Methods for detecting and diagnosing cancer associated with overexpression of the PSMA receptor

Abstract

The present invention relates to methods for the detection and diagnosis of cancers associated with overexpression of prostate-specific membrane antigen.

Description

[Technical Field]

[0001] The present invention relates to methods for the detection and diagnosis of cancers associated with overexpression of prostate-specific membrane antigen. [Background technology]

[0002] Prostate cancer is the second most common malignancy and the second most common cancer in men worldwide. In 2018, it accounted for 9.5% of all new cancer cases. The incidence of prostate cancer varies and correlates with age, occurring in 30% of men aged 40–50 years and 50–80% of men aged 80 years and older. At initial diagnosis, 80% of patients present with localized disease, 12% with regional disease, and 4% with metastatic disease. The 5-year survival rate for patients with localized or regional prostate cancer is 99%, but for those with metastatic disease, survival drops to approximately 30%.

[0003] Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein expressed in normal, benign, and malignant prostate tissue. PSMA membrane protein expression increases with prostate tumor grade, the presence of metastatic disease, and cancer recurrence. For example, PSMA membrane protein expression in prostate adenocarcinoma is 100-1000 times higher than in benign prostate tissue, and is increased by androgen deprivation, with the highest levels of this protein being expressed in high-grade and castration-resistant prostate cancer. PSMA expression levels correlate with disease progression, but there are also cases of prostate cancer in which biopsies do not reveal increased PSMA expression.

[0004] The current approach to diagnosing prostate cancer combines analysis of circulating prostate-specific antigen (PSA), positron emission tomography (PET) imaging, and prostate tissue biopsy, which requires the use of an appropriate radioactive tracer. 68Ga-PSMA-11 is one of the most widely used radiotracers for PET imaging of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer and is part of standard clinical practice at many centers. While PET imaging is possible with current radiotracers, the resolution of the images obtained is limited. As a result, small lesions may be missed, and lesions close to organs involved in the excretion of the radiotracer (e.g., the bladder) may not be adequately visualized and therefore may not be identified as cancerous. Missing such lesions can result in subsequent delays in treatment, potentially worsening patient outcomes. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for methods of diagnosing prostate cancer that are more sensitive and can better distinguish cancerous tissue from healthy tissue in a patient. [Means for solving the problem]

[0006] Summary of the invention In one aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); The present invention provides a method comprising:

[0007] In one aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; and ii) imaging the subject with PET imaging; and iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the tumor-to-background ratio (TTBR) of cancer-related lesions in the subject is greater than about 40; The present invention provides a method comprising:

[0008] In one aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of the lesion visualized by imaging in step ii); wherein the tumor-to-background ratio (TTBR) of cancer-related lesions in the subject is greater than about 40; The present invention provides a method comprising:

[0009] In one aspect, the present invention provides a method for imaging lesions in cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the lesion is characterized by a tumor-to-background ratio (TTBR) greater than about 40; The present invention provides a method comprising:

[0010] In one aspect, the present invention provides a method for imaging lesions in cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the lesion is characterized by a tumor-to-background ratio (TTBR) greater than about 40; The present invention provides a method comprising:

[0011] In one aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 administering a compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; and ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); [ka] Formula (I) Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; The present invention provides a method comprising:

[0012] In certain embodiments, 64 The dosage of the compound of Formula (I) or a salt thereof complexed with Cu is about 100 MBq. 64 The dosage of the compound of Formula (I) or a salt thereof complexed with Cu is about 150 MBq. 64 The dosage of the compound of Formula (I) or a salt thereof complexed with Cu is about 200 MBq. 64 The dose of the compound of formula (I) or a salt thereof complexed with Cu is about 300 MBq.

[0013] In certain embodiments, imaging of the subject comprises: 64 In certain embodiments, imaging of the subject occurs at about 8 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 10 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 12 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu.64 In certain embodiments, imaging of the subject occurs at about 16 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 18 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 20 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 24 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 28 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 In certain embodiments, imaging of the subject occurs at about 30 hours after administration of the compound of Formula (I) or a salt thereof complexed with Cu. 64 This occurs at about 36 hours after administration of a compound of formula (I) or a salt thereof complexed with Cu.

[0014] In certain embodiments, the tumor-to-background ratio (TTBR) is greater than about 45. In some embodiments, the TTBR is greater than about 50. In some embodiments, the TTBR is greater than about 55. In some embodiments, the TTBR is greater than about 60. In some embodiments, the TTBR is greater than about 65. In some embodiments, the TTBR is greater than about 70. In some embodiments, the TTBR is greater than about 75. In some embodiments, the TTBR is greater than about 80. In some embodiments, the TTBR is greater than about 85. In some embodiments, the TTBR is greater than about 90. In some embodiments, the TTBR is greater than about 95. In some embodiments, the TTBR is greater than about 100. In some embodiments, the TTBR is greater than about 105. In some embodiments, the TTBR is greater than about 110. In some embodiments, the TTBR is greater than about 115. In some embodiments, the TTBR is greater than about 120. In some embodiments, the TTBR is greater than about 125. In some embodiments, the TTBR is greater than about 130. In some embodiments, the TTBR is greater than about 140. In some embodiments, the TTBR is greater than about 145. In some embodiments, the TTBR is greater than about 150. In some embodiments, the TTBR is in the range of about 40 to about 150. In other embodiments, the present invention also contemplates TTBRs within ranges between the aforementioned values.

[0015] In another aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; The present invention provides a method comprising:

[0016] In another aspect, the present invention provides a method for the detection and / or diagnosis of cancer associated with overexpression of the PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 administering a compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; and ii) imaging the subject by PET imaging between about 2 hours and about 4 hours after administration of a compound of Formula (I); [ka] Formula (I) Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; The present invention provides a method comprising:

[0017] The inventors have discovered that images obtained according to the methods of the present invention provide higher resolution images compared to methods using standard of care (SOC) radiotracers for imaging PSMA-overexpressing cancers.

[0018] SOC radiotracer for PET imaging of PSMA-overexpressing cancers 68 In certain embodiments, the compound is a Ga-containing compound. 68 The Ga-containing compounds are as follows: [ka] of 68 Ga-PSMA-11.

[0019] Another radiotracer used for PET imaging of PSMA-overexpressing cancers is 18In certain embodiments, 18 F-containing compounds include the following: [ka] of 18 F-DCFPyL (Pylarify®).

[0020] PET images show the uptake and localization of radiotracers in tissue within the body. Radiotracers, which contain a compound that binds to a target (e.g., the PSMA receptor) and a positron-emitting radioisotope, localize to sites of PSMA receptor overexpression, suggesting cancer. Because the radioisotope decays while emitting a positron, detection of the emitted positrons corresponds to the location of cancer. PET images can be overlaid with other imaging modalities that reveal structural information, such as CT scans, to provide information about the location of cancer. The signal intensity in a specific region of interest indicates to the reader the relative amount of radiotracer accumulated in that particular region; higher signal intensity (or "brightness"), resulting from greater radiotracer accumulation, correlates with the presence of cancer. One measure of intensity is the standard uptake value (SUV), which is defined as the ratio of the radioactivity in the region of interest to the radioactivity injected into the subject's entire body. A higher SUV indicates areas of greater "brightness," i.e., greater radioactivity. The higher the contrast between regions of interest, i.e., the higher the SUV, the higher the resolution of the image. The SUV between images is calculated using the maximum standard uptake value (SUV max ), mean standard uptake value (SUV mean ), median standard uptake value (SUV median ), and values ​​relative to patient weight (SUV bw ), and the value relative to the patient's BMI (SUV BMI) can be compared by first determining a specific value such as . Another measure of signal intensity is the tumor-to-background ratio (TTBR), which is the ratio of the signal due to the cancer-associated tumor to the signal due to the "background" or healthy tissue of the same subject. When using TTBR as a method for comparing the uptake of compounds of formula (I), the SUV is calculated because the background intensity of the image is taken into account in the TTBR calculation. max and SUVs mean This may offer significant advantages over other intensity measurement methods such as

[0021] To correctly identify cancer based on images obtained by PET imaging, images with sufficient resolution and / or contrast are required. 64 The method comprising administering a compound of formula (I) complexed with Cu includes administering a SOC radiotracer, e.g. 68 Ga or 18 The inventors have found that the compound of formula (I) provides images with higher resolution and / or contrast than radiotracers containing F radioisotopes. The inventors have shown that localization and subsequent imaging of the compound of formula (I) at tumor sites overexpressing PSMA receptors occurs at a higher rate than with other radiotracers, i.e., the ratio of the compound at the tumor site to the background is higher. 64 Administration of a compound of formula (I) or a salt thereof complexed with Cu may result in images with higher contrast. The resulting images with higher resolution and / or contrast (especially contrast) may allow for the detection of cancer lesions that would normally be missed (e.g., due to small localization of the radioisotope conjugate and resulting low TTBR values). High-resolution images may also allow for the detection of smaller cancer lesions, especially those that are close to each other or to organs involved in excretion of the product (e.g., the bladder or kidneys).

[0022] Without wishing to be bound by theory, the inventors believe that 64The increased image resolution and / or contrast obtained when using the compound of formula (I) or a salt thereof complexed with Cu is an SOC radiotracer. 68 Ga-PSMA-11(t 1 / 2 = 68 minutes, 68 Average positron range of Ga = 3.5 mm) or 18 F-DCFPyL(t 1 / 2 = 109 minutes, 18 It has a long half-life and a short positron range (t 1 / 2 = 12.7 hours, 64 One of the reasons for this is believed to be the average positron range of Cu = 0.56 mm. 64 Because Cu has a half-life of 12.7 hours, radiolabeled compounds of Formula (I) can be manufactured in bulk with a product shelf life of up to two days. The long half-life allows for PET imaging from 1 hour to 72 hours after administration, providing flexibility in patient scheduling and potentially detecting additional lesions due to an increase in the standard uptake value (SUV) of lesions relative to background after biological clearance of the tracer from organs over time. The high resolution of images obtained according to the methods disclosed herein is also due to the properties of compounds of Formula (I). Namely, compounds of Formula (I) contain two moieties capable of targeting and binding to receptors of interest. Furthermore, the physical properties of compounds of Formula (I) allow for sufficient clearance of the radioactive agent at the target site to provide increased contrast between tumor and healthy tissue.

[0023] The positron range is the distance an emitted positron travels before losing all of its kinetic energy and annihilating with an electron. As a result, the annihilation points are uniformly distributed around the actual emission point, and images are blurred for positron ranges beyond the system's inherent spatial resolution. 68The Ga isotope has a much longer positron range, which results in a larger distribution of positron-electron annihilation events, and a larger, more diffuse area over which these events are detected (and imaged), which reduces the image resolution.

[0024] A common measure of intensity in PET images is the maximum standard uptake value (SUV max In certain embodiments, the maximum SUV (SUV max ) is higher than that obtained from comparable images using an SOC radiotracer. In certain embodiments, the maximum SUV (SUV max )teeth, 68 In certain embodiments, the maximum SUV (SUV max )teeth, 18 This is higher than the value obtained from a comparable image using an SOC radiotracer containing F. In certain embodiments, 64 SUVs resulting from the compound of formula (I) or its salts complexed with Cu max teeth, 68 It is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% higher than the same value with a Ga-containing radiotracer. 64 SUVs resulting from the compound of formula (I) or its salts complexed with Cu max teeth, 18 45%, or about 50% higher than the same value with a radiotracer containing F. As can be seen in FIG. 4, according to the methods disclosed herein (i.e., 64 SUV of lesions imaged after Cu-Sar-bisPSMA administration max is the same subject 68In images taken according to the methods disclosed herein, the SUV values ​​obtained by two different image readers were higher than those obtained when a radiotracer containing Ga was administered. max Signal strength (SUV) max ), the inventors believe that the methods disclosed herein will allow for more efficient and effective diagnosis of cancers associated with the PSMA receptor.

[0025] Figure 7 shows an SUV from an image taken from the same subject. max Here, the image taken on day 0 also shows an increase in SUV max The SUV was 20.8, but when the same imaging was repeated the next day (i.e., day 1), max The inventors found that 64 The flexibility of imaging patients after administration of the compound of formula (I) or its salt complexed with Cu is believed to enable more effective diagnosis of cancers associated with the PSMA receptor, since the use of currently available ligands and radioisotopes often misses lesions associated with such cancers that are not visualized by same-day imaging. The ability to image subjects the day after administration of the compound of formula (I) may improve patient comfort and potentially increase patient compliance with treatment. The inventors believe that 64 We found that the maximum uptake values ​​were even greater when subjects were imaged the day after imaging with a compound of Formula (I) or a salt thereof complexed with Cu. This is shown in Figure 8, where a lesion was not clearly visible in an image of the subject on the day of administration (Figure 8A), but when the same subject was imaged again the following day (Figure 8B), the lesion was accurately identified.

[0026] Another measure of intensity in PET imaging is the mean standard uptake value (SUV mean ) obtained from images generated according to the methods disclosed herein. mean )teeth, 68 Ga or 18This is higher than the value obtained from a comparable image using an SOC radiotracer containing F. In certain embodiments, 64 SUVs resulting from the compound of formula (I) or its salts complexed with Cu mean teeth, 68 This is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% higher than the same values ​​obtained with Ga-containing radiotracers. This can be seen in Figures 2(B) and (D), and is consistent with the existing data in Figures 2(A) and (C). 68 As shown in Figure 5, the lesions are visualized with higher intensity compared to the same lesions imaged with the Ga protocol. 64 SUV of lesions photographed according to Cu-Sar-bisPSMA administration mean is the same subject 68 Higher SUV in images taken according to the methods disclosed herein than when a radiotracer containing Ga was administered. mean were reported by two different image readers. The mean uptake values ​​(SUVs) according to the method disclosed herein mean ) is higher than that obtained by existing methods, the inventors believe that the method herein may provide an improved process for the diagnosis of cancers associated with the PSMA receptor.

[0027] The inventors have demonstrated that PET images obtained by the methods of the present invention are obtained by complexing a radioisotope with a compound of formula (I) (i.e., 64 Cu) has a higher resolution due to its properties. As disclosed herein, the method of the present invention involves imaging the subject at least once between about 30 minutes and about 36 hours after administration of the radiotracer. In comparison, imaging methods according to the current SOC model have radioactivities of 111 MBq to 259 MBq (FDA compliant). 68 This involves administration of Ga-PSMA-11 and images are acquired at approximately 1 hour. 68 Ga isotopes have half-lives (t 1 / 2) is short, so the time from administration to imaging must be optimized to obtain images of sufficient quality. 64 We have discovered that the long half-life of Cu radioisotopes allows for a longer time between administration and imaging. While not wishing to be bound by theory, we believe that increasing the time between administration of the radiotracer compound and subsequent imaging increases the likelihood that the radiolabeled complex will localize to the cancer site and that unbound radiotracer will be cleared from the subject. This increases the contrast between the localized radiotracer and the background, resulting in higher resolution images. This is illustrated in Figure 6, which shows the average tumor-to-background ratio. 64 In the images obtained after Cu-Sar-bisPSMA administration, 68 The mean ratio is higher compared to images after Ga-PSMA-11 administration.

[0028] The present inventors 64 The higher maximum, mean, and median SUVs obtained by imaging following administration of a Cu-complexed compound of Formula (I) or a salt thereof are also believed to be at least partially attributable to the dimeric nature of the compound of Formula (I). As seen in the structure of Formula (I), the compounds of the present invention contain two lysine-urea-glutamic acid motifs linked to a sarcofazine chelator via a linker group. The corresponding monomeric compound, i.e., sarcofazine (shown below), which contains one lysine-urea-glutamic acid motif, exhibits reduced uptake and retention compared to the dimeric compound of Formula (I) disclosed herein. [ka]

[0029] FIG. 1 shows that compounds of formula (I) have higher tumor uptake and retention compared to the corresponding monomeric compounds containing a single lysine-urea-glutamic acid motif.

[0030] In some embodiments, 64 The dose of the compound of formula (I) or a salt thereof complexed with Cu is about 200 MBq.

[0031] In certain embodiments, the cancer is prostate cancer.

[0032] In other embodiments, the cancer is primary prostate cancer. In some embodiments, the cancer is prostate cancer associated with biochemical recurrence.

[0033] In certain embodiments, the imaging is combined PET / CT imaging.

[0034] In some embodiments, imaging of the subject comprises: 64

[0033] After administration of the compound of Formula (I) or a salt thereof complexed with Cu, imaging of the subject occurs at about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, about 35 hours, or about 36 hours. In other embodiments, imaging of the subject occurs at about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, about 35 hours, or about 36 hours. 64 This occurs at about 12 hours, about 24 hours, or about 36 hours after administration of a compound of formula (I) or a salt thereof complexed with Cu.

[0035] In certain embodiments, the method includes further imaging the subject by PET imaging. In some embodiments, the further imaging step occurs about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 18 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 54 hours, and / or about 60 hours after the initial imaging step.

[0036] In certain embodiments, the method further comprises the step of MRI or ultrasound imaging.

[0037] In certain embodiments, the method further comprises determining the subject's PSA level.

[0038] In certain embodiments, the cancer is present as one or more lesions in the subject, hi some embodiments, the cancer is present as two or more lesions in the subject.

[0039] In certain embodiments, the two or more lesions are present in prostate tissue of the subject. In certain embodiments, the two or more lesions are present in tissue other than the prostate of the subject.

[0040] In another aspect, the present invention provides a method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); The present invention provides a method comprising:

[0041] In another aspect, the present invention provides a method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject with PET imaging; and iii) determining the tumor-to-background ratio (TTBR) of lesions visualized by imaging; wherein the tumor-to-background ratio (TTBR) of the cancer-related lesions in the subject detected by imaging in step ii) is greater than about 40; The present invention provides a method comprising:

[0042] In another aspect, the present invention provides a method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of lesions visualized by imaging; wherein the tumor-to-background ratio (TTBR) of the cancer-related lesions in the subject detected by imaging in step ii) is greater than about 40; The present invention provides a method comprising:

[0043] In another aspect, the present invention provides a method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 administering the compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); and iii) diagnosing the second cancer based on one or more images obtained in step ii); [ka] Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; The present invention provides a method comprising:

[0044] The present inventors 64 We have discovered that administration of a compound of formula (I) or a salt thereof complexed with Cu followed by PET imaging allows visualization of secondary cancers. Secondary cancers arise at a different site from the primary cancer (i.e., a non-primary site) and arise from metastasis of the primary cancer. This can be seen in Figure 3, and can be visualized using the methods disclosed herein. 64 Imaging with the compound of formula (I) or its salt complexed with Cu clearly identifies the lesion as seen in Figure 3(A), whereas the comparative 68 Imaging the same subject with the Ga product does not identify the same lesion. This is evident from the absence of signal in the same location in Figure 3(B). Without wishing to be bound by theory, the inventors believe that the methods disclosed herein improve the detection and identification of cancers associated with the PSMA receptor. Once a cancer is identified, the methods of the present invention also allow for more effective and efficient diagnosis of cancer, as the image of the subject exhibits higher intensity, allowing the image reader to more confidently interpret and diagnose the cancer. Figure 9 shows the identification of a second cancer (supradiaphragmatic region) in a subject, where: 18 Imaging after administration of F-labeled ligand yields negative / questionable results (SUV max = 2.3) and the same day 64 Imaging after Cu-Sar-bisPSMA administration also showed negative results (SUV max However, when the same subject was imaged the next day (day 1), SUV max The value was 17.5, i.e., four times as many lesions were clearly identified as in the previous day's imaging. Without wishing to be bound by theory, the inventors believe that the method disclosed herein 64We believe that next-day imaging of patients receiving Cu-Sar-bisPSMA will be possible. Current products and protocols for imaging and / or diagnosing cancers associated with the PSMA receptor do not allow next-day imaging due to the half-lives of the radioisotopes used, loss of the ligand and radioisotope from the patient, leakage of the radioisotope from the ligand, and the general lack of stability of such ligands.

[0045] In certain embodiments, the primary cancer is prostate cancer.

[0046] In certain embodiments, the second cancer is at a site other than the prostate.

[0047] In certain embodiments, the second cancer is in a lymph node, hi other embodiments, the second cancer is in the bone, bladder, lung, or liver.

[0048] In certain embodiments, the second cancer is associated with biochemical recurrence.

[0049] The inventors believe that the methods disclosed herein allow for the diagnosis of secondary cancers, which may have a lower density of PSMA receptors. 64 By increasing the time between administration of the Cu radiotracer and imaging, the radiotracer can be sufficiently accumulated in tumor sites with low PSMA receptor density, allowing for images with sufficient resolution. Increasing the amount of radiotracer accumulated improves the tumor-to-background ratio, resulting in images with higher contrast and resolution.

[0050] Without wishing to be bound by theory, the inventors believe that the use of the methods disclosed herein allows for the production of SOC radiotracers under comparable conditions. 68It is believed that this allows for the detection and diagnosis of secondary cancers that were not possible using the Ga-PSMA-11 radiotracer. In some embodiments, PET imaging of prostate cancer patients according to the methods disclosed herein shows overexpression of PSMA in one or more lymph nodes and the presence of a secondary cancer in the lymph nodes.

[0051] In certain embodiments, the method further comprises confirmation of the second cancer by biopsy.

[0052] In yet another aspect, the present invention provides a method for determining the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 administering the compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject with PET imaging; and iii) determining the TNM stage of the cancer based on one or more images obtained in step ii) and the ISUP grade of the tumor; [ka] Here, the ISUP grade of the tumor is determined before steps i)–iii); The present invention provides a method comprising:

[0053] In yet another aspect, the present invention provides a method for determining the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 administering the compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); and iii) determining the TNM stage of the cancer based on one or more images obtained in step ii) and the ISUP grade of the tumor; [ka] Here, the ISUP grade of the tumor is determined before steps i)–iii); The present invention provides a method comprising:

[0054] In yet another aspect, the present invention provides a method for determining the TNM stage of prostate cancer in a subject, comprising: Target, 64 administering the compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); and determining the stage of the cancer based on one or more images obtained in step ii) and the ISUP grade of the tumor; [ka] Here, the ISUP grade of the tumor is determined before steps i)–iii); The present invention provides a method comprising:

[0055] In certain embodiments, imaging a subject by PET imaging comprises: 64 In another embodiment, imaging of a subject by PET imaging occurs 12 hours after administration of a compound of Formula (I) or a salt thereof complexed with Cu. 64 In another embodiment, imaging of a subject by PET imaging occurs 18 hours after administration of a compound of Formula (I) or a salt thereof complexed with Cu. 64 Occurs 24 hours after administration of a compound of formula (I) or a salt thereof complexed with Cu.

[0056] In certain embodiments, the ISUP grade of the tumor is grade 1, grade 2, grade 3, grade 4 or grade 5.

[0057] In certain embodiments, the ISUP grade of a tumor is determined by calculating the Gleason score. In certain embodiments, the Gleason score is 6, 7, 8, 9, or 10.

[0058] In certain embodiments, the TNM stage of the prostate cancer is selected from one or more of TX, TO, T1, T2, T3, T4, NX, NO, N1, N2, N3, MX, MO, or M1.

[0059] In another aspect, the present invention provides a method of reassessing the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) first determining the stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration of the compound of formula (I) according to step i); The present invention provides a method comprising:

[0060] In certain embodiments, reassessment of the TNM stage of the subject's prostate cancer is performed to determine the progression of the subject's cancer.

[0061] In yet another aspect, the present invention provides a method for determining the progression of a cancer associated with overexpression of the PSMA receptor in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) first determining the TNM stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the TNM stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration of the compound of formula (I) according to step i); The present invention provides a method comprising:

[0062] In another aspect, the present invention provides a method of reassessing the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: [ka] Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); iii) first determining the stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration according to step i); The present invention provides a method comprising:

[0063] In certain embodiments, the TNM stage of the prostate cancer after re-evaluation is higher.

[0064] In certain embodiments, the TNM stage of the prostate cancer after re-evaluation comprises an N1, N2, or N3 stage.

[0065] In certain embodiments, the TNM stage of the prostate cancer after re-evaluation is lower.

[0066] In certain embodiments, the TNM stage of the prostate cancer after re-evaluation comprises a T0, N0, or M0 stage.

[0067] In yet another embodiment, the prostate cancer is PSMA-expressing metastatic castration-resistant prostate cancer (mCRPC) or is progressive mCRPC despite prior androgen deprivation therapy and at least enzalutamide and / or abiraterone (or other androgen receptor pathway inhibitors). In another embodiment, the prostate cancer is characterized by biochemical resistance in the subject. [Brief explanation of the drawings]

[0068] [Figure 1] In vitro tumor uptake (mean + / - SEM, n = 3 / group) expressed as percentage of injected activity per gram of tissue (%IA / g) after injection of monomeric [64Cu]Cu-SarPSMA (2 MBq, 0.9 nmol peptide) or dimeric [64Cu]Cu-Sar-bisPSMA (2 MBq, 0.2 nmol peptide) into LNCap tumor-bearing NSG mice. At 1 hour post-administration, uptake of 64Cu-Sar-bisPSMA was approximately twice that of the monomeric 64Cu-Sar-PSMA compound. At 6 and 24 hours post-administration, the amount of 64Cu-Sar-bisPSMA retained at the tumor site was significantly greater than the amount of 64Cu-SarPSMA retained under the same conditions. [Figure 2] Intra-individual comparison of PET / CT images obtained after administration of 68Ga-PSMA-11 (1A and 1C) and 64Cu-Sar-bisPSMA (1B and 1D), showing clearer delineation of the lesion and higher SUVmax. [Figure 3]PET / CT of a subject after administration of 64Cu-Sar-bisPSMA detected secondary lesions in the lymph nodes, as shown in Figure 2A. Figure 2B shows a comparative image of the same subject after administration of 68Ga-PSMA-11, in which no uptake was detected. [Figure 4] SUVmax of concordant lesions detected by PET / CT after administration of 4Cu-Sar-bisPSMA and 68Ga-PSMA-11, as detected by (A) Reader 1 and (B) Reader 2. Both readers judged that the lesions detected after administration of 64Cu-Sar-bisPSMA exhibited higher SUVmax than the same lesions after administration of 68Ga-PSMA-11. [Figure 5] SUVmean of concordant lesions detected by PET / CT after administration of 64Cu-Sar-bisPSMA and 68Ga-PSMA-11 as detected by (A) Reader 1 and (B) Reader 2. Both readers judged that the lesions detected after administration of 64Cu-Sar-bisPSMA had higher SUVmean than the same lesions after administration of 68Ga-PSMA-11. [Figure 6] Tumor-to-background ratios of concordant lesions detected by PET / CT after administration of 64Cu-Sar-bisPSMA and 68Ga-PSMA-11 as detected by (A) Reader 1 and (B) Reader 2. Both readers judged that lesions detected after administration of 64Cu-Sar-bisPSMA exhibited higher tumor-to-background ratios. [Figure 7] 64Cu-SAR-bisPSMA PET showed a positive pelvic lymph node (LN) (red circle, maximum intensity projection). CT-guided needle biopsy of the lesion was performed and was negative for PC. Subsequently, an excision biopsy of the lesion was performed, and histopathological examination confirmed the presence of PC. Images taken the next day (Figure 8B) showed a more than two-fold increase in SUVmax (maximum standardized uptake value) compared to images taken the same day (Figure 8A), increasing from 20.8 on day 0 to 50.4 on day 1. [Figure 8]Next-day imaging of the supradiaphragmatic region of a subject treated with 64Cu-Sar-bisPSMA (Figure 8B, i.e., image taken the day after 64Cu-Sar-bisPSMA administration). A lesion in this region of the subject was identified by three readers on the imaging study the day after 64Cu-Sar-bisPSMA administration, although the same lesion was less evident on the same-day imaging study (Figure 8A). [Figure 9] PET / CT fusion image of a subject receiving 18F-DCYPyL as SOC (Figure 9A, SUVmax = 2.3) showing a negative / suspicious screening result. Images of the same subject receiving 64Cu-Sar-bisPSMA on the same day (Figure 9B, SUVmax = 4.3) and the next day (Figure 9C, SUVmax = 17.5). Imaging on the day after 64Cu-Sar-bisPSMA administration revealed a lesion in the pelvic region, but imaging on the same day did not reveal the same lesion. [Figure 10] The patient was administered 64Cu-Sar-bisPSMA, and PET images of the pelvis, extrapelvic (retroperitoneal) area, and prostate bed were obtained on the same day (Figure 10A) and the following day (Figure 10B). As shown in Figure 10B, the images obtained the day after administration of 64Cu-Sar-bisPSMA showed an increase in positive lesions, and the lesions detected in the same-day images (Figure 10A) were more clearly visualized. [Figure 11] Patients were administered 64Cu-Sar-bisPSMA and underwent PET imaging of the pelvis, extrapelvic (retroperitoneal), and prostate bed on the same day (Figure 11A) and the following day (Figure 11B). Both images showed lesions in the pelvic bone, while pelvic lymph nodes were visualized only on the following day's imaging. The mean SUVmax of bone and pelvic lymph node lesions increased from 9.8 (Figure 11A) to 20.0 (Figure 11B). As shown in Figure 11B, prostate bed lesions were visualized only on the following day's imaging. [Figure 12] Cu-Sar-bisPSMA was administered, and the subject underwent PET imaging of the pelvic, extrapelvic (retroperitoneal), and prostate bed regions on the day of administration (Figure 12A) and the following day (Figure 12B). The following day's imaging revealed additional positive lesions in the subject compared to the same day's imaging. DETAILED DESCRIPTION OF THE INVENTION

[0069] Detailed Description Throughout this specification and the claims that follow, unless the context clearly indicates otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of a stated integer or step or group of integers or steps, but not to the exclusion of any other integer or step or group of integers or steps.

[0070] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the present invention, the following terms are defined as follows:

[0072] The compound of formula (I) as defined herein is a sarcofadin to which two lysine-urea-glutamic acid motifs have been attached via a linker and has the following structure: [ka]

[0073] The compound of formula (I) is also known as Sar-bisPSMA.

[0074] In certain embodiments, the compound of Formula (I) has the following structure: [ka]

[0075] Compounds used herein 68 Ga-PSMA-11 was complexed with the compound PSMA-11, which has the following structure: 68 Refers to the Ga radioisotope: [ka] 68 PSMA-11 complexed with a Ga radioisotope is called HBED-CC, HBED, PSMA-HBED, or Prostamedix TM Also known as

[0076] Compounds used herein 18 F-DCFPyL( 18 F Piflufolastat) has the following structure: 18 It refers to the compound DCFPyL, which is complexed with F radioisotope. [ka]

[0077] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compound of Formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes, including formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Pharmaceutically acceptable salts also include salts in which the primary compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further understand that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, alkali metal and alkaline earth metal salts can be prepared by reacting a compound with a suitable base using a variety of known methods. The following are further examples of acid salts obtainable by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.Additional information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, 1995. As solid pharmaceutical agents, those skilled in the art will recognize that the compounds, agents, and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and specific formula.

[0078] As used herein, the term "cancer" broadly encompasses neoplastic diseases characterized by abnormal cell growth and the potential for invading or metastasizing to other parts of the body. Cancer may be benign, meaning it does not metastasize to other parts of the body. Cancer may be malignant, meaning cancer cells may metastasize via the circulatory or lymphatic system. As used herein, the term "cancer" includes all malignant, i.e., cancerous, conditions. Cancer may exist as a tumor. Thus, the term "tumor" is used generally to define malignant cancerous or precancerous cell growths and specifically refers to solid tumors or carcinomas such as melanoma, colon cancer, lung cancer, ovarian cancer, skin cancer, breast cancer, pancreatic cancer, pharyngeal cancer, brain cancer, prostate cancer, central nervous system cancer, and kidney cancer (and other cancers), although it may also include leukemia.

[0079] In one embodiment, the condition is breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, or a hematological malignancy such as kidney cancer, stomach cancer, pancreatic cancer, brain cancer, lymphoma or leukemia.

[0080] As used herein, "standard of care" refers to the best known treatment for a given disease. In the case of prostate cancer, the current standard of care is 111MBq to 259MBq of radioactivity (FDA compliant). 68 Ga-PSMA-11 will be administered and images will be acquired by PET imaging approximately one hour later.

[0081] As used herein, the term "detection" refers to visualization of a disease in a patient. Detecting a disease may include administering a drug to the patient and subjecting the patient to one or more imaging modalities, where one or more images taken of the patient are processed to display the location of the drug within the patient's body. The imaging process for detection may also include steps such as imaging the patient to determine a baseline image, an anatomical image, etc., for comparison with images generated after drug administration.

[0082] As used herein, the term "diagnosis" refers to the detection and subsequent identification of a disease in a patient. Diagnosis of a disease takes into account one or more signs and symptoms exhibited by the patient and may involve one or more tests or examinations, such as imaging, blood tests, or biopsies. For example, a patient's disease can be diagnosed based on the signs and symptoms reported by the patient and the results of one or more imaging modalities, tissue biopsies, and blood tests to detect specific markers of the disease. In certain embodiments, the methods disclosed herein are used to diagnose cancer in a patient, and the methods include the use of PET imaging, biopsy, and / or blood tests on the patient.

[0083] As used herein, the term "prognosis" refers to predicting the course of a disease in a patient diagnosed with a particular disease. For example, if a patient is diagnosed with a particular disease, information obtained during the diagnosis process can be used to assess the extent or severity of the disease, thereby predicting the patient's specific prognosis. In certain embodiments, the methods disclosed herein enable imaging of one or more cancers in a subject, and imaging the cancer provides information on the location, severity, etc. of the cancer, thereby predicting the prognosis or likely course or outcome of the disease.

[0084] As used herein, the term "resolution" in relation to an image more specifically refers to "spatial resolution" and relates to the distance between measurements. With respect to images obtained according to the methods disclosed herein, a high-resolution image has more detailed information. In a high-resolution image, the distance between independent measurements is smaller than in a low-resolution image. More specifically, the term "spatial resolution" in PET imaging refers to the discrimination of two objects. PET imaging that enables high-resolution imaging means that two objects close to each other can be discriminated, whereas under low-resolution conditions, the same object may not be discriminated.

[0085] Resolution in PET imaging can be compared by quantifying and comparing values ​​such as the standard uptake value (SUV). Various statistical measures of SUV, such as the mean (SUV mean ), median, maximum (SUV max ) can also be determined.

[0086] As used herein, the term "tumor-to-background ratio" (TTBR) refers to the ratio of radiation uptake in a cancer-related tumor or lesion to the radiation remaining in background areas after administration of a radiotracer. For example, TTBR can be defined as the ratio of radiation uptake in a region of interest to the radiation in an appropriate background region.

[0087] In certain embodiments, the TTBR of a tumor or lesion may be greater than about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 145, or about 150. In some embodiments, the TTBR may be within a range between two of the aforementioned values. In some embodiments, the TTBR is in the range of about 40 to about 150. In some embodiments, the TTBR is in the range of about 40 to about 140. In some embodiments, the TTBR is in the range of about 40 to about 130. In some embodiments, the TTBR is in the range of about 40 to about 120. In some embodiments, the TTBR is in the range of about 40 to about 110. In some embodiments, the TTBR is in the range of about 40 to about 100. In some embodiments, the TTBR ranges from about 40 to about 90. In some embodiments, the TTBR ranges from about 40 to about 80. In some embodiments, the TTBR ranges from about 40 to about 70.

[0088] As used herein, the term "primary cancer" refers to the cancer that first occurs in a patient or is the first tumor that occurs.In certain embodiments of the method disclosed herein, cancer is primary cancer.In further embodiments, cancer is primary cancer and is prostate cancer.In some embodiments, there are multiple primary cancers, and one of the primary cancers is prostate cancer.

[0089] As used herein, the term "secondary cancer" refers to a cancer in which cells from a primary cancer have spread to a new site, i.e., the site where the primary cancer has metastasized. When metastasis occurs to form a secondary cancer, the secondary cancer is of the same type of cancer as the primary cancer. In certain embodiments, the secondary cancer is prostate cancer.

[0090] When cancer metastasizes, cells from the primary cancer spread from the original tumor to a new site, where they form a new tumor. Lymph nodes form part of the lymphatic system and are responsible for draining lymphatic fluid from organs and other parts of the body. Because lymph nodes are found throughout the body and serve as pathways to the bloodstream and circulatory system, cells that leave the primary tumor usually first come into contact with lymph nodes. In certain embodiments, the new location of a secondary cancer is a lymph node. This means that the secondary cancer is more prevalent in lymph nodes and lymphatic tissue.

[0091] In certain embodiments, the secondary cancer is located in a site other than the prostate. In some embodiments of the invention, the secondary cancer is found in a lymph node. In other embodiments, the secondary cancer is found in the bone. In other embodiments, the secondary cancer is found in the bladder. In other embodiments, the secondary cancer is found in the lung. In other embodiments, the secondary cancer is found in the liver.

[0092] As used herein, the term "TNM staging system" refers to a specific framework for describing and classifying the stage of cancer. The TNM staging system takes into account information about the primary tumor (T), the number of nearby lymph nodes with cancer (N), and whether the cancer has metastasized (M) and spread from the primary tumor to other parts of the body. [Table 1]

[0093] As used herein, "Gleason score" refers to a tumor staging system used to stage a patient's prostate cancer. Cancer cells are classified into five distinct patterns as they transform from normal prostate cells to tumor cells, and these are graded on a scale of 1 to 5. The Gleason score takes into account the histopathologically identified cell types present in a patient's biopsy sample. The most prominent cell pattern present in the specimen is assigned a Gleason grade of 1, and the second most prominent cell pattern is assigned a Gleason grade of 2. These two grades are then added together to calculate the Gleason score, which theoretically ranges from 2 to 10, although pathologists typically assign scores between 6 and 10.

[0094] As used herein, the term "ISUP grade" refers to the grade assigned to prostate cancer according to the guidelines approved by the International Society of Urological Pathology (ISUP). ISUP grade is based on the aforementioned Gleason score, that is, ISUP grade also depends on the biopsy sample taken from the patient. [Table 1]

[0095] As used herein, the term "prostate-specific antigen" (PSA) refers to a glycoprotein enzyme secreted by prostate epithelial cells. PSA is produced by both normal and malignant prostate cells, but prostate cancer patients often have elevated PSA levels. In certain embodiments, a subject's PSA level is between about 4 ng / mL and about 10 ng / mL. In other embodiments, a subject's PSA level may be less than about 4 ng / mL. In other embodiments, a subject's PSA level may be greater than about 10 ng / mL. Elevated PSA levels often indicate that a patient has prostate cancer, although some patients with PSA levels less than about 4 ng / mL do have prostate cancer, while some patients with high PSA levels, between about 4 ng / mL and about 10 ng / mL, do not have prostate cancer. Measuring a subject's PSA level can be used in combination with other techniques, such as PET imaging and CT imaging, as disclosed herein, to diagnose prostate cancer.

[0096] As used herein, the term "biochemical recurrence" with respect to prostate cancer refers to suspected recurrence of prostate cancer based on an increase in PSA levels after radical prostatectomy or radiation therapy, cryotherapy, or brachytherapy. In certain embodiments, biochemical recurrence of prostate cancer after radical prostatectomy is characterized by a detectable or rising PSA level of 0.2 ng / mL or higher, with a confirmed PSA level of 0.2 ng / mL or higher (as recommended by the American Urological Association). In other embodiments, biochemical recurrence of prostate cancer after radiation therapy, cryotherapy, or brachytherapy is characterized by a PSA level rising 2 ng / mL or higher above the nadir (as recommended by the American Society of Radiation Therapy and Oncology Phoenix Consensus Criteria).

[0097] As used herein, the term "subject" refers to a mammal, including humans, primates, livestock (e.g., sheep, pigs, cows, horses, donkeys), laboratory animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, livestock, dogs, cats), companion animals (e.g., dogs, cats), and captive wild animals. Preferably, the mammal is a human or a laboratory animal. More preferably, the mammal is a human.

[0098] In certain embodiments, the subject is a male patient.

[0099] However, these compounds are typically used in the form of pharmaceutical compositions formulated according to the desired method of administration. These compositions are prepared by methods well known in the art. In another embodiment, the present invention provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the components of the pharmaceutical composition of the present invention. Such a pack or kit includes at least one container containing a unit dose of the drug. Conveniently, the kit can provide single-dose sterile vials, allowing the physician to use the vials directly, containing the desired amounts and concentrations of the compound and radionucleotide, which can be mixed before use. Such containers can be accompanied by various documents, such as instructions for use or notices in the form prescribed by government agencies regulating the manufacture, use, or sale of pharmaceuticals, imaging agents, or biological products, reflecting approval by the agency for manufacture, use, or sale for human administration.

[0100] 64The compound of formula (I) complexed with Cu can be provided as a parenteral injection composition, which may include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating agents such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0101] These compositions may contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to add isotonic agents such as sugars and sodium chloride. Absorption delaying agents such as aluminum monostearate and gelatin can be added to delay absorption of the injection. Other additives include formulation stabilizers such as sodium gentisate and sodium ascorbate.

[0102] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0103] In the methods disclosed herein, 64 The compound of formula (I) or a salt thereof complexed with Cu is administered as an aqueous formulation, and the formulation is administered parenterally, preferably intravenously. In certain embodiments, 64 The compound of Formula (I) or a salt thereof complexed with Cu is administered intravenously as a bolus or infusion.64 The compound of formula (I) or a salt thereof complexed with Cu is administered as a single bolus intravenous injection.

[0104] Any reference in this specification to any prior publication (or information derived therefrom) or known matter should not be construed as an acknowledgement or admission, or any form of suggestion, that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field to which this specification pertains.

[0105] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications that fall within the true spirit and scope of the invention. The invention also includes all steps, features, compositions, and compounds referred to or indicated herein, individually or collectively, and any combination of any two or more of said steps or features.

[0106] Example The following examples are illustrative of the disclosure and should not be construed as limiting in any way the general nature of the disclosure of the description throughout this specification.

[0107] 64 The compound of formula (I) complexed with Cu is supplied to the clinical setting as a ready-to-use sterile formulation for intravenous injection. 64 The final formulation of the compound of formula (I) or its salt complexed with Cu contains sodium phosphate buffer, sodium gentisate and sodium ascorbate, with a final pH in the range of 4-8. 68 Ga-PSMA-11 will be manufactured at each clinical site as needed. [Example]

[0108] PET imaging of patients Patients with untreated, histopathologically proven, intermediate- to high-risk prostate cancer scheduled for radical prostatectomy were enrolled according to institutional practice. 68 Ga-PSMA-11 PET / CT was performed, followed by three dose cohorts (1:1:3) of 100MBq, 150MBq, or 200MBq. 64 Each patient received a designated dose of Cu-SAR-bisPSMA. 64 Cu-Sar-bisPSMA was administered as a single bolus IV injection. Alternatively, the indicated doses were administered 68 Ga-PSMA-11 or 18 F-DCFPyL was administered to the patient. 64 Cu-SAR-bisPSMA, 68 Ga-PSMA-11 or 18 PET / CT scans were acquired 3 hours (±1 hour) after injection of F-DCFPyL. PET / CT scans at other time points after compound injection were acquired as needed. [Example]

[0109] Acquisition parameters for PET imaging Patients were scanned using standard clinical whole-body PET / CT protocols established by each clinical site, according to an imaging manual detailing scan acquisition, processing parameters, and quality assurance procedures. The same scanner was used for each visit. Typical imaging parameters were as follows: [Table 1] [Example]

[0110] PET image analysis The primary endpoint was assessed by two independent, blinded, central readers. 64 We evaluated the detection of primary prostate cancer using Cu-SAR-bisPSMA PET / CT. 68 Ga-PSMA-11 and 64To compare lesion intensities in Cu-SAR-bisPSMA PET, both readers compared up to five matched lesions. 68 Ga-PSMA-11 and 64 Cu-SAR-bisPSMA PET / CT SUV max , SUV mean ) and tumor-background ratio (lesion SUV max and background SUV mean The ratio of 1:1 was measured as an exploratory endpoint.

[0111] Tables 1 and 2 below are based on the results of each reader. 68 After Ga-PSMA-11 administration and 64 This shows a comparison of SUV parameters obtained from PET / CT images after administration of 200MBq of Cu-SAR-bisPSMA. 64 In Cu-SAR-bisPSMA images, 68 Consistently higher SUV compared to images obtained with Ga-PSMA-11 max Value and SUV mean The values ​​were shown.

[0112] Table 1 [Table 1] TTBR = tumor-to-background ratio. * Imaging methods were compared using a two-sided Wilcoxon signed-rank test; # Violation of normality assumptions was confirmed with a Shapiro-Wilk normality test (p<0.05). Lesions are averaged per participant so that each participant contributes once to summary statistics.

[0113] Table 2 [Table 1] TTBR = tumor-to-background ratio. * Imaging methods were compared using a two-sided Wilcoxon signed-rank test; # Violation of normality assumptions was confirmed with a Shapiro-Wilk normality test (p<0.05). Lesions are averaged per participant so that each participant contributes once to summary statistics.

[0114] Tables 3 and 4 below are based on the results of each reader. 68 Ga-PSMA-11 (200 MBq) 64 This figure compares SUV parameters obtained from PET / CT images after administration of Cu-SAR-bisPSMA (200 MBq).

[0115] Table 3 [Table 1] TTBR = tumor-to-background ratio. * Imaging methods were compared using a two-sided Wilcoxon signed-rank test; # Violation of normality assumptions was confirmed with a Shapiro-Wilk normality test (p<0.05). Lesions are averaged per participant so that each participant contributes once to summary statistics.

[0116] Table 4 [Table 1] TTBR = tumor-to-background ratio. * Imaging methods were compared using a two-sided Wilcoxon signed-rank test; # Violation of normality assumptions was confirmed with a Shapiro-Wilk normality test (p<0.05). Lesions are averaged per participant so that each participant contributes once to summary statistics.

[0117] Table 5 shows the comparison of the number of positive, negative, and indeterminate images by each reader. Reader 1 had 200 MBq of 64 Cu-Sar-bisPSMA detected primary prostate cancer in 100% of patients, while reader 2 detected primary prostate cancer in 85.7% of patients. 68 This compares with 77.8% and 83.3%, respectively, when Ga-PSMA-11 was administered.

[0118] Table 5 [Table 1] *Four scans were deemed unassessable by the reader and were excluded

[0119] The resulting true positive rate (TPR) and false negative rate (FNR) are shown in Table 6. 64 Cu-Sar-bisPSMA and 68 The results were similar for both Ga-PSMA-11.

[0120] Table 6 [Table 1] 1 Indeterminate results were analyzed as negative. 2 McNemar's chi-square test with continuity correction

[0121] 64 Cu-Sar-bisPSMA or 68 The number of lesions detected by each reader was assessed using either Ga-PSMA-11 or Ga-PSMA-11. The results are shown in Table 7. For both readers, the total number of lesions, the mean number of lesions, and the median number of lesions were: 64 In imaging with Cu-Sar-bisPSMA 68 The difference in these values ​​was statistically significant.

[0122] Table 7 [Table 1] ** Imaging methods were compared using a two-tailed Wilcoxon signed-rank test. Violations of normality assumptions were confirmed by the Shapiro-Wilk normality test (p<0.05).

[0123] Only participants with evaluable scans obtained with both imaging modalities were included in the analysis. Differences between imaging modalities were observed in one participant. 68 Number of lesions detected by Ga-PSMA-11 PET / CT 64The number of lesions detected by Cu-SAR-bisPSMA PET / CT (i.e., 64 Cu - 68 Ga). Negative values ​​are 68 The number of lesions detected by Ga-PSMA-11 PET / CT 64 This indicates that the number of lesions detected by Cu-SAR-bisPSMA PET / CT was greater than the number of lesions detected by Cu-SAR-bisPSMA PET / CT. This study was not powered to detect differences at the individual level.

[0124] As shown in Table 8, the detection specificity of PET images is 64 The specificity was high for all readers, regardless of whether Cu-Sar-bisPSMA was administered on the same day or the next day. The relative decrease in specificity for next-day imaging is due to difficulties in obtaining baseline values ​​for the increased number of identified lesions, the inability to biopsy all lesions, and the low sensitivity of imaging with existing protocols.

[0125] Table 8 [Table 1] CDR: positive detection rate. DR: detection rate. PPV: positive predictive value. LNs: lymph nodes. CI: confidence interval.

[0126] The claims which define the invention are as follows:

Claims

1. 1. A method for the detection and / or diagnosis of cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 1】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); A method comprising:

2. 64 2. The method of claim 1, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

3. 3. The method of claim 1 or 2, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

4. The method of any one of claims 1 to 3, wherein the subject is imaged by PET imaging at a time point of about 10 hours after administration of the compound of formula (I).

5. 5. The method of any one of claims 1 to 4, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

6. The method of any one of claims 1 to 5, wherein the PSMA receptor-associated cancer is prostate cancer.

7. 7. The method of claim 6, wherein the prostate cancer is associated with biochemical recurrence.

8. 1. A method for the detection and / or diagnosis of cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 2】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; and ii) imaging the subject with PET imaging; and iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the tumor-to-background ratio (TTBR) of the cancer-associated lesions in the subject is greater than about 40, with a minimum of 40 and a maximum of 150; A method comprising:

9. 64 9. The method of claim 8, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

10. 10. The method of claim 8 or 9, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

11. The method of any one of claims 8 to 10, wherein the subject is imaged by PET imaging at a time point of about 10 hours after administration of the compound of formula (I).

12. 12. The method of any one of claims 8 to 11, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

13. The method of any one of claims 8 to 12, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

14. 14. The method of any one of claims 8 to 13, wherein the TTBR of the cancer-associated lesion is about 40 to about 150, about 40 to about 140, about 40 to about 130, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60.

15. The method according to any one of claims 8 to 14, wherein the cancer associated with overexpression of the PSMA receptor is prostate cancer.

16. 16. The method of claim 15, wherein the prostate cancer is associated with biochemical recurrence.

17. 1. A method for the detection and / or diagnosis of cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Transformation 3】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of the lesion visualized by imaging in step ii); wherein the tumor-to-background ratio (TTBR) of cancer-associated lesions in the subject is greater than about 40; A method comprising:

18. 64 18. The method of claim 17, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

19. 19. The method of claim 17 or 18, wherein the subject is imaged by PET imaging at about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

20. 20. The method of any one of claims 17 to 19, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

21. 21. The method of any one of claims 17 to 20, wherein the TTBR of the cancer-associated lesion is about 40 to about 150, about 40 to about 140, about 40 to about 130, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60.

22. The method of any one of claims 17 to 21, wherein the cancer associated with overexpression of the PSMA receptor is prostate cancer.

23. 23. The method of claim 22, wherein the prostate cancer is associated with biochemical recurrence.

24. 1. A method for imaging lesions in cancer associated with PSMA receptor overexpression in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 4】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the lesion is characterized by a tumor-to-background ratio (TTBR) of greater than about 40; A method comprising:

25. 64 25. The method of claim 24, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

26. 26. The method of claim 24 or 25, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

27. 27. The method of any one of claims 24 to 26, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

28. 28. The method of any one of claims 24 to 27, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

29. 29. The method of any one of claims 24 to 28, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

30. 30. The method of any one of claims 24 to 29, wherein the TTBR of the cancer-associated lesion is about 40 to about 150, about 40 to about 140, about 40 to about 130, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60.

31. The method according to any one of claims 24 to 30, wherein the cancer is prostate cancer.

32. 32. The method of claim 31, wherein the prostate cancer is associated with biochemical recurrence.

33. 1. A method for imaging lesions in cancer associated with PSMA receptor overexpression in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Transformation 5】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of one or more lesions detected by imaging in step ii); wherein the lesion is characterized by a tumor-to-background ratio (TTBR) of greater than about 40; A method comprising:

34. 64 34. The method of claim 33, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

35. 35. The method of claim 33 or 34, wherein the subject is imaged by PET imaging at about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

36. 36. The method of any one of claims 33 to 35, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

37. 37. The method of any one of claims 33 to 36, wherein the TTBR of the cancer-associated lesion is about 40 to about 150, about 40 to about 140, about 40 to about 130, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60.

38. 38. The method of any one of claims 33 to 37, wherein the TTBR of the lesion in the cancer associated with overexpression of the PSMA receptor is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150.

39. 39. The method of any one of claims 33 to 38, wherein the TTBR of the cancer-associated lesion is about 40 to about 150, about 40 to about 140, about 40 to about 130, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60.

40. The method of any one of claims 33 to 39, wherein the cancer associated with overexpression of the PSMA receptor is prostate cancer.

41. 41. The method of claim 40, wherein the prostate cancer is associated with biochemical recurrence.

42. 1. A method for the detection and / or diagnosis of cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 administering a compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; and ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); 【Transformation 6】 Formula (I) Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; A method comprising:

43. 1. A method for the detection and / or diagnosis of cancer associated with overexpression of PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Transformation 7】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; A method comprising:

44. 64 44. The method of claim 42 or 43, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

45. 45. The method of claim 44, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of Formula (I).

46. The method of claims 42-45, wherein the subject is imaged by PET imaging at a time point of about 10 hours after administration of the compound of formula (I).

47. 47. The method of any one of claims 42-46, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

48. 48. The method of any one of claims 42 to 47, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

49. 49. The method of any one of claims 42 to 48, wherein the TTBR of the cancer-associated lesion is from about 40 to about 150, from about 40 to about 140, from about 40 to about 130, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, or from about 40 to about 60.

50. The method of any one of claims 42 to 49, wherein the cancer is prostate cancer.

51. 51. The method of claim 50, wherein the prostate cancer is associated with biochemical recurrence.

52. 1. A method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Transformation 8】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); A method comprising:

53. 64 53. The method of claim 52, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

54. 54. The method of claim 52 or 53, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

55. 55. The method of any one of claims 52-54, wherein the subject is imaged by PET imaging at about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

56. The method of any one of claims 52 to 55, wherein the cancer associated with the PSMA receptor is prostate cancer.

57. 57. The method of claim 56, wherein the prostate cancer is associated with biochemical recurrence.

58. 1. A method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 9】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject with PET imaging; and iii) determining the tumor-to-background ratio (TTBR) of lesions visualized by imaging; wherein the tumor-to-background ratio (TTBR) of the cancer-related lesions in the subject detected by imaging in step ii) is greater than about 40; A method comprising:

59. 64 59. The method of claim 58, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

60. 60. The method of claim 58 or 59, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

61. 61. The method of any one of claims 58 to 60, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

62. 62. The method of any one of claims 58-61, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

63. 63. The method of any one of claims 58 to 62, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

64. 64. The method of any one of claims 58 to 63, wherein the TTBR of the cancer-associated lesion is from about 40 to about 150, from about 40 to about 140, from about 40 to about 130, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, or from about 40 to about 60.

65. The method of any one of claims 58 to 64, wherein the cancer is prostate cancer.

66. 66. The method of claim 65, wherein the prostate cancer is associated with biochemical recurrence.

67. 1. A method for the detection and / or diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 10】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least about 8 hours after administration of a compound of Formula (I); iii) determining the tumor-to-background ratio (TTBR) of lesions visualized by imaging; wherein the tumor-to-background ratio (TTBR) of the cancer-related lesions in the subject detected by imaging in step ii) is greater than about 40; A method comprising:

68. 64 68. The method of claim 67, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

69. 69. The method of claim 67 or 68, wherein the subject is imaged by PET imaging at about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

70. 70. The method of any one of claims 67 to 69, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

71. 71. The method of any one of claims 67 to 70, wherein the TTBR of the cancer-associated lesion is from about 40 to about 150, from about 40 to about 140, from about 40 to about 130, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, or from about 40 to about 60.

72. The method of any one of claims 67 to 71, wherein the cancer is prostate cancer.

73. In another aspect, the present invention provides a method for the detection and diagnosis of a secondary cancer associated with a primary cancer associated with overexpression of a PSMA receptor in a subject in need thereof, comprising: i) To the subject, 64 administering a compound of formula (I) or a salt thereof complexed with Cu at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); and iii) diagnosing the second cancer based on the one or more images obtained in step ii); 【Chemistry 11】 Here, cancer images were administered under standard of care conditions. 68 Higher resolution compared to Ga-PSMA-11; The present invention provides a method comprising:

74. 64 74. The method of claim 73, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with Cu is about 200 MBq.

75. 75. The method of claim 73 or 74, wherein the subject is imaged by PET imaging at about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

76. The method of any one of claims 73 to 75, wherein the cancer is prostate cancer.

77. 77. The method of any one of claims 73 to 76, wherein the secondary cancer is in the lymph nodes, bone, bladder, lung, or liver.

78. 1. A method for determining the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 12】 or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject with PET imaging; and iii) determining the TNM stage of the cancer based on one or more images obtained in step ii) and the ISUP grade of the tumor; wherein the ISUP grade of the tumor is determined before steps i) to iii); A method comprising:

79. 79. The method of claim 78, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of Formula (I).

80. 80. The method of any one of claims 78 to 79, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

81. 81. The method of any one of claims 78-80, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

82. 82. The method of any one of claims 78-81, wherein imaging the subject by PET imaging identifies one or more lesions associated with prostate cancer.

83. 83. The method of any one of claims 78-82, further comprising determining a tumor-to-background ratio (TTBR) of the lesions visualized by imaging, wherein the tumor-to-background ratio (TTBR) of the lesions associated with the cancer of the subject detected by imaging in step ii) is greater than about 40.

84. 84. The method of any one of claims 78 to 83, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

85. 85. The method of any one of claims 78 to 84, wherein the TTBR of the cancer-associated lesion is from about 40 to about 150, from about 40 to about 140, from about 40 to about 130, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, or from about 40 to about 60.

86. The method of any one of claims 78 to 85, wherein the ISUP grade of the tumor is grade 1, grade 2, grade 3, grade 4 or grade 5.

87. 86. The method of any one of claims 78 to 85, wherein the ISUP grade of the tumor is determined by calculation of the Gleason score.

88. 88. The method of claim 87, wherein the Gleason score is 6, 7, 8, 9 or 10.

89. 89. The method of any one of claims 78-88, wherein the TNM stage of the prostate cancer is selected from one or more of TX, TO, T1, T2, T3, T4, NX, NO, N1, N2, N3, MX, MO, or M1.

90. 1. A method for reassessing the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 13】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) first determining the stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration of the compound of formula (I) according to step i); A method comprising:

91. 91. The method of claim 90, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of Formula (I).

92. 92. The method of claim 90 or 91, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

93. 93. The method of any one of claims 90-92, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

94. 94. The method of any one of claims 90-93, wherein imaging the subject by PET imaging identifies one or more lesions associated with prostate cancer.

95. 95. The method of any one of claims 90-94, further comprising determining a tumor-to-background ratio (TTBR) of the lesions visualized by imaging, wherein the tumor-to-background ratio (TTBR) of the lesions associated with the cancer of the subject detected by imaging in step ii) is greater than about 40.

96. 96. The method of any one of claims 90 to 95, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

97. 97. The method of any one of claims 90 to 96, wherein the TTBR of the cancer-associated lesion is from about 40 to about 150, from about 40 to about 140, from about 40 to about 130, from about 40 to about 120, from about 40 to about 110, from about 40 to about 100, from about 40 to about 90, from about 40 to about 80, from about 40 to about 70, or from about 40 to about 60.

98. 1. A method for determining the progression of cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 14】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging; iii) first determining the TNM stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the TNM stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration of the compound of formula (I) according to step i); A method comprising:

99. 99. The method of claim 98, wherein imaging of the subject by PET imaging is at a time point of about 8 hours after administration of the compound of Formula (I).

100. 100. The method of claim 98 or 99, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

101. 101. The method of any one of claims 98-100, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

102. 102. The method of any one of claims 98-101, wherein imaging the subject by PET imaging identifies one or more lesions associated with prostate cancer.

103. 103. The method of any one of claims 98-102, further comprising determining a tumor-to-background ratio (TTBR) of the lesions visualized by imaging, wherein the tumor-to-background ratio (TTBR) of the lesions associated with the cancer of the subject detected by imaging in step ii) is greater than about 40.

104. 104. The method of any one of claims 98 to 103, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

105. The method of any one of claims 98 to 104, wherein the TNM stage of the prostate cancer after reassessment is higher.

106. The method of any one of claims 98 to 104, wherein the TNM stage of the prostate cancer after reevaluation comprises an N1, N2 or N3 stage.

107. The method of any one of claims 98 to 104, wherein the TNM stage of the prostate cancer after reassessment is lower.

108. The method of any one of claims 98 to 104, wherein the TNM stage of the prostate cancer after reevaluation comprises a T0, N0 or M0 stage.

109. In another aspect, the present invention provides a method of reassessing the TNM stage of prostate cancer in a subject, comprising: i) To the subject, 64 Formula (I) complexed with Cu: 【Chemistry 15】 Formula (I) or a salt thereof at a dose of about 100 MBq to about 300 MBq; ii) imaging the subject by PET imaging at least once between about 30 minutes and about 36 hours after administration of a compound of Formula (I); iii) first determining the stage of the prostate cancer based on the one or more images obtained in step ii); and iv) repeating steps i) and ii) and determining the stage of the prostate cancer based on one or more images obtained by imaging the subject after the second administration according to step i); The present invention provides a method comprising:

110. 110. The method of claim 109, wherein imaging of the subject by PET imaging is at about 8 hours after administration of the compound of formula (I).

111. 111. The method of claim 109 or 110, wherein imaging of the subject by PET imaging is at about 10 hours after administration of the compound of formula (I).

112. 112. The method of any one of claims 109-111, wherein the subject is imaged by PET imaging at about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, or about 36 hours after administration of the compound of Formula (I).

113. 113. The method of any one of claims 109 to 112, wherein imaging the subject by PET imaging identifies one or more lesions associated with prostate cancer.

114. 114. The method of any one of claims 109 to 113, further comprising determining a tumor-to-background ratio (TTBR) of the lesions visualized by imaging, wherein the tumor-to-background ratio (TTBR) of the lesions associated with the cancer of the subject detected by imaging in step ii) is greater than about 40.

115. 115. The method of any one of claims 109 to 114, wherein the TTBR of the cancer-associated lesion is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150.

116. The method of any one of claims 109 to 115, wherein the TNM stage of the prostate cancer after reassessment is higher.

117. The method of any one of claims 109 to 115, wherein the TNM stage of the prostate cancer after reevaluation comprises an N1, N2 or N3 stage.

118. The method of any one of claims 109 to 115, wherein the TNM stage of the prostate cancer after reassessment is lower.

119. The method of any one of claims 109 to 115, wherein the TNM stage of the prostate cancer after reevaluation comprises a T0, N0 or M0 stage.

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