Use of radioligand imaging agent for prostate cancer and solution thereof for injection or infusion

Abstract

This invention relates to the field of diagnostic methods, particularly prostate cancer imaging. Specifically, this invention relates to a radiopharmaceutical PSMA-binding compound for determining the presence and / or location of PSMA-positive tumors in a subject who has been diagnosed with biochemical recurrence, particularly after radical prostatectomy or radiotherapy, and the radiopharmaceutical compound is a compound of the following chemical formula (III): .

Description

[Technical Field]

[0001] This invention relates to the field of diagnostic methods, particularly prostate cancer imaging. [Previous Technology]

[0002] Prostate-specific membrane antigen (PSMA) is a transmembrane protein, also known as folic acid hydrolase or glutamic acid carboxypeptidase II. Among all known PSMA-overexpressing tumors, prostate cancer has the most extensively studied role of PSMA. Prostate cancer remains the second leading cause of cancer death in the United States (US) and the third leading cause of cancer-related death in men in Europe (Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin; 67(1):7-30, Malvezzi M, Carioli G, Bertuccio P, et al (2019) European cancer mortality predictions for the year 2019 with focus on breast cancer. Ann Oncol; 30(5):781-7). It remains the most frequently diagnosed cancer, with an estimated 9,960 new cases added to the total of 174,650 cases in 2019 (Siegel RL, Miller KD, Jemal A (2018) Cancer Statistics, 2018. CA Cancer J Clin; 68(1):7-30, Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin; 69(1):7-34). Due to the use of prostate-specific antigen (PSA) testing, most confirmed cases are located in more developed regions, but the mortality rate from metastatic, often castration-resistant, disease has changed only slightly globally (Bray F, Ren JS, Masuyer E, et al (2013). Int J Cancer; 132:1133-45). Subsequent treatment is multifaceted and may involve observation, surgery (prostatectomy), radiation therapy (external beam radiation therapy or brachytherapy), hormone therapy, and chemotherapy. The differential expression of PSMA in tumor and non-tumor tissues has led to numerous targeting strategies, including the use of PSMA-PET imaging for disease localization and therapeutic intervention. Accurate identification of lesion location and extent determines treatment decisions for prostate cancer patients. Identifying distant metastases in the early stages of prostate cancer is crucial for planning its management.

[0003] Up to 40% of prostate cancer patients develop biochemical recurrence (BCR) within 10 years of initial treatment (Isbarn et al. 2010. BJU Int; 106:37-43). Typically, a rise in PSA levels occurs months to years before clinically detectable recurrence (Van Poppel et al. 2006, (EORTC 30001). Eur J Cancer; 42:1062-7). However, it cannot differentiate between localized, regional, or systemic disease with the necessary precision for further disease management.

[0004] Therefore, it is meaningful to detect smaller and more distant lesions as early as possible, especially in patients with biochemical recurrence.

[0005] Common diagnostic tools for prostate cancer include PSA testing, digital rectal palpation, transrectal ultrasound, prostate biopsy, and histopathological examination (Schwarzenböck S, Souvatzoglou M, Krause BJ (2012). Theranostics; 2(3):318-30; Smith RA, Andrews K, Brooks D, et al (2016) Cancer screening in the United States, 2016: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin; 66(2):95-114; Prasad V, Steffen IG, Diederichs G, et al (2016). Mol Imaging Biol; 18:428-36).Furthermore, advanced imaging techniques such as magnetic resonance imaging (MRI), bone scans, computed tomography (CT), and fluoro-18-deoxyglucose ([18F]Fluorodeoxyglucose, FDG), fluoro-18-choline ([18F]Choline), carbon-11-choline ([11C]Choline), and the recently approved fluciclovine ([18F]fluciclovine) (Nanni C, Zanoni L, Pultrone C, et al (2016) (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET / CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging; 43:1601-10, Odewole OA, Tade FI, Nieh PT, et al (2016) Recurrent prostate cancer detection with Anti-3-[(18)F]FACBC PET / CT: comparison with CT. Eur J Nucl Med Mol Imaging; 43:1773-83) PET / CT was used for staging of primary prostate cancer and restaging of biochemical recurrence (Schwarzenböck S, Souvatzoglou M, Krause BJ (2012) Choline PET and PET / CT in Primary Diagnosis and Staging of Prostate Cancer. Theranostics; 2(3):318-30).

[0006] According to the Responsive Evaluation Criteria in Solid Tumors (RECIST) 1.1, computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging procedures used to measure baseline tumors and lesions selected for response assessment (Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45:228-47). However, these imaging modalities have shown limited effectiveness in staging pelvic lymph nodes in patients with prostate cancer.

[0007] Therefore, there is a need for imaging tests that are more sensitive and accurate than the currently available standard care examinations. Novel PET radiation sources promise to overcome this limitation. PET imaging is an attractive option because it is available to patients at all stages and offers the potential for a deeper understanding of tumor biology. Among the various PET probes available, a meta-analysis of several retrospective studies has indicated that ligands of 68Ga-labeled PSMA are associated with unprecedented accuracy and therapeutic efficacy (Perera M, Papa N, Christidis D, et al (2016). Eur Urol; 70:926-37; Han S, Woo S, Kim YJ, et al (2018). Eur Urol; 74:179-90, Von Eyben FE, Picchio M, von Eyben R, et al (2018). Eur Urol Focus; 4:686-93). In particular, a head-to-head clinical trial was conducted to compare the uptake of fluciclofen and [68Ga]Ga-PSMA-11 for localization of prostate cancer tumors in patients with biochemical recurrence. In patients with PSA < 2.0 ng / mL, the detection rate of [68Ga]Ga-PSMA-11 after radical prostatectomy was superior to that of fluciclofen on a per-patient and per-region basis (Calais et al. 2018 Potential Impact of 68Ga-PSMA-11 PET / CT on the Planning of Definitive Radiation Therapy for Prostate Cancer. J Nucl Med; 59(11):1714-21). However, a prospective clinical controlled trial on flusildenafil and [68Ga]Ga-PSMA-11 in patients with biochemical recurrence of prostate cancer found no statistically significant difference in the overall detection rate of prostate cancer recurrence between the two different radioligands (Pernthaler et al. 2019 A Prospective Head-to-Head Comparison of 18F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in PET / CT. Clin Nucl Med; 44(10):e566-e73).

[0008] Therefore, it is still necessary to confirm the ability to detect and locate radioligands in tumors in patients with biochemically recurrent prostate cancer with improved detection and / or localization rates.

[0009] [18F]CTT1057 is a promising new PSMA-targeted 18F-labeled PET imaging agent (WO2014143736). Unlike most other PSMA imaging agents labeled with 68Ga or 18F that share a urea backbone (e.g., [68Ga]Ga-PSMA-11, [18F]PSMA1007, [18F]DCFPyL), [18F]CTT1057 is based on a phosphoramidate architecture that can irreversibly bind to PSMA with high nanomolar affinity, which can explain the high and durable tumor uptake (Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6).

[0010] A phase 1 study of [18F]CTT1057 in 20 patients with prostate cancer (n=5 with primary stage and n=15 with metastatic castration-resistant prostate cancer (mCRPC)) demonstrated an acceptable safety profile with no radiotracer-related adverse events. The phase 1 study also showed that [18F]CTT1057 imaging was more sensitive than conventional imaging in detecting metastatic lesions (Behr et al. 2019). Another small study showed that the image quality of PET imaging with [18F]CTT1057 was qualitatively similar to that obtained with [68Ga]Ga-PSMA-11 PET (Behr S, Aggarwal R, Flavell R, et al (2017) [abstract]. J Nucl Med; 58 Suppl 1:733A). [Summary of the Invention]

[0011] This invention provides a novel method for the use of PET imaging agents to detect and locate PSMA positivity in patients diagnosed with biochemical recurrence, particularly prostate cancer patients.

[0012] In particular, an object of the present invention is to provide a method for detecting PSMA-positive tumors using a PET imaging agent that preferably provides a very high tumor-to-background ratio to a target on prostate cancer cells expressing PSMA.

[0013] Another object of the present invention is to provide a method for identifying disease sites that are very small in size.

[0014] Another object of the present invention is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, using a PET imaging agent having a biodistribution that is advantageous for detecting typical sites of the disease (such as the prostate bed, pelvic lymph nodes, and bones).

[0015] Another object of the present invention is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, which works reliably in a wide variety of clinical situations, including initial staging, restaging in cases of biochemical recurrence, and radiological or surgical planning.

[0016] Another object of the present invention is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, with an imaging agent having a high radiochemical yield and enabling high-throughput detection of patients.

[0017] Therefore, the present invention relates to a radioligand imaging agent for determining the presence and / or location of a PSMA-positive tumor in a subject who has been diagnosed with biochemical recurrence, and the radioligand imaging agent is a PSMA-binding compound comprising a phosphatamine group and a [18F]-fluorine group.

[0018] The present invention also relates to an injection or infusion solution comprising an aqueous solution containing a PSMA-binding compound and one or more pharmaceutically acceptable excipients, the PSMA-binding compound comprising a phosphatamine group and a [18F]-fluorine group, the concentration of which provides volumetric radioactivity from 150 MBq / mL to 1000 MBq / mL, for example about 370 MBq / mL.

[0019] This document also discloses a method for determining the presence and / or location of a PSMA-positive tumor in a subject preferably with prostate cancer, wherein the subject has been diagnosed with biochemical recurrence, and the method comprises: (1) administering to the subject an effective dose of a radioligand imaging agent as defined below; (2) imaging the subject by means of a PET scan, wherein the PET scan is a PET / CT scan or a PET / MRI scan; and (3) analyzing the images obtained from the PET scan to determine the presence and / or location of a PSMA-positive tumor in the subject.

Implementation Method

[0021] 〔Definition〕

[0022] The term “PSMA-positive tumor” as used herein refers to a tumor lesion that can be detected by a tracer compound containing a PSMA-binding moiety, typically a radioligand imaging agent, such as a PSMA-binding compound of formula (I), (II) or (III) labeled with 18F as described below.

[0023] Consistent with the International System of Units (SI), "MBq" is an abbreviation for "million becquerels" (MBq), a radioactive unit.

[0024] The term "PET" used here stands for Positron-emission tomography.

[0025] The term "SPECT" used here stands for Single-photon emission computed tomography.

[0026] The term "MRI" used herein stands for magnetic resonance imaging.

[0027] The term "CT" used here stands for Computed tomography.

[0028] The term "effective dose" as used herein, with respect to the radioligand imaging agents disclosed according to the present invention, refers to an amount of imaging agent sufficient to determine the presence or location of PSMA-positive lesions in a patient from an imaging study using this imaging agent. Particularly in certain embodiments, the method disclosed in this invention can determine presence and / or location more reliably than conventional imaging methods. The effective dose can be determined by the radioactivity of the injection solution at the injection time. The radioactivity of the injection solution can be derived from a measurement of the volumetric radioactivity of the injection solution at a reference time, typically measured after the injection solution is manufactured, also known as the "calibration time." The physician will adjust the volume to be injected based on the estimated volumetric radioactivity at the injection time and the known volumetric radioactivity at the calibration time.

[0029] Therefore, when referring to the volumetric radioactivity of the composition, the term "calibration time" used herein refers to radioactivity measured at a reference time, such as radioactivity measured within 60 minutes after the product is manufactured.

[0030] "Radiochemical purity" is the percentage of the radionuclide present in the chemical or biological form. Radiochromatography, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC), is a commonly accepted method in radiopharmacology for determining radiochemical purity. In certain embodiments, the radiochemical purity of the radioligand imaging agent is better than or equal to 95%.

[0031] As used herein, the term "aqueous solution" refers to a solution of one or more solutes in water. The term "aqueous solution" may also refer to an aqueous alcohol solution containing water and an alcohol, preferably water and ethanol, for example, with an alcohol content between 0% and 20%, preferably between 0% and 10%, for example between 2% and 8%, more preferably about 5%.

[0032] The term “about” or “ca.” here means that the variation range of the following numerical value can be ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0033] The term "amino acid" as used herein refers to an organic compound containing at least one amino group and at least one carboxyl group, and includes both natural and non-natural amino acids.

[0034] As used herein, the term "heteroalkylene" refers to a divalent heteroalkylene, which is a straight or branched hydrocarbon chain consisting of 1 to 35 carbon atoms and 1 to 15 heteroatoms, preferably 1 to 20 carbon atoms, and the heteroatoms are selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may be selectively oxidized (e.g., arsenic or arsenic) and the nitrogen heteroatom may be selectively quaternized. The heteroatoms O, N, and S may be placed at any internal position of the heteroalkylene and at one or both chain ends.

[0035] [Radioactive ligand imaging agent used in the method disclosed in this invention]

[0036] According to the present invention, the radioligand imaging agent used is a PSMA-binding compound containing at least a phosphatamine group and a [18F]-fluorine group, or a pharmaceutically acceptable salt thereof.

[0037] 18F radiolabeled PSMA-binding compounds have been described in the prior art and include the contents described in WO2013173583 or WO2014143736.

[0038] In some embodiments, the radioligand imaging agent disclosed in this invention is a PSMA-binding compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof:

[0039] Chemical formula (I),

[0040] Among them,

[0041] R is each independently a hydrogen or a protecting group (e.g., tert-butyl or benzyl).

[0042] R2 is independently hydrogen or C1-C6 alkyl.

[0043] R3 is phenyl or pyridyl, each substituted with a [18F]-fluoro group, and may be selectively substituted with a second group selected from halogenated, cyano, and nitro groups.

[0044] L1 is a linker, preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkyl groups and heteroalkyl groups comprising 1 to 35 carbon atoms and 1 to 15 heteroatoms, wherein the heteroalkyl group may be selectively substituted by one or more substituents selected from oxo and C1-C6 alkyl groups, and L1 is more preferably a linker selected from 1 to 6 amino acids.

[0045] In some embodiments, the radioligand imaging agent disclosed in this invention is a PSMA-binding compound of the following chemical formula (II) or a pharmaceutically acceptable salt thereof:

[0046] Chemical formula (II),

[0047] L is a linker containing a portion of the chemical formula -NH-CH2CH2-(OCH2CH2-)yC(O)- or a group of the following chemical formulas.

[0048] ,

[0049] where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

[0050] m is 1, 2, 3 or 4,

[0051] n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 independently.

[0052] R1 is phenyl or pyridyl, each substituted with [18F]-fluoro, and may optionally be substituted with a second group selected from chloro and cyano groups.

[0053] R2 is independently hydrogen or C1-C6 alkyl, and

[0054] R is each independently a hydrogen or a protecting group (e.g., tert-butyl or benzyl).

[0055] If L is a group of the following chemical formula

[0056]

[0057] The combination of m and n results in a linear connector length of 3 to 21 atoms. For example, when m is 2 and each n is 4, the connector length is 12 atoms. If m is 1 and n is 10, the connector length is also 12. The connector length is calculated using the formula m(n+2).

[0058] As used herein, the term "protecting group" refers to a group that introduces a functional group (such as phosphorous acid or carboxylic acid) that allows for chemoselectivity in subsequent chemical transformations. Such groups are described in Greene's Protective Groups in Organic Synthesis, 4th edition (the relevant portion of which is incorporated herein by reference), specifically carboxylic acid and phosphate protecting groups.

[0059] In some embodiments, the "protecting group" is alkyl, alkenyl, or haloalkyl. This includes, but is not limited to, methyl, ethyl, propyl, isopropyl, tributyl, allyl, trifluoromethyl, or trifluoroethyl. In some embodiments, the "protecting group" is benzyl or substituted benzyl, including, but not limited to, triphenylmethyl, diphenylmethyl, o-nitrobenzyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, p-nitrobenzyl, p-methoxybenzyl (PMB), 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, 4-azidomethoxybenzyl, and piperonyl.

[0060] In a preferred embodiment, the radioligand imaging agent disclosed in this invention is a PSMA-binding compound of the following chemical formula (III) or a pharmaceutically acceptable salt thereof:

[0061] Chemical Formula (III),

[0062] The compound with chemical formula (III) is also referred to in the literature as [18F]CTT1057.

[0063] Other PSMA-binding compounds used in this invention and methods for synthesizing such compounds are specifically described in WO2014 / 143736, the contents of which are incorporated herein by reference in their entirety.

[0064] In a specific embodiment, the radioligand imaging agent disclosed in this invention can be synthesized from the precursor CTT1298 of the following chemical formula (IV).

[0065] Chemical Formula (IV)

[0066] In particular, as shown in the following reaction diagram, it is achieved by coupling succinimidyl-18F-fluorobenzoate to a primary amine precursor.

[0067]

[0068] [18F]SFB can be synthesized using the following reaction scheme:

[0069]

[0070] The method for obtaining compound CTT1298 has been described in the prior art and in particular in WO2014143736 (Example 1, the contents of which are incorporated herein by reference).

[0071] Further examples of synthesis methods using ORA Neptis® Performance Synthesizer have been described in Jivan et al. 2017 (J Labelled Comp Radiopharm 2017: 60:1).

[0072] [Disclosed pharmaceutical composition]

[0073] The PSMA-binding compounds disclosed in this invention are formulated into pharmaceutical compositions, typically solutions for injection or infusion.

[0074] The solution for injection or infusion is preferably an aqueous or aqueous alcoholic solution containing the PSMA-binding compound described herein and one or more pharmaceutically acceptable excipients.

[0075] Generally, the PSMA-binding compound is present in the pharmaceutical composition at a concentration that provides volumetric radioactivity between 150 MBq / mL and 1000 MBq / mL, preferably between 200 MBq / mL and 700 MBq / mL, more preferably between 250 MBq / mL and 450 MBq / mL, for example, about 370 MBq / mL at calibration time.

[0076] Pharmaceutically acceptable excipients may be any of those currently in use. In particular, the one or more excipients may be selected from buffers, radioactive stabilizers, isotensive agents, and mixtures thereof.

[0077] The term "radiodegradation resistant stabilizer" as used herein refers to a stabilizer that protects organic molecules from radiodegradation. For example, when gamma rays emitted from a radioactive nucleus break the bonds between atoms in an organic molecule and form free radicals, these free radicals are scavenged by a stabilizer, preventing them from undergoing other chemical reactions that could lead to undesirable, potentially ineffective, or even toxic molecules. Therefore, such stabilizers are also called "free radical scavengers" or simply "group scavengers." Other alternative terms for these stabilizers are "radiostability enhancers," "radiodegradation stabilizers," or simply "quenchers." In a preferred embodiment, the radiodegradation resistant stabilizer is ethanol.

[0078] The buffer comprises a phosphate, acetate, or citrate buffer or a combination thereof, preferably a phosphate buffer. In certain embodiments, the buffer or combination of buffers is suitable for a pH between 6.5 and 7.5.

[0079] The isotropic agent contains sodium chloride, specifically at a concentration of about 0.9%.

[0080] In a particular embodiment, the injection or infusion solution contains a radioligand imaging agent as described above, such as a PSMA-binding compound of formula (I), (II) or (III), preferably a compound of formula (III), wherein the concentration of the PSMA-binding compound provides volumetric radioactivity between 150 MBq / mL and 1000 MBq / mL at calibration time, preferably between 200 MBq / mL and 700 MBq / mL, more preferably between 250 MBq / mL and 450 MBq / mL, typically about 370 MBq / mL at calibration time, and the solution may optionally contain phosphate buffer and sodium chloride.

[0081] In a particular embodiment, the solution for injection or infusion further comprises a buffer solution and an isotonic agent. The buffer solution maintains the pH between 6.5 and 7.5, preferably a phosphate buffer. The isotonic agent is preferably sodium chloride.

[0082] In a particular embodiment, the solution may further contain the maximum amount of the precursor compound used for synthesis. For example, the precursor compound of formula (IV) (also referring to CTT1298) is present at a concentration of no more than 5 μg / mL, preferably no more than 4 μg / mL, more preferably no more than 3 μg / mL, even more preferably no more than 2 μg / mL, and still more preferably no more than 1 μg / mL.

[0083] In a particular embodiment, the solution may further include a radiation-resistant decomposition stabilizer that may be suitable as an eluent during solution preparation, preferably the stabilizer and / or eluent being an alcohol, preferably ethanol. Furthermore, according to a preferred embodiment, particularly for the automated synthesis of radioligands, such as those described in the examples below, the solution is obtained from the elution of radioligands isolated from their precursor compounds.

[0084] In a preferred embodiment, the injection solution therefore comprises: (1) a radioligand imaging agent as described above, such as a PSMA-binding compound of formula (I), (II) or (III), preferably a compound of formula (III), the concentration of which provides volumetric radioactivity between 250 MBq / mL and 450 MBq / mL at the calibration time, typically about 370 MBq / mL at the calibration time; (2) sodium chloride at a concentration of 8.0 mg / mL to 9.5 mg / mL, preferably 8.6 mg / mL to 8.9 mg / mL; (3) sodium dihydrogen phosphate at a concentration of 0.03 mg / mL to 0.3 mg / mL, preferably 0.1 mg / mL to 0.2 mg / mL; and (4) disodium hydrogen phosphate at a concentration of 0.2 mg / mL to 1.2 mg / mL, preferably 0.3 mg / mL to 1.1 mg / mL. (5) Ethanol, at a concentration of 5.0 mg / mL to 50 mg / mL, preferably 10.0 mg / mL to 39.5 mg / mL, and (6) optionally, a precursor compound (e.g., the CTT1298 precursor compound of formula IV), at a concentration not exceeding 5.0 μg / mL, preferably not exceeding 4.0 μg / mL, more preferably not exceeding 3.0 μg / mL, even more preferably not exceeding 2.0 μg / mL, and still more preferably not exceeding 1.0 μg / mL.

[0085] [Subjects with biochemical relapse]

[0086] The detection method and use of the radioligand imaging agent according to the present invention are intended for use in subjects with biochemical relapse, preferably for subjects with biochemical relapse of prostate cancer.

[0087] In a particular embodiment, the detection method and use of the radioligand imaging agent according to the present invention are intended for use in subjects with prostate cancer who have experienced biochemical recurrence after radical prostatectomy or radiotherapy.

[0088] The term “biochemical recurrence” as used herein refers to the general meaning provided by the American Urological Association (AUA) criteria. More specifically, Cookson et al. 2007 J Urol;177(2):540-5 provides a definition of biochemical recurrence following radical prostatectomy. In a particular embodiment, it involves a prostate cancer patient who has undergone radical prostatectomy and has a detectable PSA level or an elevated PSA level of ≥0.2 ng / mL measured 6–13 weeks post-procedure, and optionally a second confirmatory level strictly above 0.2 ng / mL measured at least two weeks after the first measurement. Roach et al. 2006 Int J Radiat Oncol Biol Phys;65(4):965-74 provides a definition of a patient who has experienced biochemical recurrence following radiotherapy. In a particular embodiment, it involves a subject who has undergone radical radiotherapy and has experienced a biochemical relapse as defined by the American Society for Radiation Oncology (ASTRO)-Phoenix guidelines (a PSA level above the nadir PSA of 2 ng / ml or higher, defined as the lowest PSA reached (nadir PSA + 2)).

[0089] [Methods for determining the presence and location of positive tumors in subjects with biochemical relapse]

[0090] One object of the present invention is to provide a method for determining the presence or location of a PSMA-positive tumor in a subject with biochemical recurrence, typically a subject with prostate cancer.

[0091] Generally speaking, the presence and location of PSMA-positive tumors are detected by analyzing the uptake of PSMA-binding compounds after injecting a radioactive tracer (such as a PSMA-binding compound) into a subject who has been diagnosed with biochemical recurrence.

[0092] Therefore, the present invention relates to a method for determining the presence and / or location of a PSMA-positive tumor in a subject, wherein the subject has been diagnosed with biochemical recurrence, and the method comprises: (1) administering to the subject an effective dose of a radioligand imaging agent as described above, preferably a PSMA-binding compound of formula (I), (II) or (III), most preferably a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof of formula (III), (2) imaging the subject by PET scan, such as PET / CT scan or PET / MRI scan, and (3) analyzing the images obtained from the PET scan to determine the presence and / or location of a PSMA-positive tumor in the subject.

[0093] Therefore, the present invention relates to a method for determining the presence and / or location of a PSMA-positive tumor in a prostate cancer subject, wherein the subject has been diagnosed with biochemical recurrence, typically following radical prostatectomy or radiotherapy, and the method comprises: (1) administering to the subject an effective dose of a radioligand imaging agent as described above, preferably a PSMA-binding compound of formula (I), (II) or (III), most preferably a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof of formula (III); (2) imaging the subject by PET scan, such as PET / CT scan or PET / MRI scan; and (3) analyzing the images obtained from the PET scan to determine the presence and / or location of a PSMA-positive tumor in the subject.

[0094] Generally, an effective dose is the amount of imaging agent sufficient to produce acceptable images using clinically usable equipment. The amount of imaging agent used in the method of the present invention and the duration of the imaging step will depend on factors including patient weight, the nature and severity of the condition to be detected, and the nature of the treatments the patient has already undergone. Ultimately, the physician can determine the amount of imaging agent to be administered to each individual patient and the duration of the imaging step.

[0095] In a particular embodiment, a subject diagnosed with biochemical relapse receives a single effective dose of 250 to 450 MBq, typically about 370 MBq, by intravenous injection of an injectable or infusion solution containing the aforementioned radioligand imaging agent. In a particular embodiment, the injection volume does not exceed 10 mL, for example, contained between 500 μL and 10 mL, preferably between 800 μL and 5 mL, for example between 800 μL and 2 mL, and preferably about 1 mL.

[0096] Next, images of the patient’s body are acquired by positron emission tomography-magnetic resonance imaging (PET / MRI) or positron emission tomography-computed tomography (PET / CT), and the methods of acquiring images by PET / MRI or PET / CT are well known.

[0097] Generally speaking, the first PET scan is performed within a window of 60 to 120 minutes after injection / infusion, for example, at 90 minutes. It is possible to perform a second PET scan within 180 minutes after the injection of the radioligand imaging agent.

[0098] Next, the presence of one or more PSMA-positive lesions is identified, and / or the location of one or more PSMA-positive lesions is determined, through visual assessment, quantitative assessment, or analysis of both images. Images can be generated using the spatial distribution differences of the imaging agent accumulated at a site upon contact with PSMA. Spatial distribution can be measured using any method, such as a PET device. The degree of imaging agent accumulation can be quantified using methods known for quantifying radioactive emission. A particularly useful imaging method is the simultaneous study using more than one imaging agent.

[0099] In a specific embodiment, the terms "PSMA-positive tumor" or "PSMA-positive lesion" refer to a lesion visually identified in the body of a subject, preferably a lesion identified in a subject with prostate cancer, to show pathological radioligand uptake on PET / CT or PET / MRI, as shown below:

[0100] Visually, PET-positive lymph nodes are considered to be larger than the blood pool (adjacent or mediastinum blood pool);

[0101] PET-positive bone lesions are considered to be larger than physiological bone marrow;

[0102] PET-positive prostate, prostatic bed and visceral lesions are considered to be greater than the physiological background activity of the involved organs or anatomical sites, as previously reported (Fendler WP, Calais J, Eiber M, et al (2019) JAMA Oncol; 5(6):856-63, Eiber M, Maurer T, Souvatzoglou M, et al (2015) J Nucl Med; 56(5):668-74, Ceci F, Uprimny C, Nilica B, et al (2015) Eur J Nucl Med Mol Imaging; 42:1284-94).

[0103] In some embodiments of the method, subjects with biochemical relapses do not have PSMA-positive lesions detected by existing imaging.

[0104] In some embodiments, these methods for detecting PSMA-positive tumors are expected to show higher sensitivity and / or specificity compared to [68Ga]-PSMA-11 compounds, particularly in subjects with biochemically recurrent prostate cancer.

[0105] 18F-labeled tracers have the following specific advantages: 18F has a longer half-life than 68Ga, which allows the tracer to be dispensed into the PET center without a cyclotron and is easy to handle in clinical routine. In addition, 18F has a higher positron branching decay rate (96.9%) compared to 68Ga (87.7%), and the shorter positron range of 18F indicates that 18F-labeled radiopharmaceuticals can achieve higher PET imaging resolution (Conti M, Eriksson L (2016) EJNMMI Physics; 3(1):1-17). Unlike most other PSMA reagents labeled with 68Ga or 18F that share a urea backbone (e.g., [68Ga]Ga-PSMA-11, [18F]PSMA1007, [18F]DCFPyL), [18F]CTT1057 is based on a phosphatamine architecture that binds irreversibly to PSMA with high nemeroxetine affinity. This will result in higher PET scan resolution and better precision and accuracy in detecting even very small tumor lesions.

[0106] In a particular embodiment, the method is particularly useful in the management of patients with relapsed conditions.

[0107] Therefore, the present invention relates to a method for monitoring the disease status of patients with biochemical relapse, comprising: (1) administering to the subject an effective dose of a radioligand imaging agent as described above, the radioligand imaging agent being, for example, a PSMA-binding compound of formula (I), (II) or (III) or any pharmaceutically acceptable salt thereof, and preferably a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof, preferably administered by intravenous injection of an injectable solution as described above; (2) imaging the subject by a first positron emission tomography (PET) scan, for example, within a time window of 60 to 120 minutes after injection, preferably about 90 minutes after injection, and optionally a second positron emission tomography scan within 180 minutes after injection; (3) analyzing the images obtained by the positron emission tomography scan; (4) determining the presence and / or location of a PSMA-positive tumor in the subject; (5) determining a treatment regimen based on the presence and / or location of a PSMA-positive tumor in the subject; and (6) optionally treating the subject with the treatment regimen.

[0108] Accurate identification of disease location and extent determines treatment decisions for patients, typically those with prostate cancer. Identifying distant metastases in the early stages of prostate cancer is crucial for planning prostate cancer management. Increasing evidence suggests that the primary landing site for prostate cancer is outside the template of extended pelvic lymph node dissection (ePLND). Primary lymph node landing sites outside of ePLND have been reported in 47.7% of men with suspected node-positive disease on 68Ga-PSMA PET / CT (Yaxley JW, Raveenthiran S, Nouhaud FX, et al (2019a) BJU Int; 124:401-7). This is very important because the morbidity of surgery is avoidable, thus shifting the focus from treatment-intentioned management to a multimodal approach after treatment of the primary prostate tumor (Yaxley JW, Dagher J, Delahunt B, et al (2018) World J Urol; 36:15-20, Yaxley JW, Raveenthiran S, Nouhaud FX, et al (2019b) J Urol; 201:815-20).

[0109] Therefore, the treatment regimen may subsequently change between different methods, such as surgery, radiation alone, radiation plus androgen deprivation therapy, androgen deprivation therapy alone, observation / monitoring or other methods.

[0110] The present invention also relates to a kit for monitoring the disease state of a subject as described above, the kit comprising at least an effective dose of a radioligand imaging agent as described above, such as a PSMA-binding compound of formula (I), (II) or (III), preferably a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof, or an injectable or infusion solution comprising the radioligand imaging agent as described above.

[0111] The present invention also relates to a kit used in the above-described method, the kit comprising, for example, an effective dose of about 370 MBq of a radioligand imaging agent or a precursor thereof used for synthesis, bound to a pharmaceutically acceptable carrier. The imaging agent, its precursor, and the carrier are provided in solution.

[0112] In some embodiments, the kit used in the method of the present invention contains a non-radiolabeled precursor, typically a compound of formula (IV), to bind on-site to a radiolabelable reagent, such as K[18F] or Na[18F].

[0113] 〔The following embodiments E1 to E30 are provided according to the present invention〕

[0114] E1: A radioligand imaging agent used in a diagnostic method for determining the presence and / or location of a PSMA-positive tumor in a subject, particularly when the subject is a subject with prostate cancer and the PSMA-positive tumor is prostate cancer, wherein the subject has been diagnosed with biochemical recurrence, and wherein the radioligand imaging agent is a PSMA-binding compound comprising a phosphatamine group and a [18F]-fluorine group.

[0115] E1b: According to the radioligand imaging agent used in Example E1, the diagnostic method includes: (1) administering an effective dose of the radioligand imaging agent to the subject, (2) imaging the subject by positron emission tomography, wherein the positron emission tomography is a PET / CT scan or a PET / MRI scan, (3) analyzing the images obtained from the positron emission tomography, and (4) determining the presence and / or location of a PSMA-positive tumor in the subject.

[0116] E2: The radioligand imaging agent used according to Example E1 or E1b, wherein the radioligand imaging agent is a PSMA-binding compound of formula (I) or any pharmaceutically acceptable salt thereof:

[0117] Chemical formula (I),

[0118] wherein, each R is independently a hydrogen atom or a protecting group (e.g., tert-butyl or benzyl).

[0119] R2 is either hydrogen or a C1-C6 alkyl group.

[0120] R3 is phenyl or pyridyl, each substituted with a [18F]-fluoro group, and may be selectively substituted with a second group selected from halogen, cyano, and nitro groups.

[0121] L1 is a linker, preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkyl groups and heteroalkyl groups comprising 1 to 35 carbon atoms and 1 to 15 heteroatoms, wherein the heteroalkyl group may be selectively substituted by one or more substituents selected from oxo and C1-C6 alkyl groups, and L1 is more preferably a linker selected from 1 to 6 amino acids.

[0122] E3: The radioligand imaging agent used according to Examples E1, E1b or E2, wherein the radioligand imaging agent is a PSMA-binding compound of formula (II) or any pharmaceutically acceptable salt thereof:

[0123] Chemical formula (II),

[0124] L is a linker containing a part of the chemical formula -NH-CH2CH2-(OCH2CH2-)yC(O)- or a group of the following chemical formulas.

[0125]

[0126] where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0127] m is 1, 2, 3 or 4;

[0128] n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 independently;

[0129] R1 is phenyl or pyridyl, each substituted with [18F]-fluoro, and may be substituted with a second group selected from halogen, cyano and nitro groups;

[0130] R2 is independently hydrogen or a C1-C6 alkyl group; and

[0131] R is each independently a hydrogen or a protecting group (e.g., tert-butyl or benzyl).

[0132] If L is a group of the following chemical formula

[0133]

[0134] The combination of m and n results in a linear linker length of 3 to 21 atoms.

[0135] E4: The radioligand imaging agent used according to any one of Examples E1 to E3, wherein the radioligand imaging agent is a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof:

[0136] Chemical formula (III).

[0137] E5: The radioligand imaging agent used according to any one of Examples E1 to E4, wherein the subject has been diagnosed with biochemical recurrence following radical prostatectomy or radiotherapy.

[0138] E6: The radioligand imaging agent used according to any one of Examples E1 to E5, wherein the radioligand imaging agent is formulated as an injection or infusion solution, the concentration of which provides volumetric radioactivity from 150 MBq / mL to 1000 MBq / mL, for example, 370 MBq / mL ± 10% at calibration time.

[0139] E7: The radioligand imaging agent used according to any one of Examples E1 to E6, wherein the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq, typically about 370 MBq.

[0140] E8: The radioligand imaging agent used according to Example E6 or E7, wherein the subject is first PET scan imaging between 60 and 120 minutes after injection or infusion, and optionally a second PET scan imaging within 180 minutes after injection or infusion.

[0141] E9: A solution for injection or infusion, comprising an aqueous solution of the radioligand imaging agent described in any one of Examples E1 to E5 and one or more pharmaceutically acceptable excipients, wherein the concentration of the radioligand imaging agent provides volumetric radioactivity from 150 MBq / mL to 1000 MBq / mL, for example about 370 MBq / mL.

[0142] E10: The solution of Example E9 further comprises a precursor compound of the following chemical formula (IV):

[0143] Chemical formula (IV),

[0144] The concentration is not more than 5.0 μg / mL, preferably not more than 4.0 μg / mL, more preferably not more than 3.0 μg / mL, even more preferably not more than 2.0 μg / mL, and even more preferably not more than 1.0 μg / mL.

[0145] E11: The solution of Example E9 or E10 further comprises a buffer and an isotropic agent, wherein the pH value of the buffer is between 5.0 and 8.0, preferably between 6.0 and 8.0, more preferably between 6.5 and 7.5, the buffer is preferably a phosphate buffer, and the isotropic agent is preferably sodium chloride.

[0146] E12: The solution of Example E11 further includes a stabilizer that resists radiation decomposition. The stabilizer is preferably suitable as an eluent in the solution manufacturing process. Preferably, the stabilizer and / or eluent is an alcohol, preferably ethanol.

[0147] E13: The solution following Example E12 comprises: (1) sodium chloride at a concentration of 8.0 mg / mL to 9.5 mg / mL, preferably 8.6 mg / mL to 8.9 mg / mL, (2) sodium dihydrogen phosphate at a concentration of 0.03 mg / mL to 0.3 mg / mL, preferably 0.1 mg / mL to 0.2 mg / mL, (3) disodium hydrogen phosphate at a concentration of 0.2 mg / mL to 1.2 mg / mL, preferably 0.3 mg / mL to 1.1 mg / mL, (4) ethanol at a concentration of 5.0 mg / mL to 50 mg / mL, preferably 10.0 mg / mL to 39.5 mg / mL, and (5) a precursor compound optionally included at a concentration of less than 5.0 μg / mL.

[0148] E14: A method for confirming the presence and / or location of a PSMA-positive tumor in a subject, preferably a subject with prostate cancer, wherein the subject has been diagnosed with biochemical recurrence, the method comprising: (1) administering to the subject an effective dose of a radioligand imaging agent as defined in any of Examples E1 to E7; (2) imaging the subject by means of a PET scan, wherein the PET scan is a PET / CT scan or a PET / MRI scan; and (3) analyzing the images obtained from the PET scan to determine the presence and / or location of a PSMA-positive tumor in the subject.

[0149] E15: Following the method of Example E14, the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq, typically about 370 MBq.

[0150] E16: Following the method of Example E14 or E15, the presence and / or location of PSMA-positive tumor lesions with a size of 5 mm to 10 mm are determined.

[0151] E17: The method of any of Examples E14 to E16, wherein the imaging in step (2) comprises a first PET scan of the subject between 60 and 120 minutes after injection / infusion, typically about 90 minutes after injection / infusion, and optionally a second PET scan within 180 minutes after injection / infusion.

[0152] E18: The method of any of Examples E14 to E17, wherein the radioligand imaging agent is formulated as an injection or infusion solution as defined in any of Examples E9 to E13.

[0153] E19: A method for monitoring the disease status of a subject with biochemical relapse, comprising: (1) administering to the subject an effective dose of a radioligand imaging agent as described above, the radioligand imaging agent being, for example, a PSMA-binding compound of formula (I), (II) or (III) or any pharmaceutically acceptable salt thereof, preferably a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof, preferably administered by intravenous injection of an injectable solution as described above; (2) imaging the subject by a first PET scan, for example, within a time window of 60 to 120 minutes after injection, preferably about 90 minutes after injection, and optionally a second PET scan within 180 minutes after injection; (3) analyzing the images obtained from the PET scan; (4) determining the presence and / or location of a PSMA-positive tumor in the subject; (5) determining a treatment regimen based on the presence and / or location of a PSMA-positive tumor in the subject; and (6) optionally treating the subject with the treatment regimen.

[0154] E20: The method of Example E19, wherein the subject has prostate cancer.

[0155] E21: Following the method of Example E20, wherein the subject has been diagnosed with biochemical recurrence following radical prostatectomy or radiotherapy.

[0156] E22: A process for manufacturing a radioligand imaging agent used in a diagnostic method comprising the steps defined in any of Examples E14 to E18, wherein the radioligand imaging agent is defined in any of Examples E1 to E9.

[0157] E23: A solution for injection or infusion, which is an aqueous solution containing a radioligand imaging agent and one or more pharmaceutically acceptable excipients, wherein the radioligand imaging agent is a PSMA-binding compound containing a phosphatamine group and a [18F]-fluorine group, and the concentration of which provides volumetric radioactivity from 150 MBq / mL to 1000 MBq / mL, for example about 370 MBq / mL.

[0158] E24: A solution following Example E23, wherein the radioligand imaging agent is a PSMA-binding compound of formula (I) or any pharmaceutically acceptable salt thereof:

[0159] Chemical formula (I);

[0160] wherein, each R is independently a hydrogen or a protecting group (e.g., tert-butyl or benzyl),

[0161] R2 is independently hydrogen or C1-C6 alkyl.

[0162] R3 is phenyl or pyridyl, each substituted with a [18F]-fluorine group, and may be selectively substituted with a second group selected from halogen, cyano, and nitro groups.

[0163] L1 is a linker, preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkyl groups and heteroalkyl groups comprising 1 to 35 carbon atoms and 1 to 15 heteroatoms, wherein the heteroalkyl group may be selectively substituted by one or more substituents selected from oxo and C1-C6 alkyl groups, and L1 is more preferably a linker selected from 1 to 6 amino acids.

[0164] E25: A solution following Example E23 or E24, wherein the radioligand imaging agent is a PSMA-binding compound of formula (II) or any pharmaceutically acceptable salt thereof:

[0165] Chemical formula (II),

[0166] L is a linker containing a portion of the chemical formula -NH-CH2CH2-(OCH2CH2-)yC(O)- or a group of the following chemical formulas.

[0167]

[0168] where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0169] m is 1, 2, 3 or 4;

[0170] n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 independently;

[0171] R1 is phenyl or pyridyl, each substituted with [18F]-fluoro, and may be substituted with a second group selected from halogen, cyano and nitro groups;

[0172] R2 is independently hydrogen or a C1-C6 alkyl group; and

[0173] R is each independently a hydrogen or a protecting group (e.g., tert-butyl or benzyl).

[0174] If L is a group of the following chemical formula

[0175]

[0176] The combination of m and n results in a linear linker length of 3 to 21 atoms.

[0177] E26: A solution of any one of Examples E23 to E25, wherein the radioligand imaging agent is a PSMA-binding compound of formula (III) or any pharmaceutically acceptable salt thereof:

[0178] Chemical formula (III),

[0179] E27: A solution of any one of Examples E23 to E26, further comprising a precursor compound of the following chemical formula (IV):

[0180] Chemical formula (IV),

[0181] The concentration is not more than 5.0 μg / mL, preferably not more than 4.0 μg / mL, more preferably not more than 3.0 μg / mL, even more preferably not more than 2.0 μg / mL, and even more preferably not more than 1.0 μg / mL.

[0182] E28: A solution of any one of Examples E23 to E27, further comprising a buffer and an isotonic agent, wherein the pH of the buffer is between 5.0 and 8.0, preferably between 6.0 and 8.0, more preferably between 6.5 and 7.5, the buffer is preferably a phosphate buffer, and the isotonic agent is preferably sodium chloride.

[0183] E29: The solution of any of Examples E23 to E28 further includes a stabilizer that resists radiodegradation. The stabilizer is preferably suitable as an eluent in the solution manufacturing process. Preferably, the stabilizer and / or eluent is an alcohol, preferably ethanol.

[0184] E30: The solution of Example E29 comprises: (1) sodium chloride at a concentration of 8.0 mg / mL to 9.5 mg / mL, preferably 8.6 mg / mL to 8.9 mg / mL, (2) sodium dihydrogen phosphate at a concentration of 0.03 mg / mL to 0.3 mg / mL, preferably 0.1 mg / mL to 0.2 mg / mL, (3) disodium hydrogen phosphate at a concentration of 0.2 mg / mL to 1.2 mg / mL, preferably 0.3 mg / mL to 1.1 mg / mL, (4) ethanol at a concentration of 5.0 mg / mL to 50 mg / mL, preferably 10.0 mg / mL to 39.5 mg / mL, and (5) a precursor compound at a concentration of less than 5.0 μg / mL.

[0185] 〔Example〕

[0186] Example 1: Preparation of a solution containing a radioactive ligand imaging agent

[0187] The drug product is a diluted solution of concentrated mother solution of [18F]CTT1057 (radioactive drug substance, 15 ± 1 mL, with approximately 1685-6667 MBq / mL at Tm) in 0.9% sodium chloride to adjust the volumetric activity of the final solution to 370 MBq / mL ± 10% (Tc). The volume of physiological saline added was calculated based on the activity of [18F]CTT1057 obtained at the end of synthesis (Tm), with decay correction performed at calibration (Tc). Tm is the time for measuring activity in the mother solution. Tm is a few minutes after EOS (End of synthesis).

[0188] The final volume of the drug product ranges from 15 mL to 59 mL, and the quantitative composition of the final product of [18F]CTT1057 varies accordingly.

[0189] The qualitative and quantitative composition of the drug product in nominal volumes of 15 mL and 59 mL is described in Table 1.

[0190] Table 1: Qualitative and quantitative composition of 1 mL of drug product Element effect Quantity per batch (V T = 15 mL**) Quantity per batch (V T = 59 mL**) [ 18 F]CTT1057 Active substances 370 MBq (at Tc) 370 MBq (at Tc) CTT1298 Remaining chemical precursors ≤ 5.0 · 10 -3 mg* ≤ 5.0 · 10 -3 mg* Sodium chloride isotropic agents 8.55 mg 8.89 mg Sodium dihydrogen phosphate buffer 0.24 mg 0.06 mg Sodium hydrogen phosphate buffer 1.07 mg 0.27 mg ethanol Eluents, stabilizers 39.45 mg 10.03 mg Water for Injection (WFI) solvent qs 1 mL qs 1 mL Remark: Tc ≡ Calibration Time V T ≡ Total Volume *Considering a maximum injection dose of 10 mL **This amount includes the water for injection present in the 25 mL vials (0.20 ± 0.02 mL) and the 15 mL initial packaging vials (0.10 ± 0.01 mL), which is introduced in a negligible amount during sterilization.

[0191] The synthesis of the pharmaceutical substance ([18F]CTT1057) and its formulation into a pharmaceutical product (370 mbq / mL [18F]CTT1057 solution for injection) is part of an automated continuous process as described below.

[0192] (Synthesis of drug substances)

[0193] [18F]CTT1057 active material (mother solution) was obtained through a two-stage synthetic route.

[0194] In the first stage (step 1), the [18F]SFB cofactor is prepared in a one-pot, three-step procedure, starting with the radioactive fluorination of the FB initial material, followed by the saponification of ethyl ester and coupling with TSTU.

[0195]

[0196] In the second stage (step 2), the labeling of precursor CTT1298 with isolated [18f]SFB under alkaline and mild conditions leads to the formation of [18F]CTT1057.

[0197]

[0198] A two-step purification process drives the separation of byproducts and residual reagents and ultimately yields a formulated [18F]CTT1057 with a radiochemical purity ≥95%.

[0199] The entire synthesis and purification process is carried out automatically in the synthesizer described below.

[0200] (Manufacturing process of mother solution containing pharmaceutical substances)

[0201] Producing radioactive nucleus precursors ([18F] fluoride) from [18O]H2O

[0202] Radioactive nuclei were obtained by bombarding [18O]water with a purity ≥97% with a strong particle beam that accelerates protons, in the form of [18F] fluoride ions. This nuclear reaction was produced in a cyclotron target.

[0203] (Transfer of radioactivity and 18F recovery in cleanrooms)

[0204] After the bombardment, radioactive [18O] water containing [18F] fluoride was automatically transferred to a dedicated synthesis module.

[0205] (Produced from [18F] fluoride using [18F] CTT1057)

[0206] The production of [18F]CTT1057 from [18F] fluoride occurs in a lead-shielded isolator in two steps as described below.

[0207] (Manufacturing of [18F]SFB auxiliary group)

[0208] [18F]SFB cofactor was prepared in a one-pot, three-step process, including radiofluorination of FB initial material to generate Et-4-[18F]FB, followed by saponification of ethyl ester to obtain [18F]FBA, and coupling of [18F]FBA with TSTU (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate) to obtain [18F]SFB.

[0209] [18F]SFB (N-succinimino-4-[18F]fluorobenzoic acid) was then purified using a hydrophilic-lipophilic balance (HLB) purification cartridge. The [18F]SFB remained in the cartridge while the unreacted [18F]fluoride was removed to the waste.

[0210] Finally, pure [18F]SFB was eluted from HLB into a second reactor containing the precursor CTT1298 in solution using acetonitrile.

[0211] ([18F]CTT1057 drug substance manufacturing)

[0212] [18F]CTT1057 is obtained by the reaction between the [18F]SFB cofactor and the precursor CTT1298. This reaction includes:

[0213] (Coupling with CTT1298)

[0214] [18F]SFB was eluted from HLB into a second reactor containing CTT1298 solution, and the reaction was carried out in the second reactor at 40°C for 12 minutes.

[0215] (CTT1057 purified)

[0216] The crude product was diluted in water, and a two-step purification process drove the separation of byproducts and residual reagents. The diluted crude product was passed toward waste through a quaternary methylammonium (QMA) cartridge. [18F]CTT1057 was retained in the QMA along with other unwanted substances. The QMA was washed toward waste with 0.09% sodium chloride / 20% ethanol solution, and [18F]CTT1057 was eluted with 20 mM phosphate buffer at pH 2.0 and recaptured onto the HLB in a time-controlled step to minimize the decomposition of [18F]CTT1057 in acidic media.

[0217] (Prepared with CTT1057)

[0218] The final pure [18F]CTT1057 was eluted, neutralized and prepared from HLB in a single step via 5% ethanol in phosphate buffer at pH 7.4.

[0219] (Development of manufacturing processes)

[0220] The drug substance [18F]CTT1057 was developed in a one-step reaction between the prosthetic group [18F]SFB and the chemical precursor CTT1298. To ensure efficient reaction conversion, non-radioactive [18F]SFB and CTT1298 were used and several coupling reaction conditions were tested: different buffer media with pH values ​​ranging from 7 to 11, temperatures ranging from 25°C to 60°C, and durations ranging from 5 to 10 minutes.

[0221] The final adjustment of the reaction time was optimized using the [18F]CTT1057 product to achieve true concentration conditions and take into account the reaction time and decay equilibrium.

[0222] [18F]CTT1057 The final purification step in the solid phase extraction (SPE) cartridge is key to providing the product with sufficient purity. The crude product from the reaction in the alkaline matrix is ​​diluted and first purified using a QMA (quaternary methylammonium) cartridge that allows for the removal of most radiochemical impurities.

[0223] However, the [18F]CTT1057 purified by elution with physiological experimental water confirmed the presence of the chemical precursor CTT1298 in large quantities.

[0224] Isolation of CTT1298 from [18F]CTT1057 is challenging due to the similarity between the two molecules. The final strategy focused on the small difference in polarity caused by the aromatic ring of [18F]CTT1057, which allowed for selective retention of the final product using an HLB box. The final elution and formulation of the [18F]CTT1057 drug substance was optimized into a single step using phosphate buffer containing 5% ethanol.

[0225] (Preparation of solution for injection)

[0226] The drug product is a diluted solution of the concentrated mother solution of [18F]CTT1057 (radioactive drug substance, 15 ± 1 mL) in 0.9% sodium chloride to adjust the volumetric activity of the final solution to 370 MBq / mL ± 10% (Tc). The volume of physiological saline added was calculated based on the activity of [18F]CTT1057 obtained at the end of synthesis (Tm), with decay correction performed during calibration (Tc). The final volume of the drug product ranges from 15 mL to 59 mL, and the quantitative composition of the final [18F]CTT1057 product varies accordingly.

[0227] The qualitative and quantitative composition of the drug product in nominal volumes of 15 mL and 59 mL is described in Table 2.

[0228] Table 2: Qualitative and quantitative composition of 1 mL drug product Element effect Quantity per batch (V T = 15 mL**) Quantity per batch (V T = 59 mL**) [ 18 F]CTT1057 Active substances 370 MBq (at Tc) 370 MBq (at Tc) CTT1298 Chemical precursors ≤ 5.0 · 10 -3 mg* ≤ 5.0 · 10 -3 mg* Sodium chloride isotropic agents 8.55 mg 8.89 mg Sodium dihydrogen phosphate buffer 0.24 mg 0.06 mg Sodium hydrogen phosphate buffer 1.07 mg 0.27 mg ethanol Eluents, anti-radiation decomposition stabilizers 39.45 mg 10.03 mg Water for Injection (WFI) solvent qs 1 mL qs 1 mL Remark: Tc ≡ Calibration Time V T ≡ Total Volume *Considering a maximum injection dose of 10 mL **This amount includes the water for injection present in the 25 mL vials (0.20 ± 0.02 mL) and the 15 mL initial packaging vials (0.10 ± 0.01 mL), which is introduced in a negligible amount during sterilization.

[0229] The synthesis of the pharmaceutical substance ([18F]CTT1057) and its formulation into a pharmaceutical product (370 mbq / mL [18F]CTT1057 solution for injection) is part of an automated continuous process comprising the following steps:

[0230] (Receiver in the distribution cavity)

[0231] The final prepared [18F]CTT1057 bulk concentrated mother solution was transferred from the synthesis chamber to the distribution chamber.

[0232] (Measurement of radioactivity and weight of the mother solution)

[0233] Weigh the 25mL vials. The net weight of the bulk concentrated mother solution of [18F]CTT1057 is defined as the weight difference between the vial containing the product and the empty vial. The activity contained in the vial is measured using a dosing calibrator.

[0234] (Transfer of [18F]CTT1057 solution)

[0235] [18F]CTT1057 Bulk concentrated mother solution was transferred from 25mL vials to sterilized empty mother bottles.

[0236] (Dilution)

[0237] A mother bottle containing [18F]CTT1057 bulk concentrated mother solution was placed on a balance. A specified amount of 0.9% sodium chloride was automatically transferred to the mother bottle until the added sodium chloride reached the appropriate level. The concentration of the [18F]CTT1057 diluted mother solution at calibration time Tc (Tc=T0+4h) was 370 MBq / ml ± 10%.

[0238] (Homogenization (mixing) of the final [18F]CTT1057 solution)

[0239] The final [18F]CTT1057 diluted mother solution was mixed.

[0240] (Finally filtered and dispensed into 15mL vials)

[0241] Dispense the [18F]CTT1057 diluted mother solution using a semi-automatic dispensing system.

[0242] The final [18F]CTT1057 diluted mother solution in the vial is pumped through a sterile tube to a filter (for final filtration) and a sterile needle fixed to the dispensing automate.

[0243] Example 2: Clinical Research

[0244] (Protocol Summary) Full name Assessing elevated PSA levels (biochemical recurrence) in prostate cancer subjects [ 18 Phase III study of the diagnostic efficacy of CTT1057 PET imaging. Abbreviation Biochemical relapse 18 F] Study on the diagnostic efficacy of CTT1057 Test type Radioactive medicines Purpose and Reason [ 18 F]CTT1057 is a promising new prostate-specific membrane antigen (PSMA) target. 18 F-labeled positron emission tomography (PET) imaging agent. Unlike other PSMA reagents that share a urea backbone, [ 18 F]CTT1057 is based on a phosphatamine architecture that can irreversibly bind to PSMA with high nemerore affinity, which explains the high and durable tumor uptake. When using... 18 When using F-labeled PET reagents, the high resolution of CT images helps identify smaller lesions, and therefore also helps in identifying lesions in the early stages of disease. 18 The first phase of the F]CTT1057 study demonstrated an acceptable safety profile with no radioactive tracer-related adverse reactions, and [F]CTT1057 has been provided with [F]CTT1057. 18 F]CTT1057 PET provides preliminary evidence of the diagnostic efficacy of using pathology as the true standard (SoT) for detecting and locating PSMA-positive tumors. Current research aims to evaluate [using composite real-world criteria]. 18F]CTT1057 is used as a PET imaging agent to detect and locate PSMA positivity in patients diagnosed with biochemical recurrent prostate cancer. Main objectives The main evaluation objective of this study is: #Evaluate[ 18 F] CTT1057 Local Hierarchical Correct Localization Rate (CLR) #Evaluate[ 18 F]CTT1057 patient-level positive predictive value (with anatomical localization) The main clinical concern is: positive [ 18 What is the probability of tumor recurrence in a prostate cancer patient with biochemical recurrence (PSMA expression) detected and located by CTT1057 PET / CT scan? Secondary objectives #Evaluate[ 18 F] CTT1057 Patient Tier Sensitivity #Evaluate[ 18 F]Patient hierarchical specificity of CTT1057 #Evaluate[ 18 F]CTT1057 Patient-Level Negative Predictive Value #Evaluate[ 18 F] Patient triage accuracy of CTT1057 #Evaluate[ 18 F]CTT1057 Local Hierarchical Sensitivity #Evaluate[ 18 Local hierarchical specificity of F]CTT1057 #Evaluate[ 18 Local hierarchical negative predictive value of F]CTT1057 #Evaluate[ 18 F]CTT1057 Local Hierarchical Accuracy #Assess the correct detection rate (CDR) #Assess the detection rate #Assess the positive predictive value of patient stratification regarding PSA levels #Characteristics[ 18 Safety and tolerability of F]CTT1057 #[ 18 F]CTT1057 scans for inter-reader variability. #[ 18 F]CTT1057 scans for intra-reader variability. #Used for detecting lesions at the patient level [ 18 F]CTT1057 and [ 68 Concordance rate between Ga]Ga-PSMA-11 #Assess changes in patient management plans attributed to PET / CT scans All of the above primary and secondary objectives were independently assessed in patient subgroups following prostatectomy and radical radiotherapy for prostatectomy. Research Design This is a prospective, open-label, multicenter, single-arm phase III study, using the Composite Truth Test (CTS) as a reference for evaluation. 18 F]CTT1057 as a PET imaging agent to detect and locate PSMA-positive tumors in patients with biochemically recurrent prostate cancer after radical prostatectomy. The CTS used as a reference will be hierarchical in nature, with a three-tiered Real Standards (SoT) procedure, which will be applied as follows: CTS Level 1: Histopathology if available (from […]) 18 F] Prospective biopsy or rescue surgery performed within 8 weeks after a CTT1057 PET / CT scan; or histopathology is unavailable, indeterminate, or negative. CTS Level 2: Imaging diagnostic procedures performed on each patient according to the Standard of Care (SoC) for each clinical indication must include at least a high-resolution CT scan with contrast and [ 18 F] CTT1057 PET / CT scan performed 8 weeks (before or after) 68 Ga]Ga-PSMA-11PET / CT. If a specific lesion needs to be diagnosed clinically; or if neither of the above is feasible or deemed inappropriate, three months of follow-up imaging (from baseline) will also be used as part of the second stage of CTS. CTS Level 3: A 50% or greater decrease in PSA following radiation therapy in accordance with the guidelines of Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (provided that no concurrent androgen deprivation therapy (ADT) was given). All participants will undergo two PET / CT scans: one using experimental reagents. 18 F]CTT1057 and another time used [ 68Ga-PSMA-11 (as a secondary efficacy endpoint, serving as a component of CTS Level 2 and used to assess concordance between two PET / CT scans for lesion detection at the patient level. The interval between the two PET imaging procedures is at least 14 days, and the PET / CT scan sequence for each participant will be randomly assigned in a 1:1 ratio.) Study population Male participants aged ≥18 years who had biopsy-confirmed prostate cancer and elevated PSA levels following definitive prostatectomy or radiation therapy (external beam or brachytherapy) and were diagnosed with biochemically recurrent prostate cancer (PCa). Approximately 190 participants will be enrolled to ensure that at least 152 participants complete the [18F]CTT1057 PET / CT scan procedure (i.e., administration of the trial imaging agent and successful completion of the PET / CT scan, which is necessary for calculating co-primary endpoints). Subject inclusion criteria #A signed informed consent form must be obtained before participating in the research. #Prostate cancer confirmed by biopsy Biochemical recurrence is defined by the American Urological Association’s guidelines for patients undergoing radical prostatectomy (a detectable or elevated PSA level measured 6 to 13 weeks post-surgery, ≥0.2 ng / mL, with a second determination of PSA level >0.2 ng / mL at least 2 weeks later) and by the American Society for Radiation Oncology’s guidelines for patients undergoing therapeutically intended radiation therapy (a PSA ≥2 ng / mL above the nadir PSA). #Eastern Cooperative Oncology Group (ECOG) performance status 0-2 #Participants must be adults aged 18 and above Exclusion criteria for subjects #Imaging examinations requiring the required trial and care standards cannot be completed for any reason (severe claustrophobia, inability to remain still throughout the imaging period, etc.). # Any additional medical conditions, serious interictal illnesses, concurrent cancer, or other extenuating circumstances that, in the opinion of the clinical trial administrator, would pose a significant risk or impairment to safety for study participation, including but not limited to current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, need for indwelling / condom catheters, New York Heart Association Class III or IV congestive heart failure, congenital long QT syndrome, uncontrolled infection, infectious hepatitis B or hepatitis C, and 2019 novel coronavirus (COVID-19). #Having undergone a major surgery within 12 weeks prior to screening (excluding any surgery related to prostate cancer). #Known pair [ 18 F]CTT1057、[ 68 Ga]Ga-PSMA-11 or CT imaging may cause allergies, hypersensitivity reactions, or intolerance. #Previous or current use of PSMA-targeted therapy #Previously or currently treated with luteinizing hormone-releasing hormone (LHRH) analogs #Any ADT (first-generation or second-generation) within 9 months prior to screening #Any 5α-reductase inhibitors in the 30 days prior to screening #Use of other experimental drugs 30 days prior to screening #Castration resistant patients #Patients with small or more than 50% neuroendocrine prostate cancer in biopsy tissue Research on treatment The term "investigative treatment" indicates the use of at least one of two PET imaging agents: 18 F]CTT1057 and [ 68 Ga]Ga-PSMA-11 is independent of whether a PET / CT scan is obtained. Treatment of concern In this study, the experimental imaging agent of interest is [ 18 F]CTT1057 was administered as a single intravenous injection of approximately 370 MBq followed by a PET / CT scan. efficacy assessment Hierarchical CTS has three levels #Level 1: Histopathological assessment #Level 2: Imaging Diagnostic Assessment: At least one high-resolution CT scan and one [ 68 Ga]Ga-PSMA-11 PET / CT, with additional SoC imaging if other clinical indications arise. Imaging data will be centrally read. #Level 3: PSA Assessment [ 18 F]CTT1057 PET / CT assessment, centralized reading Key security assessment #Adverse Events (AEs) # Serious Adverse Events (SAEs) #Vital signs, physical examination #Electrocardiogram (ECGs) #Laboratory parameters, including hematology and clinical chemistry # and with medicine and / or treatment Other assessments Patient management questionnaire for assessing secondary efficacy endpoints attributable to changes in patient management plans due to PET / CT scans. Data Analysis To study and plan the following data analysis: The primary endpoints of the study were local hierarchical CLR and patient hierarchical positive predictive value (PPV). #Local level CLR is defined as the proportion of regions containing at least one true positive (TP) lesion (precise local correspondence between PET imaging and reference standard) among all regions containing at least one PET positive result, regardless of whether there are any coexisting false positive (FP) results in the same region. The local hierarchical CLR and its 95% confidence interval (CI) will be calculated using a logistic random-effects model that considers the correlation between regions within a patient. The lower limit of the 95% CI for the CLR needs to be greater than 0.5 to meet the primary assessment endpoint. # Patient-level PPV is defined as the proportion of all patients with positive PET / CT scans who have at least one TP lesion (precise local correspondence between PET imaging and a reference standard), regardless of any coexisting FP results. Patient-level PPV and its 95% CI will be calculated based on a binomial distribution. The lower limit of the 95% CI for patient-level PPV must be greater than 0.2 to meet the secondary assessment endpoint. The main evaluation metrics will be analyzed based on the efficacy analysis set (EFF). If pathology (CTS Level 1) is unavailable, indeterminate, or negative, centralized imaging assessment (CTS Level 2) will be used as the reference standard. Includes patient-level sensitivity, patient-level specificity, patient-level negative predictive value, patient-level accuracy, patient-level correct detection rate, patient-level detection rate, [ 18 F]CTT1057 scan inter-reader consistency, [ 18 F]CTT1057 scan intra-reader consistency, changes in patient management plans, local level sensitivity, local level specificity, local level negative predictive value, local level accuracy, [ 18 F]CTT1057 and [ 68 Other minor indicators of concordance between Ga]Ga-PSMA-11 will be analyzed. Detailed statistical methods used for these analyses will be provided in the Statistical Analysis Plan (SAP).

[0245] (Research Design)

[0246] This is a prospective, open-label, multicenter, single-arm phase III study that uses composite true criteria as a reference to evaluate the diagnostic efficacy of [18F]CTT1057 as a PET imaging agent for detecting and locating PSMA-positive tumors in patients with biochemical recurrent prostate cancer after radical prostatectomy.

[0247] Approximately 190 participants will be registered to ensure that at least 152 participants complete the [18F]CTT1057 PET / CT scan imaging, and the images will be read by 3 independent nuclear medicine physicians at a central commissioned research organization (CRO). The physicians will remain blinded to any other patient data.

[0248] The CTS used as a reference will be hierarchical in nature, with a three-level SoT procedure, which will be applied as follows:

[0249] Level 1)

[0250] Histopathology if available (prospective biopsy or rescue surgery performed within 8 weeks of [18F]CTT1057 PET / CT scan); or histopathology if unavailable, indeterminate, or negative.

[0251] Level 2)

[0252] The imaging diagnostic procedure performed on each patient according to the SoC of each clinical indication must include at least a high-resolution CT scan with contrast and a [68Ga]Ga-PSMA-11 PET / CT scan performed 8 weeks (before or after) of a [18F]CTT1057 PET / CT scan. If a specific lesion needs to be diagnosed clinically; or if neither of the above is feasible or deemed inappropriate, three months of follow-up imaging (from baseline) will also be used as part of the second level of CTS.

[0253] Level 3)

[0254] Radiation therapy (provided that no concurrent androgen deprivation therapy (ADT) was given) in each PCWG3 guideline (Scher et al 2016 Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol; 34(12):1402-18) resulted in a 50% or greater decrease in PSA.

[0255] Where histopathology is available, the assessment will be performed by the current pathologist according to the SoC, and results must be available within 2 weeks post-surgery. The pathologist will remain blinded for any PSMA-PET data (i.e., PET / CT scans). In this case, only the pathology will be used as the SoT, and therefore the imaging procedure will not be used for the calculation of the primary assessment measure.

[0256] In cases where histopathology is unavailable, the centralized readings of imaging diagnostic procedures performed on each patient for CTS Level 2 will be used as the true standard for calculating the primary assessment indicators.

[0257] In order to assess the concordance rate between [18F]CTT1057 and [68Ga]Ga-PSMA-11 in patients at different lesion levels, as well as the evaluation of secondary efficacy endpoints, all patients will undergo [68Ga]Ga-PSMA-11 PET / CT as part of the study.

[0258] In addition to central review, local review of SoC images (including [68Ga]Ga-PSMA-11) will be performed for the attending physician / clinical trial investigator’s patient management decision-making and overall assessment.

[0259] The questionnaire for planned patient management will be completed by the attending physician / clinical trial investigator first (Questionnaire 1) and then within 14 days of receiving the results of the [18F]CTT1057 PET / CT scan (Questionnaire 2). Local interpretation of the [18F]CTT1057 PET / CT images will also be performed by a local nuclear medicine physician or a radiologist with expertise in interpreting oncology PET / CT scans, and the results will be provided to the attending physician / clinical trial investigator to complete Questionnaire 2. The questionnaire will provide options for recording possible management plans, such as a) surgery, b) radiotherapy alone, c) radiotherapy plus ADT, d) ADT alone, e) observation / monitoring, f) other (free choice). Because this is an experimental diagnostic imaging product, any changes to the patient management plan between Questionnaire 1 and Questionnaire 2 should not be based solely on the [18F]CTT1057 PET / CT scan results.

[0260] (Screening Period)

[0261] Written informed consent (ICF) must be obtained before any screening procedure. Participants need to register with Interactive Response Technology (IRT) for screening. All procedures described in the assessment checklist must be performed, prioritizing laboratory and imaging assessments to allow time to obtain results at least 14 days before the planned first PET imaging day (Day 1). Eligibility must then be confirmed no later than Day 14. The screening period must last at least 28 days.

[0262] Once eligibility is confirmed, participants will be randomly assigned to one of the following two PET / CT scan sequences at a 1:1 ratio during the IRT:

[0263] Sequence 1: Day 1 [18F]CTT1057 (the clinically relevant imaging agent), followed by at least 14 days of [68Ga]Ga-PSMA-11 (as part of the CTS if necessary, and for secondary efficacy endpoints).

[0264] Sequence 2: Day 1 [68Ga]Ga-PSMA-11 (as part of CTS if necessary and for secondary efficacy endpoints), followed by at least 14 days of [18F]CTT1057 (the clinically relevant imaging agent).

[0265] (PET Imaging Day)

[0266] Two PET imaging procedures should be performed at least 14 days apart. The date of the first injection of PET imaging agent will be considered the first day of the study.

[0267] (Research Design)

[0268] A centralized reading of [18F]CTT1057 PET / CT scans will be conducted by three independent nuclear medicine physicians or radiologists with experience reading PET scans. Patient data, including patient clinical condition, histopathology / biopsy results, and existing imaging and PSA levels, will be blinded. Each reader will score the patient and region on a binary scale (0 = negative; 1 = positive). The results of the three PET readers will be individually compared to the SoT to produce performance for each reader. A PET reader will be considered successful if he / she meets predefined thresholds in both primary assessment measures, and at least two of the three readers must be successful for the overall study positivity rate.

[0269] The criteria for PET-positive lesions are as follows: A patient will be considered positive if at least one lesion in any region (i.e., the prostate bed, pelvic lymph nodes (PLN), bone, and other distal sites (extrapelvic lymph nodes and viscera)) is visually positive. If at least one lesion in a region is visually positive, that region will be considered positive. Visually PET-positive lymph nodes will be considered larger than the blood pool (adjacent or mediastinal blood pool). PET-positive bone lesions will be considered larger than physiological bone marrow.

[0270] PET-positive prostate, prostatic bed and visceral lesions will be considered to be greater than the physiological background activity of the involved organs or anatomical sites, as previously reported (Eiber et al 2015 Evaluation of Hybrid ⁶⁸Ga-PSMA Ligand PET / CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med; 56(5):668-74, Ceci et al 2015 (68)Ga-PSMA PET / CT for restaging recurrent prostate cancer: which factors are associated with PET / CT detection rate? Eur J Nucl Med Mol Imaging; 42:1284-94, Fendler et al 2019 Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol; 5(6):856-63).

[0271] The consistency of interpretation of PET scans among different readers is an important issue in medical imaging because it affects the portability of results between institutions and may impact patient care. In the qualitative assessment of PET / CT images, inter-reader and intra-reader variability will be assessed as secondary efficacy indicators to ensure consistency of interpretation, thereby ensuring reliable diagnosis, which plays a crucial role in patient management.

[0272] All patients will undergo two PET / CT scans: one [18F]CTT1057 PET / CT scan (experimental imaging agent) and one [68Ga]Ga-PSMA-11 PET / CT scan (as part of CTS Level 2 if needed, and as a secondary efficacy endpoint for assessing concordance between [18F]CTT1057 and [68Ga]Ga-PSMA-11 for detecting lesions at the patient level). The two scans for each participant will be performed at least 2 weeks apart to ensure clean safety assessment of the radiopharmaceuticals used in each PET imaging. Furthermore, to balance out any potential changes in lesions between the two PET / CT scans, the order of PET / CT scans for each patient will be randomized 1:1 upon enrollment in the trial.

[0273] (Rationality of dosage / regimen and treatment duration)

[0274] For PET diagnostic radiopharmaceuticals, only a single administration is required, usually by intravenous injection. The experimental PET radiopharmaceutical [18F]CTT1057 will be administered accordingly, with a single intravenous (iv) dose of approximately 370 MBq (266~407 MBq). This dose was demonstrated to be safe and well-tolerated in the Phase I study (Behr et al 2019 Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6), and met the standards of the European Association for Nuclear Medicine (EANM) and SNM nuclear medicine standard operating procedures (Delbeke D, Coleman RE, Guiberteau MJ, et al (2006) Procedure guideline for tumor imaging with 18F-FDG PET / CT 1.0. J Nucl Med; 47(5):885-95, Boellaard R, Delgado-Bolton R, Oyen WJG, et al (2015) FDG PET / CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging; The recommended dose of the commercial product [18F]FDG (42:328-54) was determined. Human dosimetry was investigated in the first phase study.The effective dose was estimated to be 0.023 ± 0.007 mSv / MBq, which is consistent with the effective dose of commercially available products [18F] FDG (0.019 mSv / MBq) according to EANM guidelines (Boellaard R, Delgado-Bolton R, Oyen WJG, et al (2015) FDG PET / CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging; 42:328-54) and other published effective doses (0.020-0.025 mSv / MBq) (Kaushik A, Jaimini A, Tripathi M, et al (2015) Estimation of radiation dose to patients from (18) FDG whole body PET / CT investigations using dynamic PET scan protocol. Indian J Med Res; 142:721-31), and also consistent with the effective doses of other PSMA PET reagents (Behr SC, Aggarwal). R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6). The estimated radiation dose from an intravenous injection of 370 MBq of [18F]CTT1057 was 8.51 mSV.Furthermore, this dose allows for optimized image quality, which was evaluated by two experienced nuclear medicine physicians using a 1-100 visual analog scale (VAS) (1 = no diagnosis, 100 = perfect study) and was 76 ± 5.4 (Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6).

[0275] (Risks and Benefits)

[0276] PSMA-PET scans of prostate cancer participants have been used since 2011 to assess the disease burden of biochemical recurrence (BCR) and advanced / metastatic disease, with [68Ga]Ga-PSMA-11 being the most frequently used. Clinical reports have demonstrated better sensitivity and specificity than cholinergic PET imaging for PCa, with a very low incidence of adverse events. A retrospective analysis of 1007 participants showed that [68Ga]Ga-PSMA-11 was well-tolerated with no adverse reactions after infusion (Afshar-Oromieh A, Avtzi E, Giesel FL, et al (2015) The diagnostic value of PET / CT imaging with the (68)Ga-labeled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging; 42:197-209). Recently, [68Ga]Ga-PSMA-11 was approved in the United States (December 2020) as a radiodiagnostic PET imaging agent for use in male patients with suspected metastatic prostate cancer as a candidate for preliminary definitive treatment, or for suspected recurrence based on elevated serum PSA levels ([68Ga]Ga-PSMA-11 USPI). Therefore, other PSMA-PET agents have been investigated and are under clinical development, all demonstrating good safety and tolerability. Patients with prostate cancer initially diagnosed with localized disease have been included in studies requiring histopathological comparison to determine the diagnostic efficacy of this technique. A phase I study of [18F]CTT1057 in 20 cancer patients (n=5 main phase, n=15 mCRPC (NCT02916537)) demonstrated acceptable safety with no radiotracer-related adverse events.

[0277] The biodistribution of [18F]CTT1057 in humans is similar to that of other PSMA-targeted drugs, and the exposure rate of [18F]CTT1057 is also similar to that of urea-based PET compounds, with the favorable exception of lower exposure rates to the kidneys and salivary glands. Preclinical work, dosimetry studies and clinical experience with [18F]CTT1057 have shown good imaging quality characteristics and good safety (Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6).

[0278] As this is a study of the diagnostic efficacy of an experimental PET reagent, enrolled patients are not expected to receive a direct benefit. It is anticipated that distant disease may be discovered in some patients as a result of this study, and these patients may benefit from a more appropriate management plan that is not solely based on the experimental procedure but is confirmed by SoC diagnostic procedures. The risk-benefit ratio is expected to be favorable for the [18F]CTT1057 imaging agent.

[0279] By adhering to eligibility criteria and research procedures, and through close clinical monitoring, any risks to participants in this trial will be minimized. Appropriate eligibility criteria are included in this agreement.

[0280] (Experimental and controlled drugs)

[0281] (Description and Composition)

[0282] [18F]CTT1057 370 MBq / mL solution for infusion of pharmaceutical products is a sterile, ready-to-use, multi-dose solution containing [18F]CTT1057 as the pharmaceutical substance, with a volumetric activity of 370 MBq / mL at the reference date and time (calibration time). Natural decay of the radionuclides leads to a continuous decrease in specific activity, total radioactivity, and the radioactivity concentration of the pharmaceutical product over time.

[0283] The radiopharmaceutical material was [18F]CTT1057, which was a concentrated aqueous solution (referred to as the mother solution) of a fluorine (18F)-labeled PSMA reagent produced in an automated continuous process. Considering the initial 18F activity, the obtained radiochemical yield, and the target radioactive concentration of 370 MBq / mL for calibration time, the mother solution was further diluted to the final product, [18F]CTT1057 ready-to-use injectable solution. The composition of the final product is shown in Table 3 below. Table 3: Infusion Sets 18 Composition of CTT1057 370 MBq / mL solution Element effect [18F]CTT1057 Active substances CTT1298 Chemical precursors Sodium chloride isotropic agents Sodium dihydrogen phosphate buffer Sodium hydrogen phosphate buffer Ethanol (excipient) Eluents, anti-radiation decomposition stabilizers Water for Injection (WFI) solvent Ph. Eur = European Pharmacopoeia, USP = United States Pharmacopoeia Note: Sodium chloride and water for injection are components of 0.9% sodium chloride solution for injection, and sodium dihydrogen phosphate is used in the form of a dihydrated salt.

[0284] (Storage conditions)

[0285] Store below 25°C. Shelf life is 10 hours after T0 (T0: activity measurement time of the first quality control vial). 10 hours after T0 is equivalent to 6 hours after the calibration time [Tc] (Tc=T0+4h).

[0286] (Experimental PET developer) Experimental PET developer (name and strength) pharmaceutical dosage forms route of administration Supply type Calibration time (Tc) [ 18F]CTT1057 370 MBq / mL Injectable radioactive pharmaceutical solution Intravenous administration Open label, vials or syringes [ 68 Ga]Ga-PSMA-11 (150 MBq) [ 68 Radiopharm kits for Ga-PSMA-11 are available, or ready-to-use radiopharm solutions for injection are available. Intravenous administration Open label, vials or syringes

[0287] [18F]CTT1057 radiopharmaceutical will be administered intravenously at a dose of approximately 370 MBq (range 266~407 MBq).

[0288] [68Ga]Ga-PSMA-11 radiopharmaceutical will be administered via a single intravenous injection at a dose of approximately 150 MBq. The administered dose must not be less than 111 MBq or more than 185 MBq under any circumstances. Following measurements of the syringe before and after administration in a dose calibrator, the exact dose that should have been administered to each patient will be recorded in the Case Report Form (CRF).

[0289] The experimental developer [18F]CTT1057 will be provided as follows:

[0290] As a single-dose syringe (for use in the United States) or a single multi-dose vial (for use in the European Union) for ready-to-use injectable radiopharmaceutical solutions, the volumetric activity at reference date and time (calibration time (Tc)) is 370 (±10%) MBq / mL.

[0291] The natural decay of radioactive nuclei causes a continuous decrease in reactivity, total radioactivity, and radioactivity concentration (volume activity) over time. Therefore, the volume of the injected solution will vary in order to provide the required radioactivity of the drug on the day and at the time of injection.

[0292] Component [68Ga]Ga-PSMA-11 will be provided as follows:

[0293] As a kit for the preparation of radiopharmaceuticals: a single vial of white lyophilized powder to be locally recombined with a gallium chloride (68GaCl3) hydrochloric acid solution eluted from an approved 68Ge / 68Ga generator (a clinical facility equipped with an approved 68Ge / 68Ga generator).

[0294] As a single-dose ready-to-use radiopharmacy solution: Radiopharmacy solution in vials or syringes is provided by a cooperating radiopharmacy (clinical facilities without an approved 68Ge / 68Ga generator).

[0295] Based on the current activity and physical decay (half-life 68 minutes) of the radionuclides provided by the generator, calculate the volume of the [68Ga]Ga-PSMA-11 solution for the corresponding radioactive dose to be administered according to the estimated injection time. After recombination, the [68Ga]Ga-PSMA-11 solution must be used according to the instructions in the Pharmacy Manual. [Simplified Explanation of the Diagram]

[0020] None.

Claims

1. The use of a radioligand imaging agent in the preparation of a medicament for determining the presence and / or localization of a PSMA-positive tumor in a subject, wherein the subject has been diagnosed with a biochemical recurrence of prostate cancer, and wherein the radioligand imaging agent is a PSMA-binding compound of the following chemical formula (III): chemical formula (III) or any pharmaceutically acceptable salt thereof.

2. The use as described in claim 1, wherein the subject has been diagnosed with biochemical recurrence of prostate cancer following radical prostatectomy or radiation therapy.

3. The use as described in claim 1, wherein the PSMA-positive tumor is located in the prostate bed, pelvic lymph nodes, and / or bone.

4. The use as described in claim 1, wherein the radioligand imaging agent is formulated as an injection or infusion solution having a concentration that provides volumetric radioactivity of 150 MBq / mL to 1000 MBq / mL at the calibration time.

5. The use as described in claim 2, wherein the radioligand imaging agent is formulated as an injection or infusion solution having a concentration that provides volumetric radioactivity of 150 MBq / mL to 1000 MBq / mL at the calibration time.

6. The use as described in claim 3, wherein the radioligand imaging agent is formulated as an injection or infusion solution having a concentration that provides volumetric radioactivity of 150 MBq / mL to 1000 MBq / mL at the calibration time.

7. The use as claimed in any one of claims 4 to 6, wherein the volumetric radioactivity is 370 MBq / mL ± 10% at the calibration time.

8. The use as claimed in claim 1, wherein the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq.

9. The use as claimed in claim 2, wherein the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq.

10. The use as claimed in claim 3, wherein the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq.

11. The use as claimed in claim 4, wherein the radioligand imaging agent is administered intravenously at an effective dose between 250 MBq and 450 MBq.

12. The use as claimed in any one of claims 8 to 11, wherein the radioligand imaging agent is administered intravenously at an effective dose of 370 MBq.

13. The use as described in claim 4, wherein the subject is subjected to a first positron emission tomography (PET) scan between 60 and 120 minutes after intravenous administration.

14. The use as described in claim 13, wherein a second positron emission tomography (PET) scan is performed on the subject within 180 minutes after intravenous administration.

15. The use as described in claim 8, wherein the subject is subjected to a first positron emission tomography imaging between 60 and 120 minutes after intravenous administration.

16. The use as described in claim 15, wherein a second positron emission tomography (PET) scan is performed on the subject within 180 minutes after intravenous administration.

17. The use as described in claim 1, wherein the step of determining the presence and / or location of a PSMA-positive tumor in the subject comprises: administering an effective dose of the radioligand imaging agent as defined in claim 1 to the subject, imaging the subject by positron emission tomography (PET), analyzing the images obtained from the PET scan, and determining the presence and / or location of a PSMA-positive tumor in the subject.

18. The use as described in claim 17, wherein the positron emission tomography scan is a positron emission tomography / computed tomography (PET / CT) scan or a positron emission tomography / magnetic resonance imaging (PET / MRI) scan.

19. The use of an aqueous solution for injection or infusion in the preparation of a medicament for determining the presence and / or localization of a PSMA-positive tumor in a subject, wherein the subject has been diagnosed with biochemical recurrence of prostate cancer, wherein the aqueous solution comprises the radioligand imaging agent as defined in claim 1 and one or more pharmaceutically acceptable excipients, wherein the concentration of the radioligand imaging agent provides volumetric radioactivity from 150 MBq / mL to 1000 MBq / mL.

20. The use as described in claim 19, wherein the volumetric radioactivity is 370 MBq / mL.

21. The use as claimed in claim 19, wherein the aqueous solution further comprises a precursor compound of the following chemical formula (IV): chemical formula (IV), wherein the concentration of the precursor compound is less than or equal to 5.0 μg / mL.

22. The use as described in claim 21, wherein the concentration of the precursor compound is less than or equal to 4.0 μg / mL.

23. The use as described in claim 21, wherein the concentration of the precursor compound is less than or equal to 3.0 μg / mL.

24. The use as described in claim 21, wherein the concentration of the precursor compound is less than or equal to 2.0 μg / mL.

25. The use as described in claim 21, wherein the concentration of the precursor compound is less than or equal to 1.0 μg / mL.

26. The use as described in claim 19, wherein the aqueous solution further comprises a buffer and an isotropic agent, the buffer having a pH value between 5.0 and 8.

0.

27. The use as described in claim 26, wherein the pH of the buffer is between 6.0 and 8.

0.

28. The use as described in claim 26, wherein the pH of the buffer is between 6.5 and 7.

5.

29. The use as described in claim 26, wherein the buffer is a phosphate buffer.

30. The use as described in claim 26 or claim 29, wherein the tensile agent is sodium chloride.

31. The use as described in claim 19, wherein the aqueous solution further comprises a stabilizer against radiodegradation.

32. The use as described in claim 31, wherein the stabilizer resisting radiodegradation is an alcohol.

33. The use as described in claim 32, wherein the stabilizer against radiodegradation is ethanol.

34. The use as described in claim 26, wherein the aqueous solution further comprises a stabilizer against radiodegradation.

35. The use as described in claim 34, wherein the stabilizer against radiodegradation is an alcohol.

36. The use as described in claim 35, wherein the stabilizer against radiodegradation is ethanol.

37. The use as claimed in claim 31, wherein the aqueous solution comprises: sodium chloride at a concentration of 8.0 mg / mL to 9.5 mg / mL; sodium dihydrogen phosphate at a concentration of 0.03 mg / mL to 0.3 mg / mL; disodium hydrogen phosphate at a concentration of 0.2 mg / mL to 1.2 mg / mL; and ethanol at a concentration of 5.0 mg / mL to 50 mg / mL.

38. The use as described in claim 37, wherein the aqueous solution contains sodium chloride at a concentration of 8.6 mg / mL to 8.9 mg / mL.

39. The use as described in claim 37, wherein the aqueous solution contains sodium dihydrogen phosphate at a concentration of 0.1 mg / mL to 0.2 mg / mL.

40. The use as described in claim 37, wherein the aqueous solution contains disodium hydrogen phosphate at a concentration of 0.3 mg / mL to 1.1 mg / mL.

41. The use as described in claim 37, wherein the aqueous solution contains ethanol at a concentration of 10.0 mg / mL to 39.5 mg / mL.

42. The use as described in claim 37, wherein the aqueous solution further comprises a precursor compound of chemical formula (IV) as defined in claim 21, at a concentration of less than or equal to 5.0 μg / mL.

43. The use as described in claim 42, wherein the concentration of the precursor compound is less than or equal to 4.0 μg / mL.

44. The use as described in claim 42, wherein the concentration of the precursor compound is less than or equal to 3.0 μg / mL.

45. The use as described in claim 42, wherein the concentration of the precursor compound is less than or equal to 2.0 μg / mL.

46. ​​The use as described in claim 42, wherein the concentration of the precursor compound is less than or equal to 1.0 μg / mL.