under vacuum, product 3 is obtained. The concentrated product was then processed by C 18 Purified using a SepPak Vac 2g column. The product was eluted with a solution of 70 / 30 water / acetonitrile (each containing 0.1% TFA). It was freeze-dried. ESI-MS:974[M+H] + 3 (15 mg, 15.4 μm In a solution of 1 ol (in 1 mL of DMSO), add 1 (15 mg, 26.18 μmol) and TEA. (30 μL) was added and allowed to stand at ambient temperature for 2 hours. After solvent removal, compound 5 was used. Purified by HPLC (Method 1). 1 1H NMR (DMSO-d6) δ:8.64(m, 1H) ), 8.44(m, 1H), 8.29-8.18(m, 2H), 7.77-7.75(m , 2H), 7.30-7.17(m, 15H), 6.35-6.33(m, 2H), 4. 65-4.63(m, 2H), 4.17-2.59(m, 26), 2.40-1.11( m, 30H). 13 C NMR(DMSO-d6)δ:175.00, 174.64, 17 3.82, 173.52, 172.11, 172.02, 171.05, 170.95, 158.20, 157.88, 157.39, 137.79, 137.67, 137.5 2, 129.52, 129.34, 129.27, 126.35, 54.01, 53.6 1, 52.36, 51.74, 38.37, 38.31, 37.65, 35.52, 31 .88, 29.98, 28.95, 27.61, 25.33, 22.92, 22.73. ESI-MS:1431[M+H] + HRESI+-MS:C 69 H 96 N 12 O21 About The theoretical value is 1431.7042 [M+H] + Measured value: 1431.7064.

[0205] (21S,25S)-8,15,23-Trioxo-1-((4-((1,4,7,10 -Tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-2 -Iyl(methyl)phenyl)amino)-1-thioxo-2,7,16,22,24-phenyl) Taazaheptacosan-21,25,27-tricarboxylic acid, 6 Compound 6 was prepared in the following three steps. Tan (27 mg, 0.15 mmol, in 0.5 mL of DMSO) is 1,4,7,10-T Traazacyclododecane-1,4,7,10-tetraacetate,2-[(4-isothiocyanate] Tophenyl(methyl)(p-SCN-Bn-DOTA) (100 mg, 0.15 mmol) Mix with 1.5 mL of DMSO and DIEA (132 μL, 0.75 mmol), The mixture was stirred at 40°C for 4 hours. The solvent was evaporated, and the solid residue was subjected to reversed phase C. 18 flash Chromatography (5.5g, Agilent SF10) with water and acetonitrile ( Each was purified with 0.1% TFA, and Boc-protected 7 was obtained after lyophilization. Yield: approx. 55%. ESI-MS 740[M+H] + The compound obtained in this step is then ice-collapsed. The mixture was treated with a TFA / CH2Cl2(1 / 1) solution and stirred at ambient temperature for 2 hours. The medium was evaporated, the residue was dried under vacuum, and reverse-phase flash chromatography (5.5g) was performed. When purified with Agilent SF10, compound 7 was obtained in a reasonable yield. 1 1H NMR (DMSO-d6)δ:8.80-8.64(m, 1H), 8.12-7.90(m, 2 H), 7.75-7.10(bm, 4H), 4.65-4.63(m, 1H), 4.17 -2.59(m, 27H), 2.40-1.11(m, 6H). ESI-MS:640[ M+1] + 7 (11 mg, 17 μmol, in 400 μL of DMSO) solution to 1 (10 mg, 17.4 μmol, in 200 μL of DMSO) and DIEA (27 μL, 170 μ (mol) was added and allowed to stand at ambient temperature for 2 hours. After solvent evaporation, the residue was dissolved in water. After dissolution and purification by HPLC (Method 2), compound 6 was obtained. t , 22.5 minutes. 1 1H NMR (DMSO-d6)δ:8.88(m, 1H), 8.44(m, 1H), 8.21-7. 98(m, 2H), 7.77-7.75(m, 2H), 6.35-6.33(m, 2H) , 4.65-4.63(m, 2H), 4.17-2.59(m, 29H), 2.40-1 0.11 (m, 30H). HRESI-MS:C 48 H 77 N 10 O 17 Theoretical value for S, 10 97.5183[M+H] + Measured value: 1097.5212.

[0206] [ 89 Y]4 4 (10 mg, 9.11 μmol, in 500 μL of 0.5 M NaOAc, pH 6.8) Add 50 μL of YNO3 (0.5M) to the solution of ) and steep the mixture (pH 6.1) for 30 minutes. Incubated at 90°C for a period of time. EDTA (200 μL, 30 mM, pH 6.0) Add the solution of ) and incubate the reaction mixture at 40°C for 10 minutes until unreacted. Yttrium(III) was complexed. The resulting compound was analyzed by HPLC (Method 2, R). t ,twenty one The solution was purified (in minutes), concentrated by evaporation, and freeze-dried. ESI-MS: 1370[M+H] + . C 60 H 87 N 11 O 20 Theoretical value for Y: 1370.5187; Measured value: 1370.54 35.

[0207] [ 89 Y]5. Method 2(R t HPLC purification by (26 minutes). ESI-MS: 1517[ M+H] + . C 69 H 96 N 12 O 21 Theoretical value for Y, [M+H] + 1516.5793;measurement Fixed value 1516.5793

[0208] [ 89 Y]6 HPLC, Method 2, R t , 23 minutes. HRESI+-MS. C 48 H 77 N 10 O 17 About SY The theoretical value is 1183.4007 [M+H] + Measured value: 1183.4020.

[0209] Radiochemistry: 86 Y]4~5 and [ 86 The radial label of Y]6, 86 What was explained in Y]6 It was done using the same general method.

[0210] [ 86 Y]6 A freshly prepared solution of ascorbic acid (50 μL, 220 μg) 86 YNO3(111 Add ~148 MBq (3~4 mCi) to a solution (in 500 μL of 0.1 M nitric acid). This prevented radiolysis. Approximately 50-70 μg of 6 (0.3 Add M NaOAc (under N2, purged for 2-3 minutes) to the solution, pH The mixture was neutralized by adding 60 μL of 3M NaOAc until it reached approximately 5.5-6, and then the mixture was mixed. The mixture was briefly vortexed, then incubated at 95°C for 20 minutes. The substance was diluted with 1 mL of water. For complexation, aliquots of 10-15 μL of the solution were subjected to HPLC. The product was monitored by injection. Radiolabeled product [ 86 Y]6, ITLC (Gelma Measurements using an ITLC strip (10mM EDTA) showed approximately 90-95% radiation. It was obtained with chemical yield and radiochemical purity >98%. A broad radioactive peak was observed. t , about 13.9 The desired product as a mixed isomer compound is obtained in approximately 14.8 minutes, and the free ligand is... Regarding R t The time was 15.8 minutes. The specific activity was >83.92 GBq / μmol (n=5). The acidic eluate was neutralized with 20 μL of 1 M sodium carbonate solution, and the volume of the eluate was measured. The solid residue was reduced to a vacuum-dried state. For in vivo distribution and imaging studies, It was diluted with physiological saline to the desired radioactivity concentration. Interestingly, the neutralization of the elution peak and After evaporation, when the tracer was reinjected into HPLC, a single peak was isolated at approximately 14.3 minutes. [ 86 To confirm the isomerization of Y6, compound 6 was added to a support. 86 Radiation labeling with Y, mixed The mixture was analyzed by HPLC. Only one peak was isolated at 14.3 minutes. 86 Y]4~5 For this, a single radially labeled peak was isolated.86 Y]4's R t It took 14.0 minutes Yes, non-chelated 4 R t It was 15.5 minutes, [ 86 In Y]5, R t = 16.9 minutes, non-K In rating 5, R t It took 19.5 minutes.

[0211] Animal models and assays PSMA inhibitory activity was evaluated using a fluorescence-based assay (Banerjee, Pullambha). The enzyme inhibition constant (K) was measured using tla, Byun, et al., 2011. i value ) using the Cheng-Prusoff transform (Cheng and Prusoff, 1973) We sought a sub-strain of androgen-independent PC-3 human prostate cancer xenografts (B anerjee, Pullambhatla, Byun, et al., 2011). child These sublineages express high levels of PSMA (PC-3 PIP) or naturally low levels. It has been genetically modified to produce PSMA at a certain level (PC-3 flu) (D r. Warren Heston, Cleveland Clinic, Cleveland (Ohio).

[0212] Both PSMA-expressing (PC-3 PIP) and non-expressing (PC-3 flu) cell lines were used. 10% fetal bovine serum (FBS) (Invitrogen) and 1% Pen-Strep ( In RPMI 1640 medium (Invitrogen) containing biofluids... It was grown as described above (Banerjee, Pullambhatla, Byun, et al., 2011).

[0213] 6-8 week old male non-obese diabetic mice (NOD) / severe combined immunodeficiency (SCID) mice Charles River Laboratories has PSMA+PC-3 PIP and PSMA-PC-3 flu cells (2x10 6 in 100 μL of Matrigel The xenografts were subcutaneously (SC) transplanted to the right and left flanks of the head, respectively. The diameter of the xenografts was 5-7 mm. When the m value was reached, imaging or in vivo distribution assays were performed on mice.

[0214] For in vivo distribution assays, PSMA+PC-3 PIP and PSMA-PC-3 fl u 0.55 MBq (15 μCi) was extracted from the tail vein of NOD / SCID mice carrying xenografts. )of 86 Y-4 or 86 Y-6 was injected. In each case, four mice were given 1 dose from the injection. They were slaughtered by cervical dislocation at 2, 5, and 24 hours later. Heart, lungs, liver, stomach, pancreas, spleen, Fat, kidneys, muscles, small intestine, large intestine, bladder, and PSMA+PC-3 PIP and PSMA- The PC-3 flu tumor was promptly removed. A 0.1 mL blood sample was also taken. The organs are weighed and tissue radioactivity is measured using an automated gamma counter (1282 Compugamma C). Measurements were taken at S, Pharmacia / LKB Nuclear Inc. (Tissue 1g). The percentage of the injected amount per unit (%ID / g) is obtained using a series of diluted samples of the injected radioactivity. The calculations were performed using [a specific method / tool]. All radioactivity measurements were corrected for radioactive decay up to the time of injection.

[0215] Animal imaging Small animal PET and CT For imaging studies, PSMA+PC-3 PIP and PSMA-PC-3 f NOD / SCID mice with lu tumors were anesthetized with 3% and given 1.5% isoflurane. (v / v) was maintained below. Mouse ( 86 Y-4 or 86 In Y-6, n=3. 86 In Y-5, n = 2) 100 μL of 3.33-6.21 MBq (90-168 μCi) of raw vein fluid from the tail vein. A radioactive tracer, formulated in saline solution with a pH of approximately 7, was injected. For the purpose of studying binding specificity, In mice, the known blocking dose of the PSMA inhibitor N-[[[(S)-1-carboxy-3-methyl [Butylamino]carbonyl]-L-glutamic acid (ZJ43) (Olszewski et al., 2004) (50 mg / kg) 86 Subcutaneous injection 30 minutes before the Y-4 injection. And, to another mouse 86 Only Y-4 was injected. At different time points, individuals under anesthesia were administered. Each mouse is placed prone on the scanner gantry, secured with medical tape, and then anesthetic is administered. The flow rate was increased to 0.8 L / min. The image was taken using FORE / 2D-OSEM (2-iterator). Reconstruction was performed using (16 subsets), radioactive decay, scanner latency and scattering. Radiation correction was performed. Partial volume correction (PVC) was not performed. After each PET scan. A CT scan was performed for anatomical co-registration. To facilitate the alignment of PET and CT images, PET and CT scanners A special bed for mice that fits both was used. The mice were under anesthesia and scanned. During the transition between scans, and during both scans, I was unable to move. Next, the reconstructed PET and C The T-image is transformed through rigid body transformation to capture natural landmarks (e.g., mouse limbs and bed contours). Using AMIDE software (sourceforge.net / amide) I manually aligned the position using [a specific method / tool]. I then displayed the data and analyzed it with AMIDE.

[0216] Dynamic whole-body PET and CT images can be viewed in eXplore VISTA (small) Animal PET (GE Healthcare, Little Chalfont, Buckinghamshire) (State, UK) and X-SPECT compact SPECT / CT system (Gamma Medic The images were taken at a Ideas (Northridge, California).

[0217] 86 Y-6 Anubis baboon (baboon) PET imaging Using a male Anubis baboon (8 years old, 27.1 kg) 86 We studied the distribution of Y-6 in the body. During imaging, the baboon was positioned in a supine position. For attenuation correction, low-dose CT images were used. These images were taken immediately before the first and last PET images. The PET and CT images were processed by Herm. es workstation (Hermes Medical Solutions, GREE) Alignment between time points was performed using (Minville, South Carolina). 14 Saw The contours of the organs were visualized on the CT scan with the help of fused PET / CT images. The decay-corrected average radioactivity concentration (Bq / g) was extracted from PET images for each source organ. The outline was drawn onto PET images of the kidneys, renal cortex, and prostate. The decay-corrected total radioactivity per organ quantified within the timeframe is calculated for the first six time points. Regarding the time elapsed (within 1 hour), it showed an almost 1:1 correspondence with the administered radioactivity, and the administered radioactivity It was confirmed that all brain activity was utilized in PET imaging, and subsequently, the total amount administered was measured by urination. It became less. Whole-body retention kinetics using the total amount of radioactivity quantified in each PET image. (retention kinetics) were obtained.

[0218] Nine static PET images were used as a bolus of 80.7 MBq (2.2 mCi). 86 Y -6 administered intravenously at 5, 10, 15, 20, 35 minutes, 1, 2, 3, 5, and 23 hours later. I took a picture. The image was scanned using a Discovery Rx VCT scanner (GE Health). The image was taken in 2D mode using hcare.

[0219] Radiation dose measurement For each time point, the radioactivity concentration (Bq / cm³) 3 ) of the 14 imaged organs Each measurement is taken and multiplied by the volume of the organ to obtain the time point for each organ. The total radioactivity was determined. Next, the measured values ​​were corrected for decay, and the CT density and the volume of the drawn contour were used. Dividing the calculated mass of the baboon's organs by the injected radioactivity gives the following for each time point and each organ. The ratio of the initial radioactivity per gram is obtained (FIA / g). Next, The baboon FIA / g values ​​were converted to human FIA (per organ) using the following equation (Sc hwartz et al., 2011; Woodard et al., 1975).

[0220]

number

[0221] In the formula, whole body mass ヒヒ = 27.1 kg, total body mass ヒト It weighed 73.7 kg.

[0222] In this approach, the radioactivity concentration in a specific tissue relative to the overall concentration in the body is It is assumed that this is maintained across species (i.e., organ concentration / whole-body concentration is the same for baboons and humans). The obtained human FIA values ​​were plotted as a function of time for each organ (9 data points). (Int), it was fitted to a biexponential representation.

[0223]

number

[0224] In the formula, A1, A2, λ1 bio and λ2 bio These are the fit parameters. A1 and A2 The total amount can be used to back-extrapolate the administered radioactivity in each organ. The ratio at zero time (which has been olated) is obtained, and λ1 bio and λ2 bio is biologically clear This is the Lance constant. The time-integrated radioactivity coefficient for each source organ (time-integ). (rated activity coefficient) [TIAC, formerly known as dwell time] The equation for which it was known as (Bolch et al., 2009) is given by As the name implies, we unify equation (2) and the physical decay term λ φ (Use) (Depends on the isotope used.)

[0225]

number

[0226] TIAC 90 Y, 177 Lu and 86 For Y, the corresponding physical breakdowns that are urinated upon are each different. constant: 90 Y λφ = 0.01083h -1 (T 1 / 2 =64.0 hours); 177Lu λφ=0. 00429h -1 (T 1 / 2 (=161.52 hours) and 86 Y λφ = 0.04702h -1 (T1 / 2 The calculation was performed using (=14.74 hours). The absorbed dose of radiation was calculated as time-integrated radioactivity and the absorbed dose. And according to the MIRD absorption ratio method (Bolch et al., 2009), OLI Convert using NDA / EXM software (Stabin et al., 2005) This was obtained by implementing TIAC for the bladder into MIR in OLINDA / EXM. This was obtained using the D bladder model. Input to this model requires whole-body TIAC, which is whole Fitted to body-preservation dynamics

[0227]

number

[0228] This was obtained from the equation. The urination interval was set to 2 hours. Next, TIAC was calculated as OLINDA / E Input into XM (Stabin et al., 2005) and calculate the absorbed dose per unit of radioactivity. This was obtained for 14 organs. Using a specific kidney model in OLINDA / EXM... Renal cortical dose values ​​were obtained using this method. Absorbed dose from organs outside the kidney was obtained from an internal kidney model. This was added to the calculated renal cortical dose. A special prostate model was used for prostate self-dose, and also for the bladder. The external dose was added to the prostate dose as a substitute for the whole-body dose. Unit radiation for the salivary glands The self-dose component of the absorbed dose per unit area is measured using 3D-RD Monte Carlo (EGSn The results were obtained using human CT imaging of the rc (retrograde cytology) and salivary glands. Cross-dose The components were obtained by assuming that the cross-dose for organs of similar size (pancreas) is the same.

[0229] Measured radioactivity concentration per organ at each time point (Bq / cm³) 3 ) Values ​​corrected for collapse Furthermore, the mass of the baboon's organs and the injected radiation were determined from the CT density and the volume of the drawn contour. Dividing by the number of units, the initial radioactivity per gram for each time point and each organ The ratio obtained is (FIA / g). Next, the baboon FIA / g value is compared to human FIA (per organ). The transformation was performed using the equation related to (Olszewski et al., 2004; Schwartz et al., 2011). Next, the obtained human FIA values ​​were compared with time. Plotted as numbers, fitted to a bi-exponential representation, and the time product for each source organ. Calculated radioactivity coefficient (TIAC), formerly known as residence time (Woodard et al.) The value was calculated from al., 1975). Radiation absorbed dose was converted from time-integrated radioactivity to absorbed dose. And according to the MIRD absorption ratio method (Woodard et al., 1975), OL Convert using INDA / EXM software (Bolch et al., 2009) I gained it by doing so.

[0230] Data in Microsoft Excel (Microsoft Corporation) The calculation was performed using ion, 2010, and expressed as mean ± standard deviation (SD). Using m software (GraphPAD), statistical significance at a 95% confidence level was determined. We calculated the threshold and considered P ≤ 0.05 to be statistically significant.

[0231] result Compounds 4 and 5 were synthesized using the solid-phase-liquid-phase combined peptide synthesis method shown in Schemes 4 and 5. Compounds 1 and 4 were prepared as previously reported (Banerjee, Pullambhatla, Byun, et al., 2011). DOTA Conjugate The synthesis of ligand 5 was carried out using a standard fluorenyl methoxycarbonyl (Fmoc) solid phase. Starting with Fmoc-Lys(Boc)-Wang resin using butyl synthesis (SPPS). The procedure was carried out according to Scheme 5. Three phenylalanine residues were attached to the resin-bound lysine. The compound is then plucked, followed by DOTA conjugation, and then the compound is removed from the resin. When cleaved with a 1 / 1 mixture of TFA / CH2Cl2, compound 3 was obtained in a moderate yield (approximately 20%). Next, when the free ε-amine of lysine 3 is conjugated with 1, (Davis (et al., 2009) Compound 5 was obtained. Compound 6 was mixed with commercially available DOTA-benzyl- Socyanate and N-Boc-1,4-diaminobutane (in DMSO) are converted to diisopropyl alcohol. It was synthesized by reacting it at 40°C for 4 hours in the presence of methylamine, followed by Boc By removing the group, compound 7 was obtained in a reasonable yield after purification by HPLC. Next, compound When 7 was conjugated with 1, 6 was obtained in good yield. Stable yttrium ( 89 The Y) complex was prepared by conjugates 4-6 with an aqueous solution of YNO3, as shown in schemes 4-5. It was prepared by incubation at 95°C. 86 / 89 Y(III) labeled compounds 4-5 are gold It contains three carboxylic acids coordinated to the genera, which makes the compound as a whole neutral. However, [ 86 / 89 Y]6 has four coordinating carboxylic acids, which makes the molecule negatively charged overall. It should be mentioned that it is a compound. Radiation tracer [86 Y]4~6, same The general procedure is [ 86 Ligand concentration 10 with Y]NO3 -6 30 minutes in boiling water at M It was prepared by using it in a reaction at pH 5-6.

[0232] [ka] a. (i) 20% piperidine / DMF; (ii) Fmoc-Phe-OH, HOBT, HBTU, X=2 in steps i-ii. The process was repeated twice for X=3, and three times for X=3. (iii) 20% piperidine / DMF; (iv ) DOTA-tris(tert-butyl ester)-CO2H, HOBT, HBTU, DIEA; (v) TFA / TES / H2O ( 98 / 0.5 / 1.5); b. DMSO / TEA, room temperature; c. Y(NO3)3 / NaOAc, pH 5.5, 90℃, 20 min; d. 86Y(NO3)3 / ascorbic acid Sodium hydroxypropyl alcohol (NaOAc), pH 5.5, 90°C, 20 minutes.

[0233] Scheme 4: 4~5 and [ 86 / 89 Y] Synthesis of 4-5

[0234] [ka]

[0235] Scheme 5:6 and [ 86 / 89 Y]6 synthesis

[0236] 86 Y-labeled PSMA targeting compound, 86 Y-4, 86 Y-5 and 86 The compound structure of Y-6 is shown in Figure 14. This demonstrates that the radiolabeling of target compounds yields high yield (approximately 90-97%) and high radiochemical purity (>98%). %) with high specific radioactivity (>83.92GBq / μmol(2.27Ci / μmol)). And so it proceeded. All compounds showed high binding affinity, K i The values ​​range from 0.10 to 4.69 nM. (Table 2)

[0237] [Table 2]

[0238] Small animal PET imaging Whole-body PET / CT images 86 Y-4, 86 Y-5 and 86 Y-6 (Figures 18A, 18B, The results were obtained for Figures 18C, 19A, 20A, 20B, and 20C. Three radiant tracers - All are PSMA+PC-3 PIP tumors and the kidney, a known PSMA-expressing organ. Visualization was made possible two hours after irradiation (Figures 18A, 18B, and 18C). Radiation tray Uptake in the kidney is specific to PSMA expression in the proximal tubules of mice. In addition to being included, some of these substances are purged through elimination pathways (Stabin et al., 2005). material 86 Y-5 is in the gastrointestinal tract, possibly three Phe on the linker portion. Nonspecific accumulation was observed due to increased hydrophobicity caused by the residues. 86 Y-4 PET-CT Considering the short biological half-life of this class of low molecular weight compounds, the image is taken from 1, Images were taken at 4 and 18 hours later. PSMA+PC-3 PIP tumors and kidneys and bladder The presence of radiation tracers was observed for up to 4 hours (Figure 19A). Radiation levels largely disappeared by 18 hours. However, in PSMA+PC-3 PIP tumors... Some radioactivity remained. As a further test of in vivo binding specificity, 86 Y-4 blockade The study involved pre-treating animals with 50 mg / kg of the potent and selective PSMA inhibitor ZJ43. This was done by (Silver et al., 1997). Figure 19B shows that ZJ43 is swollen. Not only within the tumor, but also in the renal cortex, another PSMA-expressing tissue. 86 The Y-4 bond can be blocked. This demonstrates that it is possible (Stabin et al., 2005). Figures 20A and 20B. Figure 20C shows the results 0.5, 2, and 12 hours after injection. 86 PET-CT scans for Y-6 It is an image. Importantly, 86 Y-6 provides faster radiation clearance from normal tissue. It shows signs of clear tumors, and within 12 hours of injection, the radioactivity is mostly excreted from the kidneys, resulting in a clean tumor. Background contrast was obtained. After just 15 minutes, PSMA+PC-3 Clear imaging of PIP tumors was achieved. In particular, 86 Y-6 is 86 Y-4 and 86 Y-5 It does not contain the additional phenylalanine moiety, and contains p-isothiocyanatobenzyl 1,4,7,10 -Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent This utilizes the addition of carboxylates to strongly retain the metal, and also improves its lipophilicity. To reduce.

[0239] Distribution in mice Based on the imaging results, the compound 86 Y-4 and 86 Y-6 is further divided into standard body components Evaluated by fabric assay (Banerjee, Pullambhatla, Byun, et al.) (al., 2011). Tables 3 and 4 show selected results 1, 2, 5 and 24 hours after injection. This shows the %ID / g uptake values ​​in organs. Both radiation tracers are PSMA+PC-3. In PIP tumor xenografts, PSMA-dependent binding was observed. 86 Y-4 showed results as early as 1 High tumor uptake was observed after several hours (29.3 ± 8.7% ID / g), and relatively slow clearing was observed. With Lance, the level was 15.7±1.7% ID / g 5 hours after injection, and 5% after 24 hours. The result was 9 ± 0.8% ID / g. PSMA+PC-3 PIP tumor vs. PSMA-PC-3 The flu tumor uptake ratio was high, ranging from 89 at 1 hour to 229 at 24 hours. Furthermore, normal tissues, such as the heart, liver, stomach, and pancreas, did not show significant uptake (approximately 1% ID). ( / g), decreased to less than 0.02% ID / g after 24 hours. PSMA+PC-3 PI The P tumor-to-muscle ratio was also high, reaching a maximum of 1046 in 24 hours. Renal uptake was As expected, the levels were high, peaking at 244.9±8.8%ID / g after 1 hour, and continued to rise until 24 hours later. The level then decreased to 1.5 ± 0.7% ID / g.

[0240] Table 4 shows, 86 The organ %ID / g uptake values ​​for Y-6 are shown. 86 Y-6 is PS MA+PC-3 rapidly accumulated within 1 hour of injection in PIP tumors, with an uptake value of 26. The concentration was 0.6 ± 1.9% ID / g. The radiotrace concentration was PSMA + PC-3 PIP tumor. The uptake continued to rise internally, reaching a peak of 32.2 ± 8.0% ID / g 5 hours after injection. The tumor's uptake remained high up to 24 hours after injection. In normal organs, for example... For example, blood, heart, liver, spleen, stomach, and pancreas take up little in the first hour, and up to 5 hours later. It decreased to less than 0.4% ID / g. 86 Renal uptake of Y-6 is (1 The values ​​were 86.5±13.6% ID / g and 54.0±9.2% ID / g at 1 hour and 2 hours, respectively. ) 86 The number was far less than in the case of Y-4.

[0241] [Table 3]

[0242] [Table 4]

[0243] Baboon PET imaging and 86 Pharmacokinetics of Y-6 Figures 21A and 21B show PET studies of the liver, salivary glands, kidneys, and bladder using radiation trays. A sacral sac was observed. For quantification purposes, contours were taken of each PET image of the kidney, renal cortex, and the entire prostate. This was drawn in the image. All organs showed two phases (rapid and slow) of biological clearance. The kidneys showed the highest uptake approximately 25 minutes after injection (8% ID / g). 68 percent of the radioactivity disappears with a biological half-life of approximately 1 hour (0.84 hours), and the remainder The radioactivity disappeared with a biological half-life of 16.6 hours. The majority of the radioactivity in the renal cortex (66 %) disappears with a biological half-life of 1.1 hours, and the remaining radioactivity has a biological half-life of approximately 19 hours. It disappeared within a certain period. Significant uptake and retention were observed in the liver and salivary glands. However, 68 Ga-labeled PSMA target substance and 124 / 131 Patients imaged with I-MIP-1095 It was milder compared to PET scans (Zechmann et al., 20 14). Table 5 summarizes the biological clearance dynamics of all organs. Dose calculation The TIAC used is shown in Table 6.

[0244] [Table 5]

[0245] [Table 6]

[0246] Organ absorbed dose Table 7 shows the results in units of mGy / MBq. 86 Y, 90 Y / 177 Organ absorbed dose for Lu This is a detailed list. For all isotopes, the renal cortex has the highest absorption line per unit of radioactivity. The amount received was therefore necessary when developing a patient-specific absorbed dose therapy plan, as the renal cortex It is thought to be a dose-limiting organ for radioactive metals used in therapy (Baechler et al.) al., 2012; Hobbs et al., 2009), the bladder comes next. postural position 86 For Y, the effective dose of 0.099 mSv / MBq was also calculated using OLINDA / EXM. did.

[0247] [Table 7]

[0248] Essay Three methods for measuring non-human primate doses 86 Y-labeled PSMA target material was synthesized and evaluated. These compounds were D, which is bound to a target urea similar to those previously published. Contains OTA- or DOTA mono-amide chelated radioactive metals (Banerjee e t al.,2010;Banerjee,Pullambhatla,Byun,et (al., 2011). DOTA and its derivatives are PET ( 86 Y) or radiopharmaceutical treatment Treatment( 90 It attracted attention because it could be used for both Y). Pharmacokinetics: It binds to PSMA. Radioactive metal chelating agents used, including those specifically designed for compounds. It has been reported that this is a matter of degree. While not intended to tie to any particular theory, this is the main point. This is thought to be due to the total charge of the radioactive ligand and the stability of the metal chelate complex. in particular, 68 Previous information on Ga-labeled PSMA-conjugated DOTA conjugate materials In the report, 68 Ga-4 showed the fastest clearance from normal tissues, including the kidneys. (Banerjee et al., 2010). However, in this study, 86 Unexpectedly high renal uptake of Y-4 was observed. 86 Based on the evaluation of Y-6, radiation therapy is necessary The desired low renal uptake and high tumor retention were demonstrated, followed by dose It was selected for quantitative PET imaging in baboons for measurement.

[0249] In the binding specificity study (Figure 19B), after 1 hour, 86 Almost all of Y-4 binding in the kidneys It was shown to be specific and not due to excretion. The evidence is that it is related to the renal parenchyma rather than the tumor. The fact that blood flow is more systemic and faster in the kidneys means that many of these substances are present in tumors more readily in the kidneys than in the kidneys. This suggests that this may be the reason for the long retention period. PSMA binding affinity is tumor vs. kidney. One factor that is thought to determine the uptake, but other factors such as lipophilicity and charge Plasma protein binding and molecular weight are also thought to play important roles. Amount 1.19mGy / MBq( 90 Y) and 0.245 mGy / MBq( 177 Lu) is Pepu The calculated value of 1.97 mGy / MBq( in reports involving cytoplasmic receptor radiotherapy) 90 Y) and 0 .45mGy / MBq( 177 Lu) (Baechler et al., 2012) (kidney) The values ​​were comparable to those for the cortex (a dose-limiting organ).

[0250] The three commonly used and clinically utilized chelating agents DOTA are all radioactive Used as a ligand. DOTA and many DOTA derivatives are kinetically and thermodynamically stable. This is because it is known to form a complex. The corresponding Y(III) complex is in vi It has been shown in many cases to be stable in VO (a desirable characteristic as a chelating agent). Yes, it exists. Importantly, DOTA is 86 Y(III) is a chemically different type of lanthanide. ,for example 177 Lu(III) and actinides, for example 225 Numerous, including Ac(III) It has also been reported to form stable complexes with trivalent metal ions. Furthermore, PSMA-bound urine The elementary material is stable under the radioactive labeling conditions used in DOTA.

[0251] recent years, 90 Y or 177 Lu-labeled version of PSMA-targeted monoclonal antibody J591 , promising results were obtained in Phase 1 and Phase 2 clinical trials (Bander et al. .,2005;Tagawa,Akhtar,et al.,2013;Tagawa, Milowsky, et al., 2013). In those cases, 111 In te Identifying antibodies were used in dose measurement calculations (Vallabhajosula et al., 2020). 05). These radiolabeled monoclonal antibodies hold potential for tumor detection and treatment. Although it is being considered, its limited tumor targeting ability and relatively high absorbed dose to red bone marrow This is detrimental to routine clinical use. As an alternative approach, 131 I-labeled PSMA Early clinical results using targeted urea small molecules showed high dose delivery to malignant lesions (Z echmann et al., 2014). In these published studies, saliva The glands showed the highest absorbed dose (4.62 mGy / MBq), followed by the liver (1.47 mGy / MBq). Both q) and kidney (1.45 mGy / MBq) followed (Zechmann et al. (l., 2014). The biggest contributor to this salivary gland absorbed dose is the uptake of free iodine. It is thought to exist and has been proven even at relatively high thyroid absorbed doses (0.91 mGy / MBq). However, this does not occur in this study. Generally, the clearance rate from normal organs is the kidney Except, 86 The results for Y-6 have been published (Zechmann et al., 2 Faster than 014.

[0252] In summary, the results of the internal distribution and dose measurements were: 86 Y-6 quantitatively affects PSMA-expressing tumors. It is a promising candidate for ET imaging, and also targets the PSMA. 90 Y-, 177 Lu type It could be a suitable imaging alternative for planning and monitoring radiopharmaceutical therapy. This suggests that.

[0253] Example 4 For PSMA-based targeted radionuclide therapy 177 Lu-SR-VI-71, 203 Pb-SR -VI-71 and 203 Pb-SR-IX-11 0.01~10μCi 177 This figure shows a study of cell uptake using Lu-SRVI71. 24 shows high uptake in PSMA+PIP and very high uptake in PSMA-flu tumors. It shows slight uptake. In addition, internal migration studies have shown that approximately 44% of the total cell-bound radioactivity is It was revealed that it undergoes internal migration. Furthermore, 10 μM N-[ [[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-L-gluta Co-incubation with minic acid (ZJ43) resulted in approximately 90% blockade in PSMA+ cells. This was observed, further confirming the excellent specificity of the substance (Figure 23). In vivo evaluation Standard PSMA+PIP and PSMA-flu mouse xenografts, as well as Figure 25A and Figure 2. SP in an instrument equipped with VECT or ultra-high sensitivity mouse collimator as disclosed in 5B and Figure 25C This was performed using ECT imaging. The highest accumulation of radioactivity was observed in PSMA+PIP tumors. It was visible at all time points. Other visible organs are the kidneys and bladder. 2 hours (59.1±12.8% ID / g) and 24 hours (40.6±5.8 ID / g) (n=4 Studies on in vivo distribution in ) showed high specificity and high uptake and retention in PSMA+ tumors. A flu (approximately 180 PIPs in 2 hours) was actually observed. Uptake was high at 89.3±28.9% in 2 hours, indicating rapid clearing within 24 hours. The trend continued (6.29 ± 3.4% ID / g).

[0254] [Table 8]

[0255] [Table 9]

[0256] [Table 10]

[0257] These results suggest that such low molecular weight herbicides possess the pharmacokinetics desirable for radionuclide therapy. The feasibility of preparing nostic materials is extremely promising. Furthermore, the data shows that This supports the idea that low molecular weight substances of this class can effectively migrate internally when bound to PSMA. It is.

[0258] Example 5 Synthesis and Use of ZCP-01 and Related Materials for PSMA-Based Targeted Radionuclide Therapy overview Various linkers for imaging and possible radiotherapy of PSMA-expressing tumors Preparation and use of PSMA-conjugated urea conjugated to chelated radioactive metals via This patent application is described in several other patents and documents as well as in this patent application (Banerjee, e t al.,2008;Banerjee,et al.,2010;Banerjee ,et al.,2011;Banerjee,et al.,Oncotarget 2011;Banerjee,et al.,2013;Banerjee,et al. (2014). Carbamate scaffolds, including F-18 labeled analogs, disclosed in Figure 29. Novel lysine-carbamate scaffold oxypentanediocate compatible with the fold ( OPA) and aminopentanioic acid (N) corresponding to the "reverse" carbamate scaffold. PSMA inhibitors based on PA have been developed in recent years. F-18 labeled NPA and OPA compound The substance showed selective uptake in xenografts of PSMA-positive tumor mice.

[0259] Radioactive metals for imaging and radiotherapy of PSMA-positive tumors and tissues. For complexation, ZCP-01 and DOTA-PEG-bound lysine OPA carbamate are examples. It is synthesized as follows. International Publication No. 2009 / 002529(A2) for use with urea. Previously disclosed in pamphlet No. 2010 / 108125(A2) and International Publication No. 2010 / 108125(A2) The width-pick metal chelate ligand and linker are used in OPA and NPA scaffolds. By combining it with a novel radioactive material for imaging and / or radiotherapy of prostate cancer, Identifiable material can be obtained.

[0260] Materials and methods (18S,22S)-2,12,20-Trioxo-1-(4,7,10-Tris(Cal) (boxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-6,9, 21-Trioxa-3,13,19-Triazatetracosan-18,22,24-Trica Rubonic acid, ZCP-01 Refer to Scheme 7, Compound 4 (8.5 mg, 0.015 mmol, 200 μL DM) Diisopropylethylamine (27 μL, 0.255 mmol) was added to the solution (in SO). Next, DOTA-NHS (15.2 mg, 0.023 mmol, 200 μL DMS) The solution was slowly added (in O) and stirred at room temperature for 2 hours. The solution was diluted with water and purified by HPLC. HPLC method: Phenomenex C 18 Lun a, 10mm * 250mm, flow rate: 8ml / min, λ: 200nm, 220nm, solvent H2O and CH3CN (0.1% TFA each). Gradient method: 0-20 minutes, 100 / 0 H2O / CH3CN ~ 80 / 20 H2O / CH3CN; 20~30 min 80 / 20 H2 O / CH3CN~0 / 100 H2O / CH3CN;31 min 100 / 0 H2O / CH3C N. HPLC retention time (t r ) = 16 minutes. ESI-MS:954(M+H). Yield: 9.4 mg (approximately 65.7%) after HPLC purification.

[0261] 113 / 115 Preparation of In-ZPC-01 ZPC-01 (5 mg, 5.24 μmol, in 500 μL of 0.5 M NaOAc, p Add 50 μL of InNO3 (0.5M) to the H6.8) solution, and mix the mixture (pH 6) for 3 Incubated at 90°C for 0 minutes. EDTA (200 μL, 30 mM, pH Add solution 6.0) and incubate the reaction mixture at 40°C for 10 minutes. The unreacted indium(III) was complexed with it. The resulting compound was purified by HPLC. (Same as ZPC-01), concentrated by evaporation and freeze-dried. ESI-MS:1066[ M+H] + . C 39 H 64 InN7O 20 The theoretical value for this is 1065.79.

[0262] 111 Preparation of In-ZPC-01 1.0 μl in 0.1N HCl 111 InCl3 (1mCi) in 20 μl 0.2M It was added to 1 mM Ourea-PEG-DOTA in NaOAc. The pH of the mixture was approximately The pH was 4.0. Next, 20 μl of 0.2 M NaOAc was added to adjust the pH to approximately 6. The mixture was maintained at 50°C for 1 hour, and the mobile phase consisted of 90% water (containing 0.1% TFA) and Radioactive HPLC was performed using a non-gradient method including 10% CH3CN (0.1% TFA). Purified. Flow rate: 1.0 mL / min; λ: 200 nm and C 18 Column (25x4.6mm) , Varian microsob-MV 100-5. Radiolabel [ 111 In]ZPC- O1 was eluted in 14.9 minutes, and the unlabeled chelating agent was eluted in 32 minutes.

[0263] Scheme 7

[0264] [ka] a. DCC, N-hydroxysuccinimide, CH2Cl2; b. Diisopropylethylamine, DMSO; TFA / water; d. DO3A-NHS (commercially available from Macrocylics)

[0265] result ZCP-01 and [In]-ZCP-01 showed high binding affinity, and their Ki values ​​were respectively The concentrations ranged from 17.82 nM to 58.21 nM and from 0.29 μM to 0.92 μM (Table 8).

[0266] [Table 11]

[0267] As shown in Figures 34A, 34B, and 34C, the in vi of [In]-ZCP-01 PSMA+PC with voSPECT imaging subcutaneously implanted in the right and left flanks, respectively. 3. Mice with PIP and PSMA-PC3 flu tumor xenografts [ 111 In] -This was done after intravenous injection of ZCP-01. However, [ 111 In]-ZCP-01 is Visualization of PSMA+PC3 PIP tumors and the kidney, a known PSMA-expressing organ, by injection. Although this was possible after 2 and 4 hours, uptake was nonspecific in flu tumors. Within 24 hours of the injection, most of the radioactivity had been eliminated from the tumor and kidneys.

[0268] These results indicate that the pharmacokinetics are desirable for tumor imaging and radiotherapy. The feasibility of preparing such low molecular weight theranostic materials is extremely promising.

[0269] References All publications, patent applications, patents, and other references cited herein are subject to the same conditions as those described herein. This indicates the level of skill of those skilled in the art in the relevant technical field. All publications, patent applications, patents, and other references are included. The references are as if individual publications, patent applications, patents, and other references were referenced more specifically and These provisions are incorporated herein by reference to the same extent as they were individually cited and invoked. The specification refers to numerous patent applications, patents, and other references, but such references It is not the case that these documents constitute part of the general knowledge in that field. It is understood.

[0270] International PCT Patent Application Pu blication No.PCT / US2008 / 007947 to Pomper , M.G., Ray, S., Mease, R.C., Foss, C.fo. r Labeled inhibitors of prostate specifi c membrane antigen (PSMA), biological ev aluation, and use as imaging agents, pub lished 2008 / 12 / 31 (WO 2009 / 002529 A2). International PCT Patent Application Pu blication No.PCT / US2010 / 028020 to Pomper , M.G., Mease, R.C.; Ray, S., Chen, Y.fo r PSMA-targeting compounds and uses ther eof, published 2010 / 09 / 23 (WO2010 / 108125 A2). International PCT Patent Application Pu blication No.PCT / US2008 / 013158 to Chandr an, S.S., Ray, S., Denmeade, S.R., Pompe r, M.G., Mease, R.C.for Prostate specifi c membrane antigen (PSMA) targeted nanop articles for therapy of prostate cancer, published 2009 / 06 / 04 (WO2009 / 070302 A1) . Aime, S., et al.Curr Pharm Biotechnol 2004, 5, 509-518. Artemov, D.Molecular magnetic resonance imaging with targeted contrast agents.J .Cell.Biochem.Oct 15 2003;90(3):518-524. Artemov, D., Mori N., Okollie, B., Bhuj walla, Z.M.Magn Reson Med 2003, 49, 403- 408. Artemov, D., Mori N., Ravi, R., Bhujwal la, Z.M.Cancer Res 2003, 63, 2723-2727. Babich, J.W., Zimmerman, C., Joyal, J., Lu, G.Radiolabeled prostate specific me mbrane antigen inhibitors.US 2013 / 003449 4 A1. Baechler, S., et al.Three-dimensional r adiobiological dosimetry of kidneys for treatment planning in peptide receptor r adionuclide therapy.Med.Phys.2012;39:611 8-6128. Bander, N.H., et al.Phase I trial of 177 lutetium-labeled J591, a monoclonal anti body to prostate-specific membrane antig en, in patients with androgen-independen t prostate cancer.J.Clin.Oncol.2005;23:4 591-4601. Banerjee, S.R., et al.Synthesis and eva luation of technetium-99m- and rhenium-l abeled inhibitors of the prostate-specif ic membrane antigen (PSMA).J.Med.Chem.20 08;51:4504-4517. Banerjee, S.R., Pullambhatla, M., Byun, Y., et al. 68 Ga-labeled inhibitors of pro state-specific membrane antigen (PSMA) f or imaging prostate cancer.J.Med.Chem.20 10;53:5333-5341. Banerjee, S.R., Pullambhatla, M., Shall al, H., et al.Sequential SPECT and Optic al Imaging of Experimental Models of Pro state Cancer with a Dual Modality Inhibi tor of the Prostate-Specific Membrane An tigen.Angew.Chem.Int.Ed.Engl.Sep 19 2011 ;50(39):9167-9170. Banerjee, S.R., et al.A modular strateg y to prepare multivalent inhibitors of p rostate-specific membrane antigen (PSMA) .Oncotarget.2011;2:1244-1253. Banergee, S.R., Pullambhatla, M., Foss, C.A., Falk, A., Byun, Y., Nimmagadda, S ., Mease, R.C., Pomper, M.G.Effect of ch elators on the pharmacokinetics of 99mTc -labeled imaging agents for the prostate -specific membrane antigen (PSMA).J.Med. Chem.2013; 56: 6108-6121. Banergee, S.R., Pullambhatla, M., Foss, C.A., Nimmagadda, S., Ferdani, R., Ande rson, C.J., Mease, R.C., Pomper, M.G.64C u-Labeled inhibitors of prostate-specifi c membrane antigen for PET imaging of pr ostate cancer.J.Med.Chem.2014; 57: 2657 -2669. Banerjee, S.R., Foss, C.A., Pullambha tla, M., Wang, Y., Srinivasan, S.R.F.K.E .Hobbs, M.Baidoo, R.C.Brechbiel, Mease, G.Sgouros, M.G.Pomper, Preclinical eval uation of 86 Y-labeled inhibitors of prost ate specific membrane antigen for dosime try estimates.J Nucl Med 2015. Baur, B.,et al.Synthesis, radiolabellin g and in vitro characterization of the G allium-68-, Yttrium-90- and Lutetium-177 -labelled PSMA ligand, CHX-A’’-DTPA-DUPA -Pep.Pharmaceuticals.2014;7:517-529. Behnam Azad, B., et al.Nanoscale 2015, 7, 4432-4442. Bodei, L., et al.Receptor radionuclide t herapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours. Eur.J.Nucl.Med.Mol.Imaging.2004;31:1038- 1046. Bolch, W.E., et al., MIRD pamphlet No.2 1: a generalized schema for radiopharmac eutical dosimetry--standardization of no menclature.J.Nucl.Med.2009;50:477-484. Boros, E., et al.J Am Chem Soc 2012, 13 4, 19858-19868. Caravan, P., et al.Inorg Chem 2007, 46, 6632-6639. Caravan, P., et al.Contrast Media Mol I maging 2009, 4, 89-100. Chandran, S.S., et al., Characterizatio n of a targeted nanoparticle functionali zed with a urea-based inhibitor of prost ate-specific membrane antigen (PSMA).Can cer Biol.Therapy.2008;7:974-982. Chappell, L.L.et al.Synthesis, characte rization, and evaluation of a novel bifu nctional chelating agent for the lead is otopes 203Pb and 212Pb, Nucl Med Biol, 2 7 (2000) 93-100. Chen, Z., Penet, et al.PSMA-targeted th eranostic nanoplex for prostate cancer t herapy.ACS Nano.2012;6:7752-7762. Cheng, Y.and Prusoff, W.H.Relationship between the inhibition constant (K1) and the concentration of inhibitor which ca uses 50 per cent inhibition (I50) of an enzymatic reaction.Biochem.Pharmacol.197 3;22:3099-3108. Cho, S.Y.et al.Biodistribution, tumor d etection, and radiation dosimetry of 18 F- DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, i n patients with metastatic prostate canc er.J.Nucl.Med.2012;53:1883-1891. Davis, S.L., et al.Bacterial thymidine kinase as a non-invasive imaging reporte r for Mycobacterium tuberculosis in live animals.PloS one 2009; 4:e6297. De Leon-Rodriguez, L.M., et al.MRI dete ction of VEGFR2 in vivo using a low mole cular weight peptoid-(Gd)8-dendron for t argeting.J.Am.Chem.Soc.Sep 22 2010;132(3 7):12829-12831. Evans, M.J., et al.Proc Natl Acad Sci U S A 2011, 108, 9578-9582. Frenzel, T., et al.Invest Radiol 2008, 43, 817-828. Geninatti-Crich, S.Contrast Media Mol I maging 2011, 6, 421-425. Ghosh, A.and Heston, W.D.Tumor target p rostate specific membrane antigen (PSMA) and its regulation in prostate cancer.J .Cell.Biochem.2004;91:528-539. Haffner, M.C., et al.Hum Pathol 2009, 4 0, 1754-1761 Haffner, M.C., et al.Mod Pathol 2012, 2 5, 1079-1085. Hanaoka, K., et al.Magn Reson Imaging 2 008, 26, 608-617. Helisch, A., et al.Pre-therapeutic dosi metry and biodistribution of 86 Y-DOTAPhe1 -Tyr3-octreotide versus 111In-pentetreot ide in patients with advanced neuroendoc rine tumours.Eur.J.Nucl.Med.Mol.Imaging. 2004;31:1386-1392. Hillier, S.M., et al.J Nucl Med 2011, 5 2, 1087-1093. Hobbs, R.F., et al. 124 I PET-based 3D-RD dosimetry for a pediatric thyroid cancer patient: real-time treatment planning a nd methodologic comparison.J.Nucl.Med.20 09;50:1844-1847. Huang, C.H.and Tsourkas, A.Curr Top Med Chem 2013, 13, 411-421. Kaiser, E., et al.Color test for detect ion of free terminal amino groups in the solid-phase synthesis of peptides.Anal Biochem 1970;34:595-598. Kam, B.L., et al.Lutetium-labelled pept ides for therapy of neuroendocrine tumou rs.Eur.J.Nucl.Med.Mol.Imaging.2012;39 Su ppl 1:S103-112. Konda, et al.Magma 2001, 12, 104-113. Kulkarni, H.M.W.,et al.First clinical r esults with Lu-177 PSMA-TUM1 for the tre atment of castrate-resistant metastatic prostate cancer.J.NUCL.Med.Meeting Abstr act Vol 55; 2014. Lanza, M., et al.J Nucl Cardiol 2004, 1 1, 733-743. Low, P.S., Chelvam, V., Kim, Y.PSMA bin ding linker conjugates and methods for u sing WO2011 / 106639, WO 2010 / 045598 A2, W O 2009 / 026177A1. Ma, D., et al.Radioimmunotherapy for mo del B cell malignancies using 90 Y-labeled anti-CD19 and anti-CD20 monoclonal anti bodies.Leukemia.2002;16:60-66. Major, J.L.and Meade, T.J.Acc Chem Res 2009, 42, 893-903. Mastarone, D.J.,et al.A modular system for the synthesis of multiplexed magneti c resonance probes.J Am Chem Soc.Apr 13 2011;133(14):5329-5337. McDevitt, M.R. Radioimmunotherapy with alpha-emitting nuclides, Eur J Nucl Med, 25 (1998)1341-1351. Mease, R.C., et al.PET imaging in prost ate cancer: focus on prostate-specific m embrane antigen.Curr.Top.Med.Chem.2013;1 3:951-962. Milowsky, M.I., et al.Vascular targeted therapy with anti-prostatespecific memb rane antigen monoclonal antibody J591 in advanced solid tumors.J.Clin.Oncol.2007 ;25:540-547. Nayak, T.K.and Brechbiel, M.W. 86 Y based PET radiopharmaceuticals: radiochemistry and biological applications.Med.Chem.20 11;7:380-388. Olson, W.C., et al.Clinical trials of c ancer therapies targeting prostate speci fic membrane antigen.Rev.Recent Clin.Tri als.2007;2:182-190. Olszewski, R.T., et al.NAAG peptidase i nhibition reduces locomotor activity and some stereotypes in the PCP model of sc hizophrenia via group II mGluR.J.Neuroch em.2004;89:876-885. Palm, S., et al.Pharmacokinetics and bi odistribution of (86)Ytrastuzumab for (9 0)Y dosimetry in an ovarian carcinoma mo del: correlative MicroPET and MRI.J.Nucl .Med.2003;44:1148-1155. Pomper, M.G., Ray, S., Mease, R.C., Fos s, C.Labeled inhibitors of prostate spec ific membrane antigen (PSMA), biological evaluation, and use as imaging agents.W O 2009 / 002529 A2. Rooney, W.D., et al.Magn Reson Med 200 7, 57, 308-318. Schulke, N., et al.The homodimer of pro state-specific membrane antigen is a fun ctional target for cancer therapy.Proc.N atl.Acad.Sci.U S A.2003;100:12590-12595. Schwartz, J., et al.Renal uptake of bis muth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody.Phys.Me d.Biol.2011;56:721-733. Silver, D.A., et al.Prostate-specific m embrane antigen expression in normal and malignant human tissues.Clin.Cancer Res .1997;3:81-85. Song, Y., et al.J Am Chem Soc 2008, 130 , 6662-6663. Stabin, M.G., et al.OLINDA / EXM: the sec ond-generation personal computer softwar e for internal dose assessment in nuclea r medicine.J.Nucl.Med.2005;46:1023-1027. Tagawa, S.T., et al.Bone marrow recover y and subsequent chemotherapy following radiolabeled anti-prostate-specific memb rane antigen monoclonal antibody j591 in men with metastatic castration-resistan t prostate cancer.Front.Oncol.2013;3:1-6 . Tagawa, S.T., et al.Phase II study of L utetium-177-labeled anti-prostate specif ic membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.Clin.Cancer Res.2013;19 :5182-5191. Tse, B.W., et al.Nanomedicine 2015, 10, 375-386. Vallabhajosula, S., et al.Pharmacokinet ics and biodistribution of 111 In- and 177 Lu -labeled J591 antibody specific for pros tate-specific membrane antigen: predicti on of 90 YJ591 radiation dosimetry based o n 111 In or 177 Lu? J.Nucl.Med.2005;46:634-64 1. Witzig, T.E., et al.Safety of yttrium-9 0 ibritumomab tiuxetan radioimmunotherap y for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma.J.Cl in.Oncol.2003; 21:1263-1270. Woodard, H.Q., et al.Letter: Expression of tissue isotope distribution.J.Nucl.M ed.1975; 16:958-959. Wu, X.et al.Bioconjug Chem 2012; 23, 15 48-1556. Yong,K.and Brechbiel, M.W.Towards trans lation of 212Pb as a clinical therapeuti c; getting the lead in!, Dalton Trans, 4 0 (2011)6068-6076. Yong, K.J.et al.(212)Pb-radioimmunother apy induces G(2)cell-cycle arrest and de lays DNA damage repair in tumor xenograf ts in a model for disseminated intraperi toneal disease, Mol.Cancer Ther.,11(2012 )639-648 Yong, K.J.et al.212Pb-radioimmunotherap y potentiates paclitaxel-induced cell ki lling efficacy by perturbing the mitotic spindle checkpoint, Br.J.Cancer, 108 (2 013)2013-2020. Yoo, J., et al.Preparation of high speci fic activity (86)Y using a small biomedi cal cyclotron.Nucl.Med.Biol.2005; 32:891 -897. Zechmann, C.M., et al.Radiation dosimetr y and first therapy results with a (124) I / (131)I-labeled small molecule (MIP-10 95) targeting PSMA for prostate cancer herapy.Eur.J.Nucl.Med.Mol.Imaging.2014; 41:1280-292.

[0271] In order to ensure a clear understanding, the above topics have been explained in some detail using examples and case studies, Those skilled in the art will see that certain changes and modifications can be made within the scope of the attached claims.

Claims

1. Equation (I): 【Chemistry 1】 (I) (In the formula, Z is tetrazole or CO 2 Q is, Q is H or a protecting group, X 1 and X 2 Each is independently NH or O, a is an integer selected from the group consisting of 1, 2, 3, and 4. c is an integer selected from the group consisting of 0, 1, 2, 3, and 4. Each R 1 , R 2 and R 4 H or C 1 -C 4 It is alkyl, Each R 3 is independently H, C 1 -C 6 alkyl or C 2 -C 12 aryl, and W is independently either O or S. Y is -NH- and can be either present or absent. L is 【Chemistry 2】 A linker selected from the group consisting of, During the ceremony, m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. Each R 5 These are H or each R independently. 6 H or C 1 -C 6 Alkyl -COO R 6 And, n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. The integer being treated is p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. Ch is a chelated portion that may contain one or more metals or radioactive metals. A compound of or a pharmaceutically acceptable salt thereof.

2. The chelated portion is 【Transformation 3】 A group consisting of is selected, where q is the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8. The compound according to claim 1, which is an integer selected from the above. 【Request Item 3】 【Chemistry 4】 【change】 (In the formula, M is a metal or a radioactive metal.) A compound of formula (I), selected from the group consisting of or a pharmaceutically acceptable salt thereof.

4. The metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc, and Y. A compound selected according to claim 1.

5. The compound according to claim 1, wherein the non-radioactive metal is Gd-157 (a stable isotope). 。

6. The aforementioned radioactive metals are Lu-177, Ac-225, Bi-213, Bi-212, and Pb. Selected from the group consisting of -212, Cu-67, In-111, Sc-47, and Y-90. The compound according to claim 1.

7. The radioactive metal is selected from the group consisting of Y-86 and Sc-44, as described in claim 1. Method of loading.

8. The radioactive metal is selected from the group consisting of Lu-177 and In-111, claim The compound described in 1.

9. Contact one or more tumors or cells with an effective amount of the compound of formula (I), Including the formation of an image, The compound of formula (I) is 【Transformation 5】 (I) (In the formula, Z is tetrazole or CO 2 Q is, Q is H or a protecting group, X 1 and X 2 Each is independently NH or O, a is an integer selected from the group consisting of 1, 2, 3, and 4. c is an integer selected from the group consisting of 0, 1, 2, 3, and 4. Each R 1 , R 2 , and R 4 H or C 1 -C 4 It is alkyl, Each R 3 H and C are independent. 1 -C 6 Alkyl or C 2 -C 12 It is Ariel, W is independently either O or S. Y is -NH- and can be either present or absent. L is a linker, and the linker is 【Transformation 6】 Selected from the group consisting of, During the ceremony, m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. Each R 5 These are H or each R independently. 6 H or C 1 -C 6 Alkyl -COO R 6 And, n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. The integer being treated is p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. Ch is a chelated portion that may contain one or more metals or radioactive metals. One or more prostate-specific membrane antigen (PSMA) tumors, or containing a pharmaceutically acceptable salt thereof. Or methods for imaging or treating cells.

10. The chelated portion is 【Transformation 7】 【change】 Selected from the group consisting of, in the formula, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. The method described in item 9.

11. The aforementioned compound, 【Transformation 8】 【change】 【change】 (In the formula, x is selected from the group consisting of 2 and 3, (M is a metal or radioactive metal.) The method according to claim 9, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof. 。

12. The metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc, and Y. The method according to claim 9, which is selected.

13. The imaging includes magnetic resonance imaging (MRI), and the non-radioactive metal is Gd The method according to claim 9, wherein the isotope is -157 (stable isotope).

14. The treatment comprises treating one or more prostate-specific membrane antigen (PSMA) tumors or cells, Radioactive metals include Lu-177, Ac-225, Bi-212, Bi-213, and Pb-21 2. Selected from the group consisting of Cu-67, In-111, Sc-47 and Y-90, The method described in item 9.

15. The imaging includes positron emission tomography (PET) imaging, and the radiation The method according to claim 9, wherein the metal is selected from the group consisting of Y-86 and Sc-44.

16. The imaging includes single-photon emission tomography (SPECT) imaging, The radioactive metal is selected from the group consisting of Lu-177 and In-111, as described in claim 9. The method.

17. The one or more PSMA-expressing tumors or cells mentioned above are prostate tumors or cells, metastatic prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma, pancreatic tumors or cells, bladder Tumors or cells, sarcomas, melanomas, mammary gland tumors or cells, colon tumors or cells, germ cells, brown Select from the group consisting of chromocytoma, esophageal tumor or cell, gastric tumor or cell, and combinations thereof. The method according to claim 9, which is selected.

18. Claim 9, wherein one or more PSMA-expressing tumors or cells are prostate tumors or cells. Method of description.

19. The aforementioned one or more PSMA-expressing tumors or cells are in vitro, in vivo, or The method according to claim 9, wherein it is ex vivo.

20. The claim 9 states that one or more PSMA-expressing tumors or cells are present in the subject. method.

21. The claim is that the compound containing the imaging agent is excreted from the tumor or cells of the subject. The method described in item 20.

22. The compound containing the imaging agent, 【Chemistry 9】 【change】 and; (In the formula, (M is a metal or radioactive metal.) A salt selected from the group consisting of or a pharmaceutically acceptable salt thereof, The method according to claim 20, which is eliminated from the kidney of the subject faster than the tumor of the subject. 。

Images