Method for diagnosing or imaging renal cell carcinoma using heterodimeric radioactive compound

Abstract

A method for diagnosing or imaging renal cell carcinoma using a FAPI-RGD heterodimeric radioactive compound. Compared with [18F]FDG / [68Ga]Ga-PSMA, the method has a better detection efficiency and can effectively identify pathological features of the invasiveness of RCC. For RCC patients with a higher WHO / ISUP grade, a higher pT staging, a higher clinical staging and adverse pathological features, there is a significanat increase in the uptake of the heterodimericic radioactive compound, which indicates that the heterodimeric radioactive compound has good potential for predicting the prognosis of RCC. In addition, the heterodimer radioactive compound has a prolonged residence time in tumors, and has a certain therapeutic potential.

Description

A method for diagnosing or imaging renal cell carcinoma using heterodimeric radioactive compounds Technical Field

[0001] The present invention relates to the field of radioactive imaging agent diagnosis or imaging, and in particular to a method for diagnosing or imaging renal cell carcinoma using heterodimer radioactive compounds. Background Art

[0002] Renal cell carcinoma (RCC) is a malignant tumor that originates in the renal tubular epithelium and accounts for 80% to 90% of renal malignant tumors. Globally, the incidence of RCC accounts for approximately 2% to 3% of adult malignant tumors, with significant regional variations in its distribution, with the highest incidence in developed Western countries such as North America and Western Europe. According to the GLOBOCAN 2020 global cancer statistics, in 2020, the global incidence of RCC ranked 14th among malignant tumors, with an age-standardized incidence rate of 6.1 per 100,000 men and 3.2 per 100,000 women, and an age-standardized mortality rate of 4.6 per 100,000 men and 1.8 per 100,000 women. The clinical manifestations of RCC are complex and varied, and early-stage RCC often lacks clinical manifestations. By the time the classic triad of RCC (hematuria, flank pain, and abdominal mass) appears, most patients are already in the advanced stage of the disease. Therefore, early diagnosis of RCC is crucial.

[0003] With the development and widespread use of medical imaging, the detection rate of early-stage renal cell carcinoma has gradually increased. Currently, over 50% of renal cell carcinomas are discovered unexpectedly during examinations for nonspecific abdominal symptoms or other organ diseases. Imaging examinations play a crucial role at various stages of the diagnosis and treatment of renal cell carcinoma: they aid in the detection, localization, characterization, and staging of primary tumor lesions; they assist in intraoperative localization; and they serve as a crucial tool for follow-up after surgery and during non-surgical treatment.

[0004] Positron emission tomography-computed tomography (PET-CT) is superior to traditional imaging methods in detecting lymph node metastasis and distant metastasis of renal cell carcinoma, especially in determining bone metastasis or skeletal muscle metastasis of renal cell carcinoma. It is now widely used in renal cell carcinoma tumor identification, tumor grading and staging, monitoring therapeutic efficacy and judging prognosis. Currently, the most widely used imaging agent in clinical PET-CT is F 18-Fluorodeoxyglucose ( 18 F-fluorodeoxyglucose, 18 F-FDG), but i.v. FAfter 18-fluorodeoxyglucose is taken, approximately 50% of the drug is excreted directly by the kidneys without being metabolized, which can seriously affect the display of renal lesions. On the other hand, the cell membrane GLUT-1 expression of grade I-II renal clear cell carcinoma is low, and the level of fluorodeoxyglucose-6-phosphate degrading enzyme in renal cell carcinoma is too high, resulting in only about half of the primary renal cell carcinoma lesions showing increased fluorodeoxyglucose metabolism, while the other half can show no difference in uptake from normal renal parenchyma. Therefore, 18 F-FDG PET-CT imaging has limited diagnostic value for primary renal cell carcinoma and is not recommended for routine clinical use (Reference 1: Liu, Y. (2016). The Place of FDG PET / CT in Renal Cell Carcinoma: Value and Limitations. Frontiers in Oncology, 6.). Other new imaging agents that have been studied more are fluorine-18 or carbon-11 labeled acetate, which have good imaging effects on well-differentiated and less malignant renal cell carcinomas and can make up for the limitations of single-stage imaging. 18 F-FDG imaging is still in the research stage and is not used as a routine examination. 68 Ga-PSMA is superior to other drugs in detecting renal cell carcinoma and its metastases. 18 F-FDG is not a promising target for renal cell carcinoma. However, the physiological uptake of F-FDG in the kidney is relatively high, and the TBR (target to background ratio) is low (Reference 2: Li Y, Zheng R, Zhang Y, Huang C, Tian L, Liu R, Liu Y, Zhang Z, Han H, Zhou F, He L, Dong P. Special issue "The advance of solid tumor research in China": 68Ga-PSMA-11PET / CT for evaluating primary and metastatic lesions in different histological subtypes of renal cell carcinoma. Int J Cancer. 2023 Jan 1; 152(1): 42-50.). Therefore, there is a huge unmet clinical need in the field of renal cell carcinoma diagnostic imaging both in China and globally.

[0005] [ 68Ga]Ga-LNC1007 is a heterodimeric radioactive compound synthesized from a fibroblast activation protein inhibitor (FAPI) and a cyclic arginine-glycine-aspartate (RGD) peptide sequence, which can simultaneously target fibroblast activation protein (FAP) and integrin α v β3 receptor. Preclinical studies have shown that [ 68 Ga]Ga-LNC1007 has good tumor affinity both in vitro and in vivo, and its uptake and retention in mouse tumors are significantly enhanced compared to single targets. 68 Ga]Ga-LNC1007 can better display RCC, which further advances the [ 68 Exploration of Ga]Ga-LNC1007PET / CT in RCC imaging.

[0006] Summary of the Invention

[0007] In the real world, the present invention surprisingly discovered that a FAPI-RGD heterodimer radioactive compound exhibited excellent detection efficacy in PET / CT imaging of renal cell carcinoma. In addition, the present invention also surprisingly discovered that the FAPI-RGD heterodimer radioactive compound also had great value in distinguishing different pathological characteristics and grades of renal cell carcinoma.

[0008] Specifically, the present invention provides a method for treating, diagnosing or imaging renal cell carcinoma, the method comprising administering to a subject a heterodimeric radioactive compound.

[0009] The present invention also provides a method for diagnosing or imaging renal cell carcinoma, characterized in that the method comprises the following steps:

[0010] Step 1: administering a heterodimeric radioactive compound to a subject;

[0011] Step 2: Imaging the target tissue of the subject using an imaging method.

[0012] Furthermore, the imaging method is an imaging technique based on magnetic resonance imaging, positron emission tomography (PET), computed tomography (CT), positron emission tomography-computed tomography (PET-CT), ultrasound (US), photoacoustic imaging (PAI), near-infrared fluorescence (NIRF), and single photon emission computed tomography (SPECT), or a method related to optical imaging (OI).

[0013] The present invention also provides a method for diagnosing or imaging renal cell carcinoma using PET-CT, the method comprising the following steps:

[0014] Step 1: administering a heterodimeric radioactive compound to a subject;

[0015] Step 2: administering a PET tracer after administering the heterodimeric radioactive compound;

[0016] Step 3: Perform a PET-CT scan on the subject.

[0017] The present invention also provides a method for distinguishing adverse pathological features of renal cell carcinoma, the method comprising administering a heterodimeric radioactive compound to a subject.

[0018] Furthermore, the adverse pathological characteristics include but are not limited to tumor necrosis, sarcomatoid changes, rhabdoid features, etc.

[0019] The present invention also provides a method for grading renal cell carcinoma, the method comprising administering to a subject a heterodimeric radioactive compound.

[0020] Furthermore, the classification is the WHO / ISUP (World Health Organization / International Society of Urological Pathology) classification.

[0021] The present invention also provides a method of treating renal cell carcinoma, comprising administering to a subject a heterodimeric radioactive compound.

[0022] The present invention further provides an application of a heterodimer radioactive compound in the preparation of a drug or imaging diagnostic reagent for treating, diagnosing or imaging renal cell carcinoma.

[0023] The present invention further provides an application of a heterodimer radioactive compound in the preparation of a drug or imaging diagnostic reagent for distinguishing different pathological characteristics of renal cell carcinoma.

[0024] The present invention further provides an application of a heterodimer radioactive compound in the preparation of a drug or imaging diagnostic reagent for grading renal cell carcinoma.

[0025] The present invention further provides a kit for diagnosing or imaging renal cell carcinoma, the kit comprising a heterodimeric radioactive compound.

[0026] The present invention further provides a pharmaceutical composition for treating, diagnosing or imaging renal cell carcinoma, characterized in that the pharmaceutical composition comprises a heterodimeric radioactive compound.

[0027] Furthermore, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent and / or additive.

[0028] Furthermore, the heterodimeric radioactive compound structure described in any of the above items is composed of a dual-targeting compound, a metal chelator and a radionuclide, and the dual-targeting compound and the metal chelator are coupled, and the radionuclide is then connected to the dual-targeting compound through the metal chelator.

[0029] Furthermore, the structure of the dual-targeting compound is as shown in formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof:

[0030] Furthermore, the structure of the heterodimeric radioactive compound is shown in formula (II):

[0031] Wherein, in formula (II):

[0032] The D is a metal chelating agent;

[0033] The R is a radioactive nuclide.

[0034] In some preferred embodiments, the metal chelator is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA).

[0035] In some preferred embodiments, the radionuclide is selected from Tc-99m, Ga-68, F-18, I-123, I-125, I-131, I-124, In-111, Ga-67, Cu-64, Zr-89, C-11, Lu-177, Re-188, Y-86, Mn-52, Sc-44, Y-90, Ac-225, As-211, Bi-212, Bi- 213, Cs-137, Cr-51, Co-60, Dy-165, Er-169, Fm-255, Au-198, Ho-166, Ir-192, Fe-59, Pb212, Mo-99, Pd-103, P-32, K-42, Re-186, Sm-153, Ra-223, Ru-106, Na-24, Sr-89, Tb149, Th-227, Xe-133, Yb-169, Yb-177.

[0036] Preferably, the structure of the dual-targeting compound is as shown in formula (I), the metal chelator is 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the radionuclide is Ga-68 or F-18.

[0037] In some specific embodiments, the structure of the heterodimeric radioactive compound is as shown in formula (III):

[0038] In other specific embodiments, the structure of the heterodimeric radioactive compound is shown in formula (IV):

[0039] Furthermore, the renal cell carcinoma described in any of the above items is clear cell renal cell carcinoma, multilocular cystic renal neoplasm of low malignant potential, papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, renal medullary carcinoma, MiT Family translocation carcinomas, succinate dehydrogenase (SDH)-deficient renal carcinoma, mucinous tubular and spindle cell carcinoma, or renal cell carcinoma), tubulocystic renal cell carcinoma, acquired cystic disease associated renal cell carcinoma, clear cell papillary renal cell carcinoma, unclassified renal cell carcinoma, papillary adenoma, or oncocytomas.

[0040] In some preferred embodiments, the renal cell carcinoma described in any of the above items is clear cell renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is multilocular cystic renal neoplasm of low malignant potential; in other preferred embodiments, the renal cell carcinoma described in any of the above items is papillary renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is chromophobe renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is collecting duct carcinoma. In some other preferred embodiments, the renal cell carcinoma described in any of the above items is renal medullary carcinoma; in some other preferred embodiments, the renal cell carcinoma described in any of the above items is MiT Family translocation carcinomas; in some other preferred embodiments, the renal cell carcinoma described in any of the above items is succinate dehydrogenase (SDH)-deficient renal carcinoma; in some other preferred embodiments, the renal cell carcinoma described in any of the above items is mucinous tubular and spindle cell carcinoma; in some other preferred embodiments, the renal cell carcinoma described in any of the above items is tubulocystic renal cell carcinoma; in some other preferred embodiments, the renal cell carcinoma described in any of the above items is acquired cystic disease associated renal cell carcinoma;In other preferred embodiments, the renal cell carcinoma described in any of the above items is clear cell papillary renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is unclassified renal cell carcinoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is papillary adenoma; in other preferred embodiments, the renal cell carcinoma described in any of the above items is oncocytoma.

[0041] Furthermore, the TNM stage of renal cell carcinoma described in any of the above items is TX, T0, T1, T1a, T1b, T2, T2a, T2b, T3, T3a, T3b, T3c, T4, NX, N0, N1, M0, or M1.

[0042] Furthermore, the clinical stage of renal cell carcinoma described in any of the above items is stage I, stage II, stage III or stage IV.

[0043] Furthermore, the subject described in any of the above items is a mammal.

[0044] Preferably, the mammal is a human.

[0045] Preferably, the human is an adult or a non-adult.

[0046] Furthermore, any of the above-mentioned administration methods is intravenous administration.

[0047] Furthermore, the effective dosage of any of the heterodimeric radioactive compounds described above is 100 to 400 MBq.

[0048] In some preferred embodiments, the effective dosage of the heterodimeric radioactive compound described in any one of the above items is 100 MBq; in other preferred embodiments, the effective dosage of the heterodimeric radioactive compound described in any one of the above items is 400 MBq; the effective dosage of the heterodimeric radioactive compound described in any one of the above items is any integer value in the range of 100 to 400 MBq (such as: 101 MBq, 101 MBq, 102 MBq, 103 MBq, 104 MBq, 105 MBq, 106 MBq, 107 MBq, 108 MBq, 109 MBq, 110 MBq, 111 MBq, 112 MBq, 113 MBq, 114 MBq, 115 MBq, 116 MBq, 117 MBq, 118 MBq, 119 MBq, 120 MBq, 121 MBq, 122 MBq, 123 MBq, 124 MBq, 125 MBq, 126 MBq, 127 MBq, 128 MBq, 129 MBq, 130 MBq, 131 MBq, 132 MBq, 133 MBq, 134 MBq, 135 MBq, 136 MBq, 137 MBq, 138 MBq, 139 MBq, 140 MBq, 141 MBq, 142 MBq, 143 MBq, 144 MBq, 145 MBq, 146 MBq, 147 MBq, 148 MBq, 149 MBq, 150 MBq, 151 MBq, 152 MBq, 153 MBq, 154 MBq, 155 MBq, 156 MBq, 157 MBq 6MBq, 117MBq, 118MBq, 119MBq, 120MBq, 121MBq, 122MBq, 123MBq, 124MBq, 125MBq, 126MBq, 127MBq, 128MBq, 129MBq, 130MBq, 131MBq, 132MBq, 133MBq, 134MBq, 135MBq, 136MBq, 137MBq, 138MBq, 139MBq, 140MBq, 141MBq, 142MBq, 143MBq, 144MBq, 145MBq, 146MBq, 147MBq, 148MBq, 149MBq, 150MBq, 151MBq , 152MBq, 153MBq, 154MBq, 155MBq, 156MBq, 157MBq, 158MBq, 159MBq, 160MBq, 161MBq, 162MBq, 163MBq, 164MBq, 165MBq, 166MBq, 167MBq, 168MBq, 169M Bq, 170MBq, 171MBq, 172MBq, 173MBq, 174MBq, 175MBq, 176MBq, 177MBq, 178MBq, 179MBq, 180MBq, 181MBq, 182MBq, 183MBq, 184MBq, 185MBq, 186MBq, 187 MBq、188MBq、189MBq、190MBq、191MBq、192MBq、193MBq、194MBq、195MBq、196MBq、197MBq、198MBq、199MBq、200MBq、201MBq、202MBq、203MBq、204MBq、2 05MBq, 206MBq, 207MBq, 208MBq, 209MBq, 210MBq, 211MBq, 212MBq, 213MBq, 214MBq, 215MBq, 216MBq, 217MBq, 218MBq, 219MBq, 220MBq, 221MBq, 222MBq,<h2 style=";text-align:left;direction:ltr">223MBq, 224MBq, 225MBq, 226MBq, 227MBq, 228MBq, 229MBq, 230MBq, 231MBq, 232MBq, 233MBq, 234MBq, 235MBq, 236MBq, 237MBq, 238MBq 239MBq、240MBq、241MBq、242MBq、243MBq、244MBq、245MBq、246MBq、 247MBq、248MBq、249MBq、250MBq、251MBq、252MBq、253MBq、254MBq、 255MBq, 256MBq, 257MBq, 258MBq, 259MBq, 260MBq, 261MBq, 262MBq, 263MBq, 264MBq, 265MBq, 266MBq, 267MBq, 268MBq, 269MBq, 270MBq, 271MBq, 272MBq, 273MBq, 274MBq, 275MBq, 276MBq, 277MBq, 278MBq, 279MBq, 280MBq, 281MBq, 282 MBq、283MBq、284MBq、285MBq、286MBq、287MBq、288MBq、289MBq、290MBq、291MBq、292MBq、293MBq、294MBq、295MBq、2 96MBq、297MBq、298MBq、299MBq、300MBq、301MBq、302MBq、303MBq、304MBq、305MBq、306MBq、307MBq、308MBq、309MBq、 310MBq, 311MBq, 312MBq, 313MBq, 314MBq, 315MBq, 316MBq, 317MBq, 318MBq, 319MBq, 320MBq, 321MBq, 322MBq, 323MBq, 324MBq, 325MBq, 326MBq, 327MBq, 328MBq, 329MBq, 330MBq, 331MBq, 332MBq, 333MBq, 334MBq, 335MBq, 336MBq, 337 MBq、338MBq、339MBq、340MBq、341MBq、342MBq、343MBq、344MBq、345MBq、346MBq、347MBq、348MBq、349MBq、350MBq、3 51MBq、352MBq、353MBq、354MBq、355MBq、356MBq、357MBq、358MBq、359MBq、360MBq、361MBq、362MBq、363MBq、364MBq、365MBq, 366MBq, 367MBq, 368MBq, 369MBq, 370MBq, 371MBq, 372MBq, 373MBq, 374MBq, 375MBq, 376MBq, 377MBq, 378MBq, 379MBq, 380MBq, 381MBq, 382 MBq, 383MBq, 384MBq, 385MBq, 386MBq, 387MBq, 388MBq, 389MBq, 390MBq, 391MBq, 392MBq, 393MBq, 394MBq, 395MBq, 396MBq, 397MBq, 398MBq, 399MBq. ) or non-integer values ​​(such as but not limited to 101.5MBq, ... 205.87MBq, ... 345.65MBq, ... etc.); In another preferred embodiment, the effective dosage of any of the heterodimeric radioactive compounds described above is any integer value or non-integer optional range within the range of 100 to 400MBq.

[0049] Furthermore, the diagnosis or imaging described in any of the above items is based on the imaging techniques of magnetic resonance, positron emission tomography (PET), computed tomography (CT), positron emission tomography-computed tomography (PET-CT), ultrasound (US), photoacoustic imaging (PAI), near-infrared fluorescence (NIRF), and single photon emission computed tomography (SPECT) or is related to optical imaging (OI).

[0050] In some preferred embodiments, any of the above-mentioned diagnosis or imaging is based on PET-CT imaging technology.

[0051] The present invention also provides a use of a dual-targeting compound in the preparation of a drug for treating renal cell carcinoma. The dual-targeting compound is a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof:

[0052] The heterodimer radioactive compound provided by the present invention (with [ 68 Ga]Ga-LNC1007 is a promising imaging agent for RCC. 18 F]FDG or [ 68Ga]Ga-PSMA has better detection efficiency and can effectively identify the pathological characteristics of RCC invasiveness. For RCC patients with higher WHO / ISUP grade, higher pT stage, higher clinical stage, and adverse pathological features, the heterodimer radioactive compound provided by the present invention (with [ 68 Ga]Ga-LNC1007 as a representative example) was significantly increased, which suggests that the heterodimeric radioactive compound provided by the present invention (with [ 68 Ga]Ga-LNC1007 as a representative example) PET / CT has the potential to predict the prognosis of RCC. In addition, preclinical and preliminary clinical studies have shown that the heterodimeric radioactive compound provided by the present invention (with [ 68 Ga]Ga-LNC1007 is a representative example) prolonged the retention time in the tumor, indicating that the β- or α-nuclides-labeled dual-targeting compound of Formula I has certain therapeutic potential in advanced renal cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 shows the PET / CT image of patient 1.

[0054] Figure 2 shows the PET / CT images of patient 2.

[0055] Figure 3 from top to bottom are [ 68 Ga]Ga-LNC1007 SUV max Relationship diagram with FAP expression, 68 Ga]Ga-LNC1007 SUV max Relationship diagram with RGD expression and [ 68 Ga]Ga-LNC1007 SUV max Relationship diagram with FAP+RGD expression.

[0056] Figure 4 shows, from top to bottom, the relationship between WHO / ISUP grade and FAP expression, the relationship between WHO / ISUP grade and RGD expression, and the relationship between WHO / ISUP grade and FAP+RGD expression.

[0057] Figure 5 shows, from top to bottom, the relationship between adverse pathological features and FAP expression, the relationship between adverse pathological features and RGD expression, and the relationship between adverse pathological features and FAP+RGD expression.

[0058] Figure 6 shows, from top to bottom, the expression relationship diagrams of TL-1007 and FAP, the expression relationship diagram of TL-1007 and RGD, and the expression relationship diagram of TL-1007 and FAP+RGD.

[0059] Figure 7 shows three cases of renal clear cell carcinoma patients [ 68 Ga]Ga-LNC1007 PET / CT images and immunohistochemical staining. DETAILED DESCRIPTION

[0060] Although the present invention has been described in detail, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also be understood that the terms used herein are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0061] Hereinafter, the key elements of the present invention will be described. These key elements are listed together with specific embodiments, however, it should be understood that they can be combined in any way and in any quantity to produce other embodiments. The examples and preferred embodiments of the various descriptions should not be interpreted as limiting the present invention to the embodiments that are only clearly described. This description should be understood to support and encompass embodiments that combine the embodiments that are clearly described with any number of disclosed and / or preferred key elements. In addition, unless the context otherwise indicates, it should be understood that the description of the present application discloses any arrangement and combination of all described key elements in the present application.

[0062] Throughout the specification and appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of the stated members, integers or steps, but not the exclusion of any other unstated members, integers or steps. The term "consist of" is a specific embodiment of the term "comprise" in which any other unstated members, integers or steps are excluded. In the context of the present invention, the term "comprise" encompasses the term "consist of". Thus, the term "comprising" encompasses "including" as well as "consisting", for example, a composition "comprising" X may consist solely of X, or may include additional contents, such as X+Y.

[0063] In the present invention, different features of the alternatives and embodiments can be combined with one another, unless otherwise indicated.

[0064] For the purpose of clarity and readability, the following definitions are provided. Any technical features mentioned in these definitions can be interpreted in each embodiment of the present invention. Additional definitions and explanations can be specifically provided in the context of these embodiments.

[0065]

definition

[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0067] The term "metal chelator" as used herein refers to a polydentate (multi-bonded) ligand capable of forming two or more separate coordination bonds (or "coordination") with a central (metal) ion. Specifically, one or more molecules sharing an electron pair may also be referred to as a "Lewis base." The chelator of the present invention is preferably selected based on its ability to coordinate the desired central (metal) ion, which is typically a radionuclide to which the present invention relates. Preferably, the "metal chelator" of the present invention is selected from the following compounds or derivatives thereof:

[0068] The term "pharmaceutically acceptable" as used herein refers to compounds or agents that are compatible with the compounds of the present invention and do not interfere with and / or substantially reduce their diagnostic or therapeutic activity. Pharmaceutically acceptable carriers preferably have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject to be treated.

[0069] The term "pharmaceutically acceptable salt" as used herein can be prepared by conventional methods, such as by reacting any free base and / or acid of the dual-targeted compound according to the present invention with at least a stoichiometric amount of the desired salt-forming acid or base, respectively. Pharmaceutically acceptable salts of the present invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, argmme, benzathine penicillin, diethanolamine, ethanolamine, procame, and tromethamine. Pharmaceutically acceptable salts according to the present invention also include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, edisylate, etopoate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methylbromide, methylsulfate, naphthenate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, toluenesulfonate, and triethiodide.

[0070] Dual-targeted compounds and / or heterodimer radioactive compounds disclosed herein can exist in specific geometric or stereoisomeric forms. In addition, compounds can also be optically active. Dual-targeted compounds and / or heterodimer radioactive compounds of the present invention can also include cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures and their other mixtures. Other asymmetric carbon atoms can be present in substituents such as alkyl. For example, if a specific enantiomer of a group or dual-targeted compounds and / or heterodimer radioactive compounds is desired, it can be prepared by asymmetric synthesis or by utilizing chiral auxiliary agents to derive, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cut to provide the pure desired enantiomer. Alternatively, in the case where a group or dual targeting compound and / or heterodimer radioactive compound comprises a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed by a suitable optically active acid or base, and the diastereomers thus formed are subsequently resolved by fractional crystallization or chromatographic means well known in the art, and the pure enantiomer is subsequently recovered. A "stereoisomer" is a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Therefore, a stereoisomerically pure compound with one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound with two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Therefore, the dual-targeted compound and / or heterodimeric radioactive compound structural formula disclosed herein include its enantiomers and / or stereoisomers.

[0071] The "clear cell renal cell carcinoma" described in the present invention is the most common pathological subtype of renal cell carcinoma, accounting for approximately 60% to 85% of renal cell carcinoma. Its histopathology shows that the cancer cells have clear or eosinophilic cytoplasm and clear cell membranes; a delicate vascular network composed of small thin-walled blood vessels can be seen in the tissue; tumor cells have nested and alveolar structures; tumor giant cells can be seen in tumor areas with sarcomatoid differentiation, and tumor cells with rhabdomyosarcoma differentiation can be seen with broad eosinophilic cytoplasm accompanied by eccentric nuclei and prominent nucleoli, indicating a poor prognosis; necrosis, fibromyxoid stroma, calcification, and ossification can be seen in some tumors.

[0072] The "papillary renal cell carcinoma" described in the present invention accounts for approximately 7% to 14% of renal cell carcinomas and is the second most common renal cell carcinoma after clear cell renal cell carcinoma. Its age of onset, male-female incidence ratio, symptoms and signs are similar to those of clear cell renal cell carcinoma. It is divided into two subtypes, type I and type II, based on histopathological changes. The tumor cells are composed of papillary or tubular structures with thin vascular axes. Foamy macrophages and cholesterol crystals can be seen in the core of the papilla; the tumor cells are small with scarce cytoplasm (type I) or the tumor cells have abundant eosinophilic cytoplasm and high tumor cell nuclear grade (type II), with areas of necrosis, sarcomatoid differentiation and rhabdoid differentiation. Studies have shown that patients with type I papillary renal cell carcinoma have a better prognosis than patients with type II.

[0073] The "chromophobe renal cell carcinoma" described in this invention accounts for approximately 4% to 10% of renal cell carcinomas. It can occur in children and the elderly, with an average age of onset of 60 years, and the incidence is roughly equal in men and women. Compared with other subtypes of renal cell carcinoma, it has no specific clinical symptoms or signs. Imaging features often show a larger tumor with uniform tumor density or signal, and the absence of hemorrhage, necrosis, and calcification. Histopathology: The tumor presents a solid, lamellar structure, but may also present as small nests, microcysts, trabeculae, and occasionally papillary structures. Focal calcifications and thick fibrous septa may be present; unlike clear cell carcinoma, the blood vessels in the tumor are thick-walled, not thin-walled; the tumor cells are large and polygonal, with transparent, slightly reticular cytoplasm and very clear cell membranes (chromophobe cells). Tumor cells with eosinophilic cytoplasm may also be seen. The perinuclear halo of the tumor cell nucleus is one of the characteristics of this type, and binucleated cells may also be seen. Recent studies have revealed that there is an oncocytic subtype of chromophobe cell carcinoma, whose histological features include: small cells with fine eosinophilic granular cytoplasm; eosinophils located in the center of the cell nests, while cells with pale cytoplasm are located at the periphery of the cell nests; irregularly shrunken nuclei, chromatin condensation and blockiness, binucleated cells and perinuclear halos can be seen; round cells can also be seen.

[0074] The "low-grade malignant potential multilocular cystic renal cell tumor" described in this document was previously referred to as multilocular cystic renal cell carcinoma in versions prior to 2016. The tumor is composed of multilocular cysts with a cyst wall composed of single or clustered clear cells and a non-expandable growth pattern. Its morphology is indistinguishable from clear cell carcinoma (G1 / 2), lacking necrosis, vascular invasion, or sarcomatoid differentiation. It must be differentiated from clear cell renal carcinoma, which may present with cystic changes, extensive hyalinization, hemorrhage, and hemosiderin deposition. Its immunophenotype is similar to that of clear cell renal cell carcinoma.

[0075] The term "collecting duct carcinoma" as used herein refers to a malignant epithelial tumor arising from the Bellini collecting ducts; the term "renal medullary carcinoma" as used herein refers to a malignant epithelial tumor arising from the collecting ducts of the juxtacortical region. Patients with renal medullary carcinoma almost always have sickle cell hematology. Both types of carcinoma share certain similarities in gross and histological appearance. It is important to note that Bellini collecting duct carcinoma is often a diagnosis of exclusion, and tumor location is crucial for diagnosis. Histologically, irregular tubular structures with highly cellular atypia are observed. Microscopically, renal medullary carcinoma tumors appear poorly differentiated and sheet-like, with tumor cells arranged in adenoid cystic structures. Numerous neutrophil infiltration and sickle-shaped red blood cells are also observed within the tumor.

[0076] The "MiT family translocation renal cell carcinoma" described in this invention includes two types of tumors, each associated with the presence of fusion genes for two transcription factors (TFE3 and TFEB). Xp11 translocation causes TFE3 gene fusion; t(6;11) causes MALAT1-TFEB fusion. This tumor is more common in childhood, accounting for only 1.6% to 4% of adult renal cell carcinomas. t(6;11) renal cell carcinoma is less common than Xp11 translocation renal cell carcinoma. It is generally non-characteristic. Microscopically, Xp11 translocation renal cell carcinoma manifests as papillae formed by clear cells with scattered psammoma-like calcifications, while t(6;11) translocation 11 renal cell carcinoma manifests as cell nests composed of both large and small cells, within which basement membrane-like material can be seen. Immunohistochemistry reveals decreased expression of epithelial markers, such as CK and EMA, and expression of PAX8 and other renal tubular markers. Xp11 renal cell carcinomas partially express melanin markers and TFE3, while t(6;11) renal cell carcinomas consistently express melanin markers, such as HMB45, MelanA, CathepsinK, and TFEB. FISH may reveal TFE3 or TFEB fusion genes.

[0077] Acquired renal cyst-associated renal cell carcinoma (RCC), as described herein, often presents with a history of end-stage renal disease and acquired cystic renal disease, and is most common in patients undergoing long-term hemodialysis. Grossly, the lesions are often bilateral, multifocal, and well-defined, with a surrounding polycystic kidney background. Histologically, they are characterized by microcystic structures and abundant intratumoral deposits of eosinophilic oxalate crystals. Immunohistochemically, they are renal cell carcinoma, positive for CD10 and AMACR, and negative for CK7.

[0078] The "clear cell papillary renal cell carcinoma" described in this invention accounts for 1% to 4% of renal tumors, has no gender predilection, and occurs sporadically or in association with end-stage renal disease or VHL syndrome. Grossly, it presents as a small, well-defined, encapsulated mass, often with cystic changes. Histologically, it demonstrates a papillary architecture with relatively uniform cell size, clear cytoplasm, nuclei arranged away from the basement membrane, visible processes, and G1 or G2 nuclear grading. Tumor necrosis, extrarenal invasion, and vascular tumor emboli are rare. Immunohistochemistry reveals diffuse CK7 positivity, cup-shaped CAIX positivity, PAX2, PAX8, and CK34βE12 positivity, and negativity for P504S and CD10. It should be noted that in cases with atypical morphology, if P504S or CD10 positivity is accompanied by diminished diffuse CK7 positivity, a clear cell carcinoma diagnosis is more likely.

[0079] The "hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma" described in this article refers to a type of renal cell carcinoma associated with germline mutations in the fumarate hydratase gene and associated extrarenal leiomyomatosis. Grossly, the tumor may present as a cystic appearance with prominent mural nodules. Histologically, it resembles papillary renal cell carcinoma or collecting duct carcinoma; intranuclear inclusions and perinuclear halos may be observed in the nuclei. Immunohistochemistry demonstrates loss of fumarate hydratase expression.

[0080] The "succinate dehydrogenase-deficient renal cell carcinoma" described in this article is relatively rare and is mostly hereditary. Grossly, it presents as a well-defined solid mass. Tumor cells are arranged in solid, nested, or tubular structures; the cytoplasm is vacuolated and eosinophilic to clear, with regular, smooth nuclear contours, fine chromatin, and inconspicuous nucleoli (similar to neuroendocrine cells); the cytoplasm is vacuolated; and high-grade nuclei are occasionally present. Immunohistochemistry reveals a loss of succinate dehydrogenase expression, with loss of succinate dehydrogenase B being the most common.

[0081] Tubulocystic renal cell carcinoma, as described herein, is relatively rare and often presents as an incidental tumor during physical examination. Grossly, it presents as a grayish-white sponge-like or Swiss cheese-like appearance. Microscopically, it presents as small to medium-sized tubular structures with large cystic cavities lined by a single layer of flattened, cuboidal, or columnar epithelium, with hobnail-shaped cells present; their nuclei are equivalent to those of G3. Immunohistochemistry positive for high-molecular-weight keratin.

[0082] The "mucoid tubular and spindle cell carcinoma" described in this article accounts for less than 1% of renal tumors. It generally presents as a well-defined solid mass. Histologically, it demonstrates elongated or anastomosing tubular structures with areas of spindle cells visible. The nuclei are low-grade, and the stroma is basophilic and myxoid. Immunohistochemistry is positive for CK7, PAX2, and P504S.

[0083] The term "unclassified renal cell carcinoma" as used in this article currently encompasses cancers that lack the characteristics of established renal cell carcinoma subtypes and can be either low-grade or high-grade. This includes the following types: renal cell carcinomas with pathological features of more than one renal cell carcinoma, renal cell carcinomas with mucinous secretions, renal cell carcinomas with unclassified epithelial components, low-grade or high-grade unclassified oncocytic tumors, and sarcomatoid carcinomas. As our understanding of renal cell carcinoma deepens, the proportion of cases classified as "unclassified" will decrease.

[0084] The TNM staging system described in the present invention was developed by the American Joint Committee on Cancer Staging (AJCC). The present invention uses the 8th edition updated in 2017 (see below). It is understood that if the staging system is adjusted later, it should also be incorporated into the present invention.

[0085] 2017 8th Edition AJCC TNM Staging for Renal Cell Carcinoma

[0086] Clinical staging / prognostic groups for renal cell carcinoma

[0087] The "pharmaceutical composition" described in the present invention is a preparation containing the heterodimeric radioactive compound described in the present invention. It is understood that the pharmaceutical composition may also contain necessary, pharmaceutically acceptable carriers, excipients, diluents and / or additives, and the "carriers, excipients, diluents and / or additives", and each component may exhibit different functional effects. Those skilled in the art can usually select appropriate pharmaceutically acceptable carriers, diluents and / or additives based on the formulation of the pharmaceutical composition / preparation, including but not limited to fillers, bulking agents, carriers, disintegrants, binders, lubricants, glidants, coatings, solvents and cosolvents, buffers, preservatives, adjuvants, antioxidants, wetting agents, defoaming agents, thickeners, sweeteners, flavorings and moisturizers, etc.

[0088] The pharmaceutical composition (or preparation) containing the heterodimer radioactive compound provided by the present invention can be in any suitable form. For example, it can be in solution or powder form, with or without a diluent to prepare an injectable suspension, and can include additional ingredients, including but not limited to a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can be saline, water, lactic acid, mannitol, or a combination thereof (including but not limited to). The excipient of the present invention promotes the processing of the dual-targeted compound and / or heterodimer radioactive compound provided by the present invention into a pharmaceutically acceptable preparation. Appropriate preparation depends on the selected route of administration. Additional details regarding the carriers, excipients, diluents and / or additives described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which or the prior art as to the recognition and definition of excipients are incorporated herein by reference.

[0089] "Subjects" for diagnosis and treatment as described herein generally include humans and non-human animals, and preferably include mammals (e.g., non-human primates, including marmosets, tamarins, spider monkeys, owl monkeys, vervet monkeys, squirrel monkeys, and baboons, macaques, chimpanzees, orangutans, gorillas; cows; horses; sheep; pigs; chickens; cats; dogs; mice; rats; rabbits; guinea pigs, etc.), including chimeric and transgenic animals and disease models. In the context of the present invention, the term "subject" preferably refers to a non-human primate or a human, most preferably a human.

[0090] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0091] [Example]

[0092] Example 1 Real-world study

[0093] Methods: Twenty-five pathologically confirmed RCC patients were enrolled in this study. The maximum standardized uptake value (SUVmax), mean SUV (SUVmean), gross tumor volume (GTV), and total lesion-tracer (TL-tracer) of the lesions were calculated based on the corresponding PET / CT images. Pathological characteristics of all patients, including the World Health Organization / International Society of Urological Pathology (WHO / ISUP) grade and adverse pathological features (tumor necrosis / sarcomatoid changes / rhabdoid features), were also recorded.

[0094] The results are shown in Figures 1 to 7, where:

[0095] Figure 1 shows the PET / CT images of patient 1 (57-year-old female, diagnosed with renal papillary cell carcinoma, WHO / ISUP grade II). 68 Ga]Ga-LNC1007, the control group was [ 18 F]FDG. 68 Ga]Ga-LNC1007 PET / CT (see a, b, and c in Figure 1) showed the primary lesion in the right kidney (indicated by the triangle arrows in b and c, SUV max 6.8) and retroperitoneal lymph node metastases (arrows in b and c, SUV max 13.2) have a higher uptake of imaging agents. 18 F]FDG PET / CT (see d, e, and f in Figure 1) showed similar imaging agent uptake in the primary lesion of the right kidney (indicated by the triangle arrows in e and f, SUV max 6.6), but the uptake of lymph node metastases was significantly lower than [ 68 Ga]Ga-LNC1007 (the straight arrows in e and f point to SUV max 7.7).

[0096] Figure 2 shows the PET / CT images of patient 2 (male, diagnosed with clear cell renal cell carcinoma, WHO / ISUP grade III). The experimental group was [ 68 Ga]Ga-LNC1007, the control group was [ 68 Ga]Ga-PSMA. in,[ 68 Ga]Ga-LNC1007PET / CT showed the primary lesion in the right kidney (see the triangle arrow in Figure 2b, SUV max 13.5), bilateral lung metastases (see the solid arrows in Figure 2c, SUV max6.8) and right scapula metastasis (see dashed arrow in Figure 2d, SUV max 5.2) There is a higher uptake of imaging agents. 68 Ga]Ga-PSMA PET / CT showed the primary lesion in the right kidney (see the triangle arrow in Figure 2f, SUV max 25.2) imaging agent uptake increased, and the bilateral lung metastases (see the solid arrows in Figure 2g, SUV max 3.0) and right scapula metastasis (see dashed arrow in Figure 2h, SUV max 2.7) has relatively low imaging agent uptake.

[0097] Figure 3 from top to bottom are [ 68 Ga]Ga-LNC1007 SUV max Relationship diagram with FAP expression, SUV max Relationship diagram with RGD expression and SUV max Figure 4 shows the relationship between WHO / ISUP grade and FAP expression, WHO / ISUP grade and RGD expression, and WHO / ISUP grade and FAP+RGD expression from top to bottom; Figure 5 shows the relationship between adverse pathological features and FAP expression, adverse pathological features and RGD expression, and adverse pathological features and FAP+RGD expression from top to bottom; Figure 6 shows the relationship between TL-1007 and FAP expression, TL-1007 and RGD expression, and TL-1007 and FAP+RGD expression from top to bottom. Among them, [ 68 Ga]Ga-LNC1007 SUV max , WHO / ISUP grade, and adverse pathological features were significantly correlated with FAP expression, RGD expression, and the sum of FAP+RGD expression (see Figures 3 to 5). TL-1007 was not correlated with FAP expression (see Figure 6, j), but was significantly correlated with RGD expression and FAP+RGD expression (see Figure 6, k and l).

[0098] Figure 7 shows three cases of renal clear cell carcinoma patients [ 68 Ga]Ga-LNC1007 PET / CT images and immunohistochemical staining. The primary renal lesion is marked with a triangular arrow, and SUV max The FAP expression scores of these three cases were all 0, and integrin α v The β3 expression scores were 1, 1, and 2, respectively. [ 68 Ga]Ga-LNC1007 can show that these FAPs are negative for expression and integrin α v β3-positive lesions.

[0099] in,[ 68 The chemical structure of Ga]Ga-LNC1007 is as follows:

[0100] The results show:

[0101] 1.[ 68 The detection rate of Ga]Ga-LNC1007PET / CT for RCC primary lesions is higher than that of [ 18 F]FDG. In terms of the number of metastatic lesions detected, [ 68 Ga]Ga-LNC1007 and [ 18 F]FDG and [ 68 Ga]Ga-PSMA is equivalent, but metastatic lesions are 68 The uptake of Ga]Ga-LNC1007 was significantly higher than that of [ 68 Ga]Ga-PSMA.

[0102] 2. At the same time, the present invention also counted [ 68 The differences of various parameters of Ga]Ga-LNC1007PET / CT in different pathological characteristics and grades were found. max , TBR, and TBR-delay can distinguish the presence or absence of adverse pathological features, WHO / ISUP grade, and M stage. SUV was calculated by ROC analysis. max , SUV mean 、TBR、D max , GTV-1007, and TL-1007 are effective in distinguishing adverse pathological features and staging. The results showed that: SUV max , SUV mean 、TBR、D max , GTV-1007 and TL-1007 can effectively distinguish adverse pathological features and WHO / ISUP grades, while SUV mean and TBR can effectively distinguish clinical stages. 68 Ga]Ga-LNC1007PET / CT is of great value in distinguishing different pathological characteristics and grades of RCC.

[0103] 3. In addition, combined with the results of immunohistochemical staining, it was found that [ 68 Ga]Ga-LNC1007PET / CT SUV max , SUV mean and FAP expression, integrin α v β3 expression and FAP and integrin α v The total expression of β3 was positively correlated, and the expression of FAP and integrin α vβ3 expression and FAP and integrin α v The total expression of β3 is significantly correlated with WHO / ISUP grade and adverse pathological features. 68 Ga]Ga-LNC1007 SUV max and SUVs mean May partly reflect the FAP and integrin α v In addition, most RCCs showed low expression of FAP and α v β3 receptor high expression, [ 68 Ga]Ga-LNC1007 can inhibit the expression of these FAP- / α v β3 + The lesion is visualized, thereby improving the efficiency of lesion detection.

[0104] In summary, this study shows that 68 Ga]Ga-LNC1007 is a promising imaging agent for RCC. 18 F]FDG / [ 68 Ga]Ga-PSMA has better detection efficiency and can effectively identify the pathological characteristics of RCC invasion. For RCC patients with higher WHO / ISUP grade, higher pT stage, higher clinical stage, and adverse pathological features, [ 68 The uptake of Ga]Ga-LNC1007 was significantly increased, which suggests that [ 68 Ga]Ga-LNC1007PET / CT has the potential to predict the prognosis of RCC. In addition, preclinical and preliminary clinical studies have shown that [ 68 Ga]Ga-LNC1007 prolonged the tumor retention time, indicating that β- or α-nuclides-labeled LNC1007 has certain therapeutic potential in advanced renal cancer.

[0105] Example 2 68 Clinical trials of Ga]Ga-LNC1007

[0106] 1. Research Objectives

[0107] This study focuses on exploring 68 The drug safety, radiation safety, drug PK, biodistribution, image quality and diagnostic efficacy of Ga]Ga-LNC1007.

[0108] 2. Research Results

[0109] In this study, the experimental data showed that [ 68 Ga]Ga-LNC1007 showed good clinical safety and radiation safety, as well as good diagnostic / imaging effects in RCC patients.

[0110] The above description is merely a preferred embodiment, which is intended to be illustrative and non-limiting of the combinations of features necessary to implement the present invention. The titles provided are not intended to limit the various embodiments of the present invention. Terms such as "comprising," "including," and "including" are not intended to be limiting. In addition, unless otherwise indicated, the absence of a numeral modifier includes the plural form, and "or" and "or" mean "and / or." Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0111] All disclosures and patents mentioned in this application are incorporated herein by reference. Without departing from the scope and spirit of the present invention, multiple modifications and variants of the described method and composition of the present invention will be apparent to those skilled in the art. Although the present invention has been described by specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, those multiple variants of the described pattern that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims

1. A method for treating, diagnosing or imaging renal cell carcinoma, characterized in that The method comprises administering a heterodimeric radioactive compound to a subject, wherein the heterodimeric radioactive compound structure is composed of a dual-targeting compound, a metal chelator and a radionuclide, and the dual-targeting compound is a compound having a structure as shown in formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof:

2. The method according to claim 1, characterized in that The structure of the heterodimer radioactive compound is shown in formula (II): Wherein, in formula (II): The D is a metal chelating agent; The R is a radioactive nuclide.

3. The method according to any one of claims 1 to 2, characterized in that: The metal chelator is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA).

4. The method according to any one of claims 1 to 3, characterized in that: The radionuclide is selected from Tc-99m, Ga-68, F-18, I-123, I-125, I-131, I-124, In-111, Ga-67, Cu-64, Zr-89, C-11, Lu-177, Re-188, Y-86, Mn-52, Sc-44, Y-90, Ac-225, As-211, Bi-212, Any one of Bi-213, Cs-137, Cr-51, Co-60, Dy-165, Er-169, Fm-255, Au-198, Ho-166, Ir-192, Fe-59, Pb212, Mo-99, Pd-103, P-32, K-42, Re-186, Sm-153, Ra-223, Ru-106, Na-24, Sr-89, Tb149, Th-227, Xe-133, Yb-169, Yb-177.

5. The method according to any one of claims 1 to 4, characterized in that: The structure of the dual-target compound is shown in formula (I), the metal chelator is 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), the radionuclide is Ga-68 or F-18, and the structure of the heterodimer radioactive compound is shown in formula (III) or (IV):

6. The method according to claim 1, characterized in that The renal cell carcinoma is clear cell renal cell carcinoma, multilocular cystic renal neoplasm of low malignant potential, papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, renal medullary carcinoma, MiT Family translocation carcinomas, succinate dehydrogenase (SDH)-deficient renal carcinoma, mucinous tubular and spindle cell carcinoma, and renal cell carcinoma. renal cell carcinoma, tubulocystic renal cell carcinoma, acquired cystic disease associated renal cell carcinoma, clear cell papillary renal cell carcinoma, renal cell carcinoma, unclassified, papillary adenoma, or oncocytomas.

7. The method according to claim 6, characterized in that The TNM stage of renal cell carcinoma is TX, T0, T1, T1a, T1b, T2, T2a, T2b, T3, T3a, T3b, T3c, T4, NX, N0, N1, M0 or M1.

8. The method according to claim 6, characterized in that The clinical stage of renal cell carcinoma is stage I, stage II, stage III or stage IV.

9. The method according to claim 1, characterized in that: The subject is a mammal.

10. The method according to claim 9, characterized in that The mammal is preferably a human.

11. The method according to claim 10, characterized in that The human being is an adult or a non-adult.

12. The method according to claim 1, characterized in that The administration method is intravenous administration.

13. The method according to claim 1, characterized in that The effective dosage of the heterodimer radioactive compound is 100-400 MBq.

14. The method according to claim 1, characterized in that The diagnosis or imaging is based on imaging techniques such as magnetic resonance, positron emission tomography (PET), computed tomography (CT), positron emission tomography-computed tomography (PET-CT), ultrasound (US), photoacoustic imaging (PAI), near-infrared fluorescence (NIRF) or single photon emission computed tomography (SPECT), or is related to optical imaging (OI).

15. The method according to claim 14, characterized in that The diagnosis or imaging is based on PET-CT imaging technology.

16. A method for diagnosing or imaging renal cell carcinoma, characterized in that The method comprises the following steps: Step 1: administering a heterodimeric radioactive compound to a subject, wherein the structure of the heterodimeric radioactive compound consists of a dual-targeting compound, a metal chelator and a radionuclide, and the heterodimeric radioactive compound, the dual-targeting compound, the metal chelator and / or the radionuclide are defined as the heterodimeric radioactive compound, the dual-targeting compound, the metal chelator and / or the radionuclide as described in any one of claims 1 to 5; Step 2: Imaging the target tissue of the subject using an imaging method.

17. The method according to claim 16, characterized in that The imaging method is based on imaging techniques such as magnetic resonance, positron emission tomography (PET), computed tomography (CT), positron emission tomography-computed tomography (PET-CT), ultrasound (US), photoacoustic imaging (PAI), near-infrared fluorescence (NIRF), and single photon emission computed tomography (SPECT), or methods related to optical imaging (OI).

18. A method for PET-CT diagnosis or imaging of renal cell carcinoma, characterized in that: The method comprises the following steps: Step 1: administering a heterodimeric radioactive compound to a subject, wherein the structure of the heterodimeric radioactive compound consists of a dual-targeting compound, a metal chelator and a radionuclide, and the heterodimeric radioactive compound, the dual-targeting compound, the metal chelator and / or the radionuclide are defined as the heterodimeric radioactive compound, the dual-targeting compound, the metal chelator and / or the radionuclide as described in any one of claims 1 to 5; Step 2: administering a PET tracer after administering the heterodimeric radioactive compound; Step 3: Perform a PET-CT scan on the subject.

19. A method for distinguishing adverse pathological features of renal cell carcinoma, characterized in that: The method comprises administering to a subject a heterodimeric radioactive compound, wherein the structure of the heterodimeric radioactive compound consists of a dual-targeting compound, a metal chelator and a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide are defined as the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide described in any one of claims 1-5.

20. The method according to claim 19, characterized in that The adverse pathological features include, but are not limited to, tumor necrosis, sarcomatoid changes, rhabdoid features, etc.

21. A method for grading renal cell carcinoma, characterized in that: The method comprises administering to a subject a heterodimeric radioactive compound, wherein the structure of the heterodimeric radioactive compound consists of a dual-targeting compound, a metal chelator and a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide are defined as the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide described in any one of claims 1-5.

22. The method according to claim 21, characterized in that The classification described is the WHO / ISUP classification.

23. A method for treating renal cell carcinoma, characterized in that: The method comprises administering to a subject a heterodimeric radioactive compound, wherein the structure of the heterodimeric radioactive compound consists of a dual-targeting compound, a metal chelator and a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide are defined as the heterodimeric radioactive compound, dual-targeting compound, metal chelator and / or radionuclide described in any one of claims 1-5.

24. Use of a heterodimeric radioactive compound in the preparation of a drug or imaging diagnostic agent for treating, diagnosing or imaging renal cell carcinoma, wherein the structure of the heterodimeric radioactive compound is composed of a dual-targeting compound, a metal chelator and / or a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and radionuclide are as shown in any one of claims 1-5.

25. Use of a heterodimeric radioactive compound in the preparation of a drug or imaging diagnostic agent for distinguishing different pathological characteristics of renal cell carcinoma, wherein the structure of the heterodimeric radioactive compound is composed of a dual-targeting compound, a metal chelator and / or a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and radionuclide are as shown in any one of claims 1-5.

26. Use of a heterodimeric radioactive compound in the preparation of a drug or imaging diagnostic agent for grading renal cell carcinoma, wherein the structure of the heterodimeric radioactive compound is composed of a dual-targeting compound, a metal chelator and / or a radionuclide, and the heterodimeric radioactive compound, dual-targeting compound, metal chelator and radionuclide are as shown in any one of claims 1-5.

27. A kit for diagnosing or imaging renal cell carcinoma, characterized in that The kit comprises the heterodimeric radioactive compound according to any one of claims 1-5.

28. A pharmaceutical composition for treating, diagnosing or imaging renal cell carcinoma, characterized in that The pharmaceutical composition comprises the heterodimeric radioactive compound according to any one of claims 1-5.

29. The pharmaceutical composition according to claim 28, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent and / or additive.

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