How to diagnose prostate cancer

Abstract

The present disclosure relates to the field of diagnostic methods, more particularly to prostate cancer imaging.In particular, the present disclosure relates to a radiopharmaceutical PSMA-binding compound for use in determining the presence and / or localization of PSMA-positive tumor in a subject in need thereof, said subject being diagnosed with biochemical recurrence, particularly after radical prostatectomy or radiation therapy, said radiopharmaceutical compound being a compound of formula (III). [Formula 1] TIFF2024514293000047.tif38106

Description

[Technical field]

[0001] The present disclosure relates to the field of diagnostic methods, and more specifically to prostate cancer imaging. [Background technology]

[0002] Prostate-specific membrane antigen (PSA), also known as folate hydrolase or glutamate carboxypeptidase II, is a transmembrane protein. Of all known PSMA-overexpressing tumors, prostate cancer is the cancer in which the role of PSMA has been most extensively studied. Prostate cancer is the second most lethal cancer in the United States (US) and the third leading cause of cancer-related deaths 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 is also the most commonly diagnosed cancer with an estimated increase of 9,960 new cases in 2019 out of a total of 174,650 cases (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). Although the majority of diagnosed cases are in more developed regions due to the use of PSA testing, there is only a small difference in mortality worldwide, which is due to metastatic and often castration-resistant disease (Bray F, Ren JS, Masuyer E, et al (2013). Int J Cancer; 132:1133-45). Subsequent treatment is multifaceted and may include observation, surgery (prostatectomy), radiation therapy (external beam or brachytherapy), hormone therapy, and chemotherapy.The differential expression of PSMA from tumor to non-tumor tissue has led to a number of targeting strategies involving both disease localization using PSMA-PET imaging as well as therapeutic intervention. Accurate identification of the location and extent of disease determines treatment decisions for prostate cancer patients. Therefore, identification of distant metastatic disease at the early stage of prostate cancer is important in planning the management of prostate cancer.

[0003] Up to 40% of patients with prostate cancer will develop biochemical recurrence (BCR) within 10 years after initial treatment (Isbarn et al 2010. BJU Pat Int; 106:37-43). PSA levels usually rise months to years prior to clinically detectable recurrence (Van Poppel et al 2006, (EORTC 30001). Eur J Cancer; 42:1062-7). However, it is not possible to distinguish between localized, regional, or systemic disease with the necessary accuracy that is essential for further disease management (Bott 2004. Prostate Cancer and Prostatic Dis; 7:211-6).

[0004] It is therefore pertinent to detect smaller distant disease as early as possible, especially in patients with biochemical recurrence.

[0005] Routine diagnostic tools for prostate cancer include PSA testing, digital rectal examination, transrectal ultrasound, prostate biopsy, and histopathology (Schwarzenbock 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). In addition, further imaging techniques such as magnetic resonance imaging (MRI), bone scintigraphy, CT, and PET / CT with [18F]fluorodeoxyglucose (FDG), [18F]choline, [11C]choline, and the recently approved [18F]fluciclovine have been shown to be useful in the diagnosis of pulmonary hypertension (PHD) (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), and for staging primary prostate cancer and restaging biochemical recurrence (Schwarzenbock 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] CT and MRI are standard of care imaging procedures to measure tumors and lesions at baseline selected for response evaluation by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (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 show limited availability at the pelvic nodal stage in patients with prostate cancer.

[0007] Thus, there is a need for imaging tests that are more sensitive and accurate than the currently available standard of care tests. Novel PET radiotracers hold promise for overcoming this limitation. PET imaging is an attractive option because it offers the possibility of staging patients and providing insight into tumor biopsy. Among the various available PET probes, PSMA 68Ga-labeled ligands have been associated with unprecedented accuracy and efficacy of treatment in multiple meta-analyses of retrospective studies (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, several head-to-head studies have demonstrated the efficacy of Ga-labeled ligands for prostate cancer tumor localization in patients with biochemical recurrence [ 18 F]Fluciclovine vs. 68 Detection rates were calculated by patient and region for [Ga]Ga-PSMA-11 uptake after radical prostatectomy in patients with a PSA < 2.0 ng / ml. 68 Ga]Ga-PSMA-11 vs. [ 18 F]fluciclovine was superior to 68Ga-PSMA-11 PET / CT (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, in patients with biochemical recurrence of prostate cancer, 18 F]Fluciclovine vs. 68 A larger prospective head-to-head comparison study with [Ga]Ga-PSMA-11 found no statistical difference in overall detection rate for prostate cancer recurrence between the two different radioligands (Pernthaler et al. 2019 A Prospective Head-to-Head Comparison of 18 F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in PET / CT. Clin Nucl Med; 44(10):e566-e73).

[0008] Thus, there remains a need to identify radioligands capable of detecting and localizing tumors in prostate cancer patients with biochemical recurrence with improved detection rates and / or localization.

[0009] [ 18 [F]CTT1057 is a promising novel PSMA targeting 18 It is a F-labeled PET contrast agent (International Publication No. WO 2014143736). It shares a urea skeleton. 68 Ga or 18 Many other PSMA agents labeled with either F (e.g., 68 Ga]Ga-PSMA-11, 18 F]PSMA1007, 18 F]DCFPyL), unlike 18 [F]CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA with high nanomolar affinity, which may explain the higher and longer-lasting tumor uptake (Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18 F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6).

[0010] In 20 prostate cancer patients (n=5 primary stage and n=15 metastatic castration-resistant prostate cancer (mCRPC)) 18 The Phase 1 study of F-CTT1057 has demonstrated a tolerable safety profile without any radiotracer-related adverse reactions. The Phase 1 study also demonstrated that metastatic lesions were more clearly visualized by conventional imaging than by 18 F]CTT1057 imaging with higher sensitivity (Behr et al. 2019). 18 F]CTT1057 PET imaging image quality,68 The results were qualitatively similar to those obtained with [Ga]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] The present disclosure provides novel methods of using PET imaging agents for the detection and localization of PSMA positivity in patients diagnosed with biochemical recurrence, particularly in patients with prostate cancer.

[0012] In particular, it is an object of the present disclosure to provide methods for detecting PSMA-positive tumors using PET imaging agents with high affinity for targeting PSMA-expressing cancer cells, preferably prostate cancer cells, resulting in a very high tumor-to-background ratio.

[0013] Another object of the present disclosure is to provide a method for identifying very small volume sites of disease.

[0014] Another object of the present disclosure is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, with a PET imaging agent that has a favorable biodistribution for detection of typical sites of disease such as the prostate bed, pelvic lymph nodes, and bone.

[0015] Another object of the present disclosure is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, that works reliably in a variety of different clinical settings, including initial staging, restaging upon biochemical recurrence, and planning for radiation or surgery.

[0016] Another object of the present disclosure is to provide a method for detecting PSMA-positive tumors, preferably prostate cancer tumors, with an imaging agent that has a high radiochemical yield that allows for high patient throughput.

[0017] Thus, the present disclosure provides a radioligand imaging agent for use in determining the presence and / or localization of a PSMA positive tumor in a subject, said subject having been diagnosed with biochemical recurrence, said radioligand imaging agent comprising a phosphoramidate group and [ 18 The present invention relates to radioligand imaging agents that are PSMA-binding compounds that contain a [F]-fluoro group.

[0018] The present disclosure also provides a method for the preparation of a compound comprising administering to a subject a subject, comprising administering to a subject a subject a phosphoramidate group and an 18 The present invention relates to an injection or infusion solution, which is an aqueous solution comprising a PSMA-binding compound comprising a [F]-fluoro group, and one or more pharma- ceutically acceptable excipients.

[0019] Also disclosed herein is a method for determining the presence and / or localization of a PSMA-positive tumor in a subject, preferably a prostate cancer subject, wherein the subject has been diagnosed with biochemical recurrence, the method comprising: [i] administering to said subject an effective dose of a radioligand imaging agent as defined below; [ii] imaging the subject with either a PET scan, a PET / CT or a PET / MRI scan; [iii] analyzing the images obtained by the PET scan; Including, Thereby determining the presence and / or localization of a PSMA-positive tumor in said subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition As used herein, the term "PSMA positive tumor" refers to a tumor that is resistant to a PSMA-positive tumor, the tumor being treated with a tracer compound that contains a PSMA binding moiety, typically of formula (I), (II) or (III) as described below. 18 Refers to tumor lesions that can be detected with a radioligand imaging agent, such as a F radiolabeled PSMA binding compound.

[0021] Consistent with the International System of Units, "MBq" is the abbreviation for the unit of radioactivity "megabecquerel."

[0022] As used herein, "PET" stands for Positron Emission Tomography.

[0023] As used herein, "SPECT" stands for single photon emission computed tomography.

[0024] As used herein, "MRI" stands for magnetic resonance imaging.

[0025] As used herein, "CT" stands for computed tomography.

[0026] As used herein, the term "effective dose" of a radioligand imaging agent for use with the method of the present disclosure refers to a sufficient amount of imaging agent to determine the presence or localization of PSMA-positive lesions in a patient from imaging studies using said imaging agent. In particular, in specific embodiments, the presence and / or localization is determined by the method of the present disclosure more reliably than traditional imaging methods. The effective dose can be determined by the radioactivity of the injected solution at the time of injection. The radioactivity of the injected solution can be derived from a measurement of the volumetric radioactivity of the injectable solution at a reference time, typically referred to as the "calibration time", after the generation of the injectable solution. The physician adjusts the volume to be injected based on the estimated volumetric radioactivity at the time of injection and the known volumetric radioactivity at the calibration time.

[0027] Thus, as used herein, the term "calibration time", when referring to the volumetric activity of a composition, refers to the activity measured at a reference data and time, for example, within 60 minutes after making the product.

[0028] "Radiochemical purity" is the percentage of the stated radionuclide present in the stated chemical or biological form. Radiochromatographic methods, such as HPLC or thin layer chromatography (TLC), are commonly accepted methods for determining radiochemical purity in radiopharmacology. In a specific embodiment, the radiochemical purity of the radioligand imaging agent is 95% or greater.

[0029] As used herein, "aqueous solution" refers to a solution of one or more solutes in water. The term "aqueous solution" also refers to an aqueous alcoholic solution containing water and alcohol, preferably ethanol, for example, alcohol is present at 0%-20%, preferably 0%-10%, for example, between 2%-8%, more preferably about 5%.

[0030] The term "about" or "approximately" means herein that the following value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0031] As used herein, the term "amino acid" refers to an organic compound that contains at least one amino group and at least one carboxylic acid group, and includes both natural and unnatural amino acids.

[0032] As used herein, the term "heteroalkylene" refers to a divalent heteroalkyl, a straight or branched hydrocarbon chain consisting of 1 to 35, preferably 1 to 20, carbon atoms and 1 to 15 heteroatoms selected from the group consisting of O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (e.g., sulfoxide or sulfone) and the nitrogen heteroatom is optionally quaternized. The heteroatom(s), O, N and S, can be placed at any interior position of the heteroalkylene group and at either or both of the chain termini.

[0033] Radioligand Imaging Agents for Use in the Methods of the Disclosure A radioligand imaging agent for use according to the present disclosure comprises at least one phosphoramidate group and 18 F]-fluoro group, or any pharma- ceutically acceptable salt thereof.

[0034] 18 F radiolabeled PSMA binding compounds have been described in the prior art, including those described in WO2013173583 or WO2014143736.

[0035] In certain embodiments, the radioligand imaging agent for use according to the present disclosure has formula (I):

[0036] [ka] [In the formula, each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); each R2 is independently hydrogen or C1-C6 alkyl; R3 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro; L1 is a linker preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkylene, and heteroalkylene containing 1-35 carbon atoms and 1-15 heteroatoms, said heteroalkylene being optionally substituted with one or more substituents selected from oxo and C1-C6 alkyl, more preferably L1 is a linker selected from 1-6 amino acids. or a pharma- ceutically acceptable salt thereof.

[0037] In certain embodiments, the radioligand imaging agent for use according to the present disclosure has formula (II):

[0038] [ka] [In the formula, L is a moiety of the formula -NH-CH2CH2-(OCH2CH2-)yC(O)-, or

[0039] [ka] wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 1, 2, 3, or 4; Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. is a linker comprising the group R1 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of chloro and cyano; Each R2 is independently hydrogen or C1-C6 alkyl; each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); However, L is expressed as

[0040] [ka] If the group is The combination of m and n results in linear linker lengths from 3 to 21 atoms. or any pharma- ceutically acceptable salt thereof. For example, if m is 2 and each n is 4, then the linker is 12 atoms long. If m is 1 and n is 10, then the linker is also 12 atoms long. The length of the linker is calculated using the formula m·(n+2).

[0041] As used herein, a "protecting group" is a group introduced onto a functional group (e.g., a phosphorous or carboxylic acid) that allows for chemoselectivity in subsequent chemical transformations. Such groups, specifically carboxylic acid and phosphate protecting groups, are described in Greene's Protective Groups in Organic Synthesis, 4th Edition, relevant portions of which are incorporated by reference.

[0042] In some embodiments, the "protecting group" is an alkyl, alkenyl, or haloalkyl, including, but not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoromethyl, or trifluoroethyl. In some embodiments, the "protecting group" is benzyl or substituted benzyl, including, but not limited to, triphenylmethyl (trityl), 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.

[0043] In a preferred embodiment, the radioligand imaging agent for use according to the present disclosure has formula (III):

[0044] [ka] or any pharma- ceutically acceptable salt thereof.

[0045] The compound of formula (III) may also be represented by the formula: 18 It is referred to in the literature as [F]CTT1057.

[0046] Other PSMA binding compounds for use according to the present disclosure and methods for the synthesis of such compounds are described, inter alia, in WO 2014 / 143736, the contents of which are incorporated herein in their entirety.

[0047] In specific embodiments, the PSMA binding compound for use according to the present disclosure has the following formula (IV):

[0048] [ka] from the precursor CTT1298, in particular according to the following reaction scheme:

[0049] [ka] Succinimidyl- 18 F-fluorobenzoates can be synthesized by coupling to primary amine precursors.

[0050] [ 18 F]SFB can be prepared by the following reaction scheme:

[0051] [ka] can be synthesized through

[0052] Methods for obtaining the compound CTT1298 have been described in the art, in particular in WO2014143736 (Example 1, the contents of which are incorporated herein by reference).

[0053] Other examples of synthesis methods on the ORA Neptis® Perform Synthesizer are further described in Jivan et al 2017 (J Labelled Comp Radiopharm 2017: 60:1).

[0054] Pharmaceutical Compositions of the Present Disclosure The PSMA binding compounds for use according to the present disclosure are formulated as pharmaceutical compositions, typically solutions for injection or infusion.

[0055] The injection or infusion solution is preferably an aqueous or aqueous-alcoholic solution comprising a PSMA binding compound described herein and one or more pharma- ceutically acceptable excipients.

[0056] Typically, the PSMA binding compound may be present in the pharmaceutical composition at a concentration that results in a volumetric radioactivity, at a calibration time, of between 150 and 1000 MBq / mL, preferably between 200 and 700 MBq / mL, more preferably between 250 and 450 MBq / mL, for example about 370 MBq / mL.

[0057] The pharma- ceutically acceptable excipients may be any of those conventionally used. In particular, the excipient or excipients may be selected from buffers, stabilizers against radiation degradation, isotonicity agents, and mixtures thereof.

[0058] As used herein, "radiolysis stabilizer" refers to a stabilizer that protects organic molecules against radiolysis, for example, when gamma radiation emitted from a radionuclide breaks bonds between atoms of organic molecules to form radicals, these radicals are then captured by a stabilizer that prevents the radicals from undergoing any other chemical reactions that may result in undesirable, potentially ineffective, or even toxic molecules. Therefore, these stabilizers are also referred to as "free radical scavengers" or "radical scavengers" for short. Other alternative terms for these stabilizers are "radiostability enhancers", "radiolysis stabilizers", or simply "quenchers". In a preferred embodiment, the radiolysis stabilizer is ethanol.

[0059] The buffer may be a phosphate buffer, an acetate buffer, or a citrate buffer, or a combination thereof, preferably a phosphate buffer. In a specific embodiment, the buffer or combination of buffers is suitable for a pH of 6.5 to 7.5.

[0060] Isotonicity agents include sodium chloride, particularly at a concentration of about 0.9%.

[0061] In a specific embodiment, said injection or infusion solution comprises a radioligand imaging agent as described in the preceding sections, e.g., a PSMA binding compound of Formula (I), (II) or (III), preferably a compound of Formula (III), at a concentration providing a volumetric activity of between 150-1000 MBq / mL at the calibration time, preferably 200-700 MBq / mL, more preferably 250-450 MBq / mL, typically about 370 MBq / mL at the calibration time, and optionally a phosphate buffer and sodium chloride.

[0062] In a specific embodiment, the solution for injection or infusion further comprises a buffer, preferably a phosphate buffer, for a pH between 6.5 and 7.5, and an isotonic agent, preferably sodium chloride.

[0063] In a specific embodiment, the solution can further comprise the maximum amount of precursor compound used in synthesis.For example, the precursor compound of formula (IV) (also referred to as CTT1298) is present at a concentration of 5 μg / mL or less, preferably 4 μg / mL or less, more preferably 3 μg / mL or less, even more preferably 2 μg / mL or less, even more preferably 1 μg / mL or less.

[0064] In a specific embodiment, the solution may further comprise a stabilizer against radiolysis that may be suitable as an eluent during the preparation of the solution, preferably said stabilizer and / or eluent is an alcohol, preferably ethanol. Indeed, according to a preferred embodiment, in particular in the automated synthesis of radioligands, for example as described in the examples below, the solution is obtained from the elution of the radioligand for separation from its precursor compound.

[0065] Thus, in a preferred embodiment, the injectable solution comprises: (i) a radioligand imaging agent as described in the preceding section, e.g. a PSMA-binding compound of formula (I), (II) or (III), preferably a compound of formula (III), at a concentration that provides a volumetric activity of 250 to 450 MBq / mL at the calibration time, typically about 370 MBq / mL at the calibration time; (ii) NaCl, at a concentration of 8.0 to 9.5 mg / mL; preferably 8.6 to 8.9 mg / mL; (iii) NaH2PO4, at a concentration of 0.03 to 0.3 mg / mL; preferably 0.1 to 0.2 mg / mL; (iv) Na2HPO4, at a concentration of 0.2 to 1.2 mg / mL; preferably 0.3 to 1.1 mg / mL; (v) ethanol, at a concentration of 5 to 50 mg / mL; preferably 10.0 to 39.5 mg / mL; and (vi) optionally, a precursor compound (e.g., a CTT1298 precursor compound of formula IV) at a concentration of 5.0 μg / mL or less, preferably 4.0 μg / mL or less, even more preferably 3.0 μg / mL or less, even more preferably 2.0 μg / mL or less, preferably 1.0 μg / mL or less; Includes.

[0066] Subjects with biochemical recurrence The detection methods and uses of radioligand imaging agents according to the present disclosure are intended for subjects with biochemical recurrence, preferably subjects with prostate cancer with biochemical recurrence.

[0067] In a specific embodiment, the detection methods and uses of radioligand imaging agents according to the present disclosure are intended for subjects with prostate cancer with biochemical recurrence after radical prostatectomy or after radiation therapy.

[0068] As used herein, the term "biochemical recurrence" refers to its general meaning as proposed by the American Urological Association criteria. More specifically, a definition of biochemical recurrence after radical prostatectomy is provided in Cookson et al 2007 J Urol;177(2):540-5. In a specific embodiment, it relates to a subject with prostate cancer who has undergone radical prostatectomy and has a detectable or elevated PSA level measured 6-13 weeks after surgery that is equal to or greater than 0.2ng / ml, and optionally a second confirmatory level measured at least 2 weeks after the first measurement that is strictly greater than 0.2ng / ml. A definition of a subject with biochemical recurrence after radiation therapy can be provided in Roach et al 2006 Int J Radiat Oncol Biol Phys;65(4):965-74. In a specific embodiment, it relates to subjects who have undergone therapeutic radiation therapy with biochemical recurrence according to the American Society for Radiation Oncology (ASTRO)-Phoenix criteria (PSA greater than nadir defined as the lowest PSA achieved, PSA ≥ 2 ng / ml (nadir PSA+2)).

[0069] Methods for determining the presence and localization of positive tumor in subjects with biochemical recurrence - Patents.com It is an object of the present disclosure to provide methods for determining the presence or localization of PSMA-positive tumors in subjects with biochemical recurrence, typically prostate cancer subjects.

[0070] Typically, the presence and localization of PSMA-positive tumors is detected by analyzing uptake of a PSMA-binding compound following injection of a radiotracer, e.g., in said subject who has been diagnosed with biochemical recurrence.

[0071] Accordingly, the present disclosure provides a method for determining the presence and / or localization of a PSMA-positive tumor in a subject, wherein the subject has been diagnosed with biochemical recurrence, the method comprising: [i] administering to said 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 of the following formula (III):

[0072] [ka] or any pharma- ceutically acceptable salt thereof; [ii] imaging the subject by PET scan, e.g., PET / CT or PET / MRI scan; [iii] analyzing the images obtained by the PET scan; Including, thereby determining the presence and / or localization of a PSMA-positive tumor in said subject. It concerns the method.

[0073] Accordingly, the present disclosure provides a method for determining the presence and / or localization of a PSMA-positive tumor in a subject with prostate cancer, said subject having been diagnosed with biochemical recurrence, typically following radical prostatectomy or radiation therapy, said method comprising: [i] administering to said 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 of the following formula (III):

[0074] [ka] or any pharma- ceutically acceptable salt thereof; [ii] imaging the subject by PET scan, e.g., PET / CT or PET / MRI scan; [iii] analyzing the images obtained by the PET scan; Including, Thereby, the presence and / or localization of a PSMA-positive tumor in said subject is determined.

[0075] In general, an effective dose is an amount of contrast agent sufficient to obtain acceptable imaging using equipment available for clinical use. The amount of contrast agent used in the disclosed methods and the duration of the imaging step depend, among other things, on the patient's weight, the nature and severity of the condition being detected, the nature of the therapeutic treatment the patient is undergoing, etc. Ultimately, the physician can determine the amount of contrast agent to administer to each individual patient and the duration of the imaging step.

[0076] In a specific embodiment, a subject diagnosed with biochemical recurrence receives a single effective dose of 250-450 MBq, typically about 370 MBq, by intravenous injection of an injection or infusion solution containing the radioligand contrast agent described above. In a specific embodiment, the volume of the injection does not exceed 10 mL, for example 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.

[0077] Images of the patient's body are then obtained by positron emission tomography-magnetic resonance imaging (PET / MRI) or positron emission tomography-computed tomography (PET / CT) imaging. Methods for obtaining images by PET / MRI or PET / SCAN are well known in the art.

[0078] Typically, the first PET scan is performed 60-120 minutes after injection / infusion, for example in a 90 minute window, with the possibility of a second PET scan being performed up to 180 minutes after injection of the radioligand contrast agent.

[0079] The image is then analyzed by visual evaluation, quantitative evaluation, or both to identify the presence of one or more PSMA-positive lesions and / or determine the localization of one or more PSMA-positive lesions. The image can be generated by the difference in spatial distribution of the imaging agent that accumulates at the site when it contacts PSMA. The spatial distribution can be measured by any method, for example, using a PET device. The degree of accumulation of the imaging agent can be quantified using known methods for quantifying radioactive emissions. A particularly useful approach can utilize two or more imaging agents to perform simultaneous studies.

[0080] In a specific embodiment, the term "PSMA-positive tumor" or "PSMA-positive lesion" refers to a visually identified lesion in a subject, preferably a prostate cancer subject, that shows uptake of a pathology radioligand imaging agent on PET / CT or PET / MRI, as follows: · Visible PET-positive lymph nodes considered superior to blood pool (adjacent or mediastinal blood pool); ·PET positive bone lesions considered superior to physiological bone marrow; PET-positive prostate, prostate bed, and visceral lesions that are deemed superior to the physiological background activity of the involved organ or anatomical site, as previously described (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).

[0081] In certain embodiments of the methods, subjects with biochemical recurrence do not have PSMA-positive lesions detected by conventional imaging.

[0082] In certain embodiments of the method, the method comprises administering to a subject, particularly a subject with prostate cancer with biochemical recurrence, 68 Ga]-PSMA-11 compound is expected to exhibit improved sensitivity and / or specificity for the detection of PSMA-positive tumors compared to the [Ga]-PSMA-11 compound.

[0083] 18 F-labeled tracers have the following practical advantages: 18 F is 68 It has a longer half-life than Ga, and the tracer distributes to the PET center without a cyclotron, allowing for easy handling in clinical practice. 18 F(96.9%) vs. 68 The branching decay of the high positron of Ga(87.7%) is 18 With the shorter positron range of F, 18 This is confirmed by higher PET image resolution than can be achieved with F-labeled radiopharmaceuticals (Conti M, Eriksson L (2016) EJNMMI Physics; 3(1):1-17). 68 Ga or 18 Many other PSMA agents labeled with either F (e.g., 68 Ga]Ga-PSMA-11, 18 F]PSMA1007, 18 F]DCFPyL), unlike 18 [F]CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA with high nanomolar affinity, resulting in higher resolution of PET scans and greater precision and accuracy in detecting even the smallest lesions in tumors.

[0084] In specific embodiments, the methods are particularly useful in managing patients to treat recurrences.

[0085] Thus, the present disclosure also provides a method for monitoring a disease status of a subject for biochemical recurrence, said method comprising: [i] administering to said subject an effective dose of a radioligand imaging agent as described above, such as a PSMA-binding compound of formula (I), (II) or (III) or any pharma- ceutical acceptable salt thereof, more preferably of formula (III) below:

[0086] [ka] or any pharma- ceutical acceptable salt thereof, preferably by intravenous injection of an injectable vehicle as described above; [ii] imaging the subject, for example, with a first positron emission tomography (PET) scan in a window from 60 to 120 minutes after injection, preferably at about 90 minutes, and optionally with a second PET scan up to 180 minutes after injection; [iii] analyzing the images obtained by the PET scan; [iv] determining the presence and / or localization of a PSMA-positive tumor in the subject; [v] determining a treatment option dependent on the presence and / or localization of a PSMA-positive tumor in said subject; [vi] optionally treating the subject with said treatment option. The present invention relates to a method comprising the steps of:

[0087] Accurate identification of the localization and extent of disease determines treatment decisions for patients, typically those with prostate cancer. Identification of distant metastatic disease at an early stage of prostate cancer is important in planning prostate cancer management. There is increasing evidence that initial landing sites for prostate cancer are outside the extended pelvic lymph node dissection (ePLND) template. Initial lymph node landing sites outside of ePLND are: 68It has been reported in 47.7% of men with suspected node-positive disease on Ga-PSMA PET / CT (Yaxley JW, Raveenthiran S, Nouhaud FX, et al (2019a) BJU Int; 124:401-7). This is of great importance as it avoids the occurrence of surgery if there is a change in management from one of therapeutic intent to one that requires a multimodality 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).

[0088] Thus, treatment options may subsequently vary among different approaches such as surgery, radiation alone, radiation and androgen ablation therapy, androgen ablation therapy alone, observation / surveillance, and the like.

[0089] The present disclosure also provides a kit for monitoring a disease state in a subject as described above, said 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), more preferably a radioligand imaging agent of formula (III) below:

[0090] [ka] or a pharma- ceutical acceptable salt thereof. Or a kit comprising said injection or infusion solution containing the radioligand imaging agent described above.

[0091] The present disclosure further relates to a kit for use in the aforementioned method, said kit comprising an effective dose, for example about 370 MBq, of a radioligand imaging agent or a precursor thereof for the aforementioned synthesis, in combination with a pharma- ceutically acceptable carrier, wherein the imaging agent, its precursor, and carrier are provided in solution.

[0092] In certain embodiments, the kit for use in the methods of the present disclosure includes a kit for detecting K[ 18 F] or Na[ 18 F], typically a compound of formula (IV).

[0093] In accordance with the present disclosure, the following embodiments E1 to E30 are provided.

[0094] E1: A radioligand imaging agent for use in a diagnostic method for determining the presence and / or localization of a PSMA-positive tumor in a subject, in particular wherein the subject is a prostate cancer subject, the PSMA-positive tumor is prostate cancer, the subject has been diagnosed with biochemical recurrence, and the radioligand imaging agent comprises a phosphoramidate group and [ 18 F]-fluoro group-containing PSMA-binding compound.

[0095] E1b: The method further comprises: [i] administering to the subject an effective dose of the radioligand imaging agent; [ii] imaging the subject with either a PET scan, a PET / CT or a PET / MRI scan; [iii] analyzing the images obtained from the PET scan; and [iv] determining the presence and / or localization of a PSMA-positive tumor in said subject. A radioligand imaging agent for use as described in E1, comprising:

[0096] E2: The agent is of formula (I):

[0097] [ka] [In the formula, each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); each R2 is independently hydrogen or C1-C6 alkyl; R3 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro; L1 is a linker preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkylene, and heteroalkylene containing 1-35 carbon atoms and 1-15 heteroatoms, said heteroalkylene being optionally substituted with one or more substituents selected from oxo and C1-C6 alkyl, more preferably L1 is a linker selected from 1-6 amino acids. or any pharma- ceutically acceptable salt thereof.

[0098] E3: Formula (II):

[0099] [ka] [In the formula, L is a moiety of the formula -NH-CH2CH2-(OCH2CH2-)yC(O)-, or

[0100] [ka] wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 1, 2, 3, or 4; Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. is a linker comprising the group R1 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro, is phenyl or pyridyl; Each R2 is independently hydrogen or C1-C6 alkyl; each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); However, L is expressed as

[0101] [ka] If the group is The combination of m and n results in linear linker lengths from 3 to 21 atoms. and any pharma- ceutically acceptable salt thereof.

[0102] E4: Formula (III):

[0103] [ka] or any pharma- ceutically acceptable salt thereof.

[0104] E5: The radioligand imaging agent for use according to any one of embodiments E1 to E4, wherein said subject has been diagnosed with biochemical recurrence following radical prostatectomy or radiation therapy.

[0105] E6: A radioligand imaging agent for use according to any one of the embodiments E1 to E5, formulated as a solution for injection or infusion at a concentration resulting in a volumetric radioactivity of 150 to 1000 MBq / mL, for example 370 MBq / mL±10%, at the calibration time.

[0106] E7: A radioligand imaging agent for use according to any one of the embodiments E1 to E6, administered intravenously at an effective dose comprised between 250 and 450 MBq, typically around 370 MBq.

[0107] E8: The radioligand imaging agent of E6 or E7, wherein the first PET scan of the subject is performed between 60 and 120 minutes after injection or infusion, and optionally the second scan is performed up to 180 minutes after injection or infusion.

[0108] E9: A solution for injection or infusion, which is an aqueous solution comprising the radioligand contrast agent defined in any of E1 to E5 at a concentration resulting in a volumetric activity of between 150 and 1000 MBq / mL, for example about 370 MBq / mL, and one or more pharma- ceutically acceptable excipients.

[0109] E10: Formula (IV):

[0110] [ka] The solution of E9, wherein the precursor compound of is present at a concentration of 5.0 μg / mL or less, preferably 4.0 μg / mL or less, more preferably 3.0 μg / mL or less, even more preferably 2.0 μg / mL or less, and even more preferably 1.0 μg / mL or less.

[0111] E11: A solution according to E9 or E10, further comprising a buffer, preferably a phosphate buffer, for a pH between 5.0 and 8.0, preferably 6.0 and 8.0, more preferably 6.5 and 7.5, and an isotonicity agent, preferably sodium chloride.

[0112] E12: The solution according to E11, further comprising a stabilizer against radiolysis, preferably a stabilizer suitable as an eluent during preparation of the solution, preferably said stabilizer and / or eluent being an alcohol, preferably ethanol.

[0113] E13: [i] NaCl, at a concentration of 8.0 to 9.5 mg / mL; preferably 8.6 to 8.9 mg / mL; [ii] NaH2PO4, at a concentration of 0.03 to 0.3 mg / mL; preferably 0.1 to 0.2 mg / mL; [iii] Na2HPO4, at a concentration of 0.2 to 1.2 mg / mL; preferably 0.3 to 1.1 mg / mL; [iv] ethanol, at a concentration of 5 to 50 mg / mL; preferably 10.0 to 39.5 mg / mL; and [v] optionally, at a concentration of less than 5.0 μg / mL, a precursor compound The solution according to E12, comprising:

[0114] E14: A method for determining the presence and / or localization 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: [i] administering to said subject an effective dose of a radioligand imaging agent defined in any of embodiments E1-E7; [ii] imaging the subject with either a PET scan, a PET / CT or a PET / MRI scan; [iii] analyzing the images obtained by the PET scan; Including, Thereby determining the presence and / or localization of a PSMA-positive tumor in the subject.

[0115] E15: The method of E14, wherein said radioligand imaging agent is administered intravenously at an effective dose comprised between 250 and 450 MBq, typically about 370 MBq.

[0116] E16: Determine the presence and / or localization of PSMA-positive tumor lesions of 5-10 mm in size, as described above with respect to E14 or E15.

[0117] E17: The method of E14 to E16, wherein the imaging step (ii) comprises a first PET scan performed 60-120 minutes after injection / infusion, typically about 90 minutes after injection / infusion, and optionally a second scan performed up to 180 minutes after injection / infusion.

[0118] E18: The method of any one of E14 to E17, wherein said radioligand imaging agent is formulated as an injectable or infusible solution as defined in any one of embodiments E9 to E13.

[0119] E19: A method for monitoring a subject's disease status for biochemical recurrence, said method comprising: [i] administering to said subject an effective dose of a radioligand imaging agent as described above, such as a PSMA-binding compound of formula (I), (II) or (III) or any pharma- ceutical acceptable salt thereof, more preferably of formula (III) below:

[0120] [ka] or any pharma- ceutical acceptable salt thereof, preferably by intravenous injection of an injectable vehicle as described above; [ii] imaging the subject, for example, with a first positron emission tomography (PET) scan in a window from 60 to 120 minutes, preferably at about 90 minutes, and optionally with a second PET scan up to 180 minutes after injection; [iii] analyzing the images obtained by the PET scan; [iv] determining the presence and / or localization of a PSMA-positive tumor in the subject; [v] determining a treatment option depending on the presence and / or localization of a PSMA-positive tumor in the subject; and [vi] optionally treating the subject with said treatment option. A method comprising:

[0121] E20: The method of E19, wherein the subject is suffering from prostate cancer.

[0122] E21: The method of E20, wherein the subject has been diagnosed with biochemical recurrence following radical prostatectomy or radiation therapy.

[0123] E22: A method for producing a radioligand imaging agent for use in a diagnostic method comprising the steps defined in any one of the embodiments E14 to E18, wherein said radioligand imaging agent is defined in any one of E1 to E9.

[0124] E23: Phosphoramidate groups and [ 18 and a solution for injection or infusion, which is an aqueous solution comprising a radioligand imaging agent that is a PSMA-binding compound that contains a [F]-fluoro group, and one or more pharma- ceutically acceptable excipients.

[0125] E24: The radioligand imaging agent has formula (I):

[0126] [ka] [In the formula, each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); each R2 is independently hydrogen or C1-C6 alkyl; R3 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro; L1 is a linker preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkylene, and heteroalkylene containing 1-35 carbon atoms and 1-15 heteroatoms, said heteroalkylene being optionally substituted with one or more substituents selected from oxo and C1-C6 alkyl, more preferably L1 is a linker selected from 1-6 amino acids. or any pharma- ceutically acceptable salt thereof.

[0127] E25: The radioligand imaging agent has formula (II):

[0128] [ka] [In the formula, L is a moiety of the formula -NH-CH2CH2-(OCH2CH2-)yC(O)-, or

[0129] [ka] wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 1, 2, 3, or 4; Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. is a linker comprising the group R1 is [ 18 F]-fluoro group and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro, is phenyl or pyridyl; Each R2 is independently hydrogen or C1-C6 alkyl; each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); However, L is expressed as

[0130] [ka] If the group is The combination of m and n results in linear linker lengths from 3 to 21 atoms. and any pharma- ceutically acceptable salt thereof.

[0131] E26: The radioligand imaging agent has formula (III):

[0132] [ka] or any pharma- ceutically acceptable salt thereof.

[0133] E27: Formula (IV):

[0134] [ka] The solution of any one of embodiments E23 to E26, wherein the precursor compound of is present in a concentration of 5.0 μg / mL or less, preferably 4.0 μg / mL or less, more preferably 3.0 μg / mL or less, even more preferably 2.0 μg / mL or less, and even more preferably 1.0 μg / mL or less.

[0135] E28: The solution according to any one of embodiments E23 to E27, further comprising a buffer, preferably a phosphate buffer, for a pH between 5.0 to 8.0, preferably 6.0 to 8.0, more preferably 6.5 to 7.5, and an isotonicity agent, preferably sodium chloride.

[0136] E29: The solution according to any one of embodiments E23 to E28, further comprising a stabilizer against radiolysis, preferably a stabilizer suitable as an eluent during preparation of the solution, preferably said stabilizer and / or eluent is an alcohol, preferably ethanol.

[0137] E30: [i] NaCl, at a concentration of 8.0 to 9.5 mg / mL; preferably 8.6 to 8.9 mg / mL; [ii] NaH2PO4, at a concentration of 0.03 to 0.3 mg / mL; preferably 0.1 to 0.2 mg / mL; [iii] Na2HPO4, at a concentration of 0.2 to 1.2 mg / mL; preferably 0.3 to 1.1 mg / mL; [iv] ethanol, at a concentration of 5 to 50 mg / mL; preferably 10.0 to 39.5 mg / mL; and [v] Precursor compound at a concentration of less than 5.0 μg / mL 20. The solution of claim E29, comprising: EXAMPLES

[0138] [Example 1] Preparation of solutions containing radioligand imaging agents The drug was prepared by adjusting the volume activity of the final solution to 370MBq / mL ± 10% (Tc) in NaCl 0.9% [ 18 Dilute solution of [F]CTT1057 concentrated mother liquor (radioactive drug substance, 15 ± 1 mL, approximately 1685-6667 MBq / mL at Tm). The volume of saline added is the volume obtained at the end of the synthesis (Tm) [ 18 [F]CTT1057 activity, calculated according to decay corrected to the time of calibration (Tc). Tm is the time of measurement of activity in the mother liquor. Tm is minutes after EOS.

[0139] The final volume of the drug product ranged from 15 to 59 mL, and therefore [ 18 The quantitative composition of the [F]CTT1057 final products varies.

[0140] The qualitative and quantitative composition of the drug in standard volumes of 15 mL and 59 mL is given in Table 1.

[0141] [Table 1]

[0142] drug substance([ 18 Synthesis of CTT1057 and its use as a pharmaceutical agent ([F]CTT1057) 18 Formulation of [F]CTT1057 into a 370 MBq / mL injectable solution) is part of an automated continuous process described in the next section.

[0143] Synthesis of API [ 18 F]CTT1057 active substance (mother liquor) is obtained via a two-step synthetic route.

[0144] In the first stage (step 1), 18The [F]SFB prosthetic group is prepared in a one-pot, three-step procedure beginning with radiofluorination of the FB starting material, followed by saponification of the ethyl esther and coupling with TSTU.

[0145] [ka]

[0146] In the second step (step 2), labeling of the isolated precursor CTT1298 with [18F]SFB under mildly basic conditions resulted in [ 18 F]CTT1057 formation.

[0147] [ka]

[0148] A two-step purification process led to the separation of by-products and residual reagents, resulting in a final formulation with radiochemical purity ≥ 95%. 18 Obtain F]CTT1057.

[0149] The entire synthesis and purification is carried out automatically on the synthesizer described below.

[0150] Manufacturing method of mother liquor containing pharmaceutical ingredient [ 18 O]H2O to radionuclide precursors ([ 18 F] fluoride) generation Radionuclides are produced by ionizing them with an intense beam of accelerated protons to a purity of 97% or more. 18 O] by water impact [ 18 F] fluoride ion. This nuclear reaction occurs in a cyclotron target.

[0151] Radioactivity transfer and clean room 18 Recovery of F After the impact, [ 18 Irradiated [F]fluoride-containing 18 O] Water is automatically transferred to a dedicated synthesis module.

[0152] [ 18 [F] from fluoride 18 Generation of F]CTT1057 [ 18 [F] from fluoride 18 The production of [F]CTT1057 is carried out in a lead-blocked isolator in two steps as described below.

[0153] [ 18 Preparation of the [F]SFB prosthetic group [ 18 F]SFB prosthetic group is Et-4-[ 18 Radiofluorination of the FB precursor starting material followed by [F]FB 18 Saponification of the ethyl ester to obtain [F]FBA and the saponification with TSTU (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate) 18 F]SFB to [ 18 It is prepared in a one-pot, three-step procedure including the coupling of [F]FBA.

[0154] Next, 18 [F]SFB (N-succinimidyl-4-[18F]fluorobenzoate) is purified through an HLB purification cartridge. 18 F]SFB remains in the cartridge while it is unreacted[ 18 F] fluoride is transferred to the waste.

[0155] Finally, pure [ 18 [F]SFB is eluted from the HLB with acetonitrile into a second reactor containing the precursor CTT1298 in solution.

[0156] Manufacturing of [18F]CTT1057 drug substance [ 18 F]CTT1057 is a prosthetic group containing 18 F]SFB and the precursor CTT1298.

[0157] Coupling to CTT1298 - [18 [F]SFB is eluted from the HLB into a second reactor containing the CTT1298 solution. The reaction is carried out in the second reactor at 40° C. for 12 min.

[0158] CTT1057 Purification - The crude product is diluted with water and a two-step purification process induces separation of by-products and residual reagents. The diluted crude product is passed through a QMA cartridge to waste. 18 [F]CTT1057 remains in the QMA along with other undesirable species. The QMA is rinsed into waste with a solution of 0.09% NaCl / 20% EtOH and [ 18 F]CTT1057 was eluted with 20 mM phosphate buffer at pH 2.0 and recaptured in HLB in a time-controlled step to obtain [ 18 F]CTT1057 degradation.

[0159] CTT1057 Formulation - Pure and finally formulated [ 18 [F]CTT1057 is dissolved, neutralized, and formulated from the HLB in one single step with 5% ethanol in phosphate buffered saline solution blending solution at pH 7.4.

[0160] Manufacturing process development drug substance[ 18 F]CTT1057 has the prosthetic group [ 18 A one-step reaction between [F]SFB and the chemical precursor CTT1298 was developed. To ensure an efficient conversion reaction, non-radioactive [ 19 Using [F]SFB and CTT1298, several coupling reaction conditions were tested: pH ranging from 7 to 11, temperatures from approximately 25 °C to 60 °C, and different buffered media over a period of 5 to 10 min.

[0161] The final adjustment of the reaction time is done to have actual concentration conditions and to take into account the balance of reaction time vs. decay. 18 F]CTT1057 was produced and optimized.

[0162] [ 18The final purification step of [F]CTT1057 was key to deliver the product in adequate purity: the reaction crude was diluted in a basic medium and first purified on a QMA (quaternary methylammonium) cartridge, which allows the removal of most of the radiochemical impurities.

[0163] However, the saline-purified [ 18 Elution of [F]CTT1057 demonstrated the presence of abundant chemical precursor CTT1298.

[0164] therefore,[ 18 Separation of CTT1298 from [F]CTT1057 is difficult due to the similarity of the two molecules. 18 F]CTT1057. The small difference in polarity due to the aromatic ring was focused on. This method allows selective retention of the final product using HLB cartridges. 18 [F]Final dissolution and formulation of CTT1057 drug substance was optimized in one step using a phosphate-buffered saline solution containing 5% ethanol.

[0165] Preparation of solutions for injection The drug was prepared by adjusting the volume activity of the final solution to 370MBq / mL ± 10% (Tc) in NaCl 0.9% [ 18 F]CTT1057 concentrated mother liquor diluted solution (radioactive drug substance, 15 ± 1 mL). The volume of saline added is the volume obtained at the end of the synthesis (Tm) [ 18 The activity of [F]CTT1057 is calculated according to its decay corrected for the time of calibration (Tc). The final volumes of the drug products range from 15 to 59 mL, therefore, [ 18 The quantitative composition of the [F]CTT1057 final products varies.

[0166] The qualitative and quantitative composition of the drug in standard volumes of 15 mL and 59 mL is given in Table 2.

[0167] [Table 2]

[0168] drug substance([ 18 Synthesis of CTT1057 and its use as a pharmaceutical agent ([F]CTT1057) 18 [F]Formulation of CTT1057 into a 370 MBq / mL injectable solution is part of an automated continuous process that includes the following steps:

[0169] Receiving step in the dispensing cell - the final formulation [ 18 [F]CTT1057 bulk concentrated mother liquor is transferred from the synthesis cell to the dispensing cell.

[0170] Measuring the weight and radioactivity of the mother liquor Weigh a 25mL vial. 18 The net weight of the F]CTT1057 bulk concentrated mother liquor is defined as the difference in weight between the product vial and the empty vial. The activity contained in the vial is measured with a dose calibrator.

[0171] 18 Step for transferring F-CTT1057 solution - [ 18 F]CTT1057 bulk concentrated mother liquor is transferred from the 25 ml vial to an empty sterile mother vial.

[0172] Dilution step - [ 18 Place the mother vial containing the CTT1057 bulk concentrated mother liquor on the balance. Transfer a predetermined amount of NaCl 0.9% to the mother vial until the appropriate amount of NaCl is automatically added. At the calibration time Tc (Tc=T0+4h), the [ 18 Obtain [F]CTT1057 diluted mother liquor.

[0173] final 18 Homogenizing (mixing) the F-CTT1057 solution - Final [ 18 F]CTT1057 diluted mother liquor is mixed.

[0174] Final filtration and distribution of the final 15 ml vials - 18[F]CTT1057 diluted mother liquor is distributed using a semi-automated dispensing system.

[0175] The final [ 18 [F]CTT1057 diluted mother liquor is pumped through a sterile tube connected to a filter (used for final filtration) and a sterile needle fixed to the distribution automaton.

[0176] [Example 2] Clinical Trials Protocol Overview

[0177] [Table 3-1]

[0178] [Table 3-2]

[0179] [Table 3-3]

[0180] [Table 3-4]

[0181] [Table 3-5]

[0182] [Table 3-6]

[0183] [Table 3-7]

[0184] [Table 3-8]

[0185] research design This is a PET imaging agent for the detection and localization of PSMA-positive tumors in prostate cancer patients diagnosed with biochemical recurrence (BCR) after radical prostatectomy or radiotherapy, using a composite true standard as the criterion. 18 This is a prospective, open-label, multicenter, single-arm phase 3 study evaluating the diagnostic performance of F]CTT1057.

[0186] Approximately 190 participants were enrolled, with at least 152 participants receiving PET / CT scan imaging. 18 F]CTT1057 will be read out at a central contract research organization (CRO) by three independent nuclear medicine physicians who will ensure completion but will be blinded to any other patient data.

[0187] The CTS used as a reference is hierarchical in nature with a three-level SoT procedure, which applies as follows:

[0188] Level 1) Histopathology, if available ([ 18 F] From a prospective biopsy or salvage procedure performed within 8 weeks following CTT1057 PET / CT scan); or if histopathology is not available, indeterminate or negative:

[0189] Level 2) [ 18 At least a high-resolution CT scan with contrast performed within 8 weeks (either before or after) of the [F]CTT1057 PET / CT scan 68 Imaging diagnostic procedures performed in each patient clinically indicated per SoC should include [Ga]Ga-PSMA-11 PET / CT. Three-month follow-up imaging (from baseline) should also be used as part of CTS Level 2 if clinically indicated for the diagnosis of specific lesions; or if neither of the above two are feasible or considered appropriate:

[0190] Level 3) ≤50% decline in PSA following radiotherapy (unless concomitant androgen deprivation therapy (ADT) is given) per PCWG3 criteria (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).

[0191] If pathology is available, evaluation by a local pathologist will be performed at every SoC and results must be available within 2 weeks after surgery. The pathologist will be blinded to any PSMA-PET data (i.e., both PET / CT scans). In this case, only pathology will be used as the SoT, so the imaging procedure will not be used in the calculation of the coprimary endpoint.

[0192] If pathology is not available, a central readout of the imaging diagnostic procedure performed on each participant for CTS level 2) will be used as the true standard for calculation of the co-primary endpoints.

[0193] All patients were assessed for CTS level 2 (if required as the true standard) and for detection of lesions at the patient level [ 18 F]CTT1057 and [ 68 As part of the study, both secondary endpoints of concordance between [Ga]Ga-PSMA-11 and [ 68 Ga]Ga-PSMA-11 PET / CT.

[0194] In addition to the core rethinking, the SoC image ([ 68 [Ga]Ga-PSMA-11) to be used by the treating physician / investigator for patient management decisions and global evaluation.

[0195] The planned patient management questionnaire was 18 F] To be completed by the treating physician / investigator prior to learning the results of the CTT1057 PET / CT scan (Questionnaire 1) and within 14 days after learning the results (Questionnaire 2). 18 F]Local review of the CTT1057 PET / CT images will also be performed by a local nuclear medicine physician or radiologist with expertise in reading oncology PET / CT scans and the results will be provided to the treating physician / investigator upon completion of Questionnaire 2. Options will be given in the questionnaire to capture available management plans such as a) Surgery, b) Radiation alone, c) Radiation and ADT, d) ADT alone, e) Observation / Monitoring, f) Other (free text box). Any changes in the patient management plan between Questionnaire 1 and Questionnaire 2 will be considered as a randomized controlled trial as this is an investigational diagnostic imaging product. 18 F]CTT1057 should not be based solely on PET / CT scan results. Other diagnostic procedures must be performed for each SoC to confirm and implement a modified management plan.

[0196] Screening Period A written informed consent form (ICF) must be obtained prior to any screening procedures. Participants must be enrolled in the Interactive Response Technology (IRT) for screening. All procedures outlined in the assessment schedule must be performed and testing and imaging assessments must be prioritized to allow time for results to be obtained at least 14 days before the first planned PET imaging date (Day 1). Eligibility must then be confirmed no later than Day -14. The screening period must last a maximum of 28 days.

[0197] Once eligibility is confirmed, participants will be randomized to IRT and assigned in a 1:1 ratio to one of the following two PET / CT scan sequences:

[0198] Sequence 1: Day 1 18F]CTT1057 (the investigational contrast agent of interest) followed by at least 14 days apart [ 68 1)Ga]Ga-PSMA-11 (as part of CTS, if necessary, for secondary endpoints)

[0199] Sequence 2: Day 1 68 Ga]Ga-PSMA-11 (as part of CTS, if necessary, for secondary endpoints) followed by at least 14 days apart [ 18 F]CTT1057 (the investigational contrast agent of interest)

[0200] PET imaging date The two PET imaging procedures are performed at least 14 days apart. The day of the first PET contrast injection is considered study day 1.

[0201] research design [ 18 Core reading of the F]CTT1057 PET / CT scans will be performed by three independent nuclear medicine physicians or radiologists with experience in PET reading who are blinded to patient data including patient clinical status, histopathology / biopsy results, conventional imaging and PSA level results. Patients and regions will be graded by each reader on a two-point scale (0=negative, 1=positive). Results from the three PET readers will be compared individually for SoT to generate a reader-specific performance. An individual PET reader will be considered successful if it meets pre-specified thresholds for both co-primary endpoints, and at least two of the three readers must be successful for overall study positivity.

[0202] The criteria that should be applied for a positive PET result are as follows: Patients are considered positive if at least one lesion in any area is visibly positive (i.e., prostate bed, pelvic lymph nodes (PLNs), skeleton, and other distant sites (extrapelvic lymph nodes and viscera)). A region is considered positive if at least one lesion in the region is visibly positive. Visible PET-positive lymph nodes are considered superior to blood pools (adjacent or mediastinal blood pools). PET-positive bone lesions appear to be superior to physiological bone marrow.

[0203] PET-positive prostate, prostate bed, and visceral lesions are considered superior to physiological background activity of the involved organ or anatomical site, as previously described (Eiber et al. 2015 Evaluation of Hybrid 63 Ga-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).

[0204] Consistency in the interpretation of PET scans, both between different readers and within a reader, is a significant challenge in medical imaging, as it can affect the inter-institutional operability of results and thus patient care. 18 The degree of inter- and intra-reader variability in the qualitative assessment of [F]CTT1057 PET / CT images was evaluated as a secondary endpoint to ensure consistency of interpretation, and therefore reliable diagnosis, which has a central role in patient management.

[0205] All patients underwent two PET / CT scans: 18 F]CTT1057 PET / CT scan (investigational contrast agent) and 68 Ga]Ga-PSMA-11 PET / CT scan (as part of CTS level 2 if indicated and for detection of lesions at the patient level) 18 F]CTT1057 and [ 68 The secondary endpoint of evaluation of concordance between [Ga]Ga-PSMA-11 and [Ga+]Ga-PSMA-11 will be studied. The two scans will be performed at least 2 weeks apart for each participant to ensure clear safety profile evaluation for the radiopharmaceutical of each PET imaging. Furthermore, to counterbalance any potential changes in lesions between the two PET / CT scans, each patient's PET / CT scan sequence will be randomly assigned in a 1:1 ratio after enrollment.

[0206] Rationale for dose / regimen and duration of treatment For PET diagnostic radiopharmaceuticals, only a single dose is required, usually intravenously. Therefore, investigational PET radiopharmaceuticals [ 18[F]CTT1057 is administered as a single intravenous (iv) dose of approximately 370 MBq (range 266 to 407 MBq). This dose was shown to be safe and well tolerated in a 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 is in line with the recommended dose of commercially available [18F]FDG according to both the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine guidelines (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; 42:328-54). Human dosimetry was studied in a Phase 1 trial.The effective dose was estimated to be 0.023 ± 0.007 mSv / MBq, which is in line with the effective dose of commercially available [18F]FDG according to the EANM guidelines (0.019 mSv / MBq) (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 publications (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), as well as with the effective dose of other PSMA PET agents (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 iv administration of 370MBq of [18F]CTT1057 is 8.51mSV.Furthermore, this dose yielded optimal image quality, graded at 76 ± 5.4 on a visual analog scale (VAS) of 1 to 100 (1 = nondiagnostic, 100 = complete study) by two experienced nuclear medicine physicians (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).

[0207] Risks and Benefits The use of PSMA-PET scanning in prostate cancer participants to assess disease burden in both the setting of biochemical recurrence (BCR) and progressive / metastatic disease has been largely [ 68 [Ga]Ga-PSMA-11, which has been ongoing since 2011. Publications reporting clinical use have shown better sensitivity and specificity than cholinergic PET imaging for PCa, with very low adverse event rates. 68 [Ga]Ga-PSMA-11 has been shown to be well tolerated with no adverse events following infusion in a retrospective analysis of 1007 participants (Afshar-Oromieh A, Avtzi E, Giesel FL, et al (2015) The diagnostic value of PET / CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging; 42:197-209). Recently, [ 68 Ga]Ga-PSMA-11 is a candidate for early definitive therapy in patients with suspected metastasis or with serum PSA levels ([ 68It has been approved in the United States (December 2020) as a radioactive diagnostic PET imaging agent in men with prostate cancer suspected of recurrence based on elevated [Ga]Ga-PSMA-11 USPI). Other PSMA-PET agents have since been investigated and are under clinical development, all of which show favorable safety and tolerability profiles. Prostate cancer patients diagnosed with localized disease at primary staging are enrolled in a study requiring histopathologic comparison to determine the diagnostic yield of the technique. A randomized controlled trial was conducted in 20 prostate cancer patients (n=5 primary staging, n=15 mCRPC (NCT02916537)). 18 Phase 1 studies of [F]CTT1057 have demonstrated an acceptable safety profile without any radiotracer-related adverse reactions. 18 The biodistribution of [F]CTT1057 was similar to that of other PSMA-targeting agents, 18 The exposure rates of [F]CTT1057 are also similar to those of urea-based PET compounds, with the exception of lower exposure to the kidneys and salivary glands. 18 Preclinical studies, dosimetry studies, and clinical experience with [F]CTT1057 suggest good image quality characteristics and a favorable safety profile (Behr SC, Aggarwal R, VanBrocklin HF, et al (2019) Phase I Study of CTT1057, an 18 F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer. J Nucl Med; 60(7):910-6).

[0208] Because this is a study of the diagnostic performance of an investigational PET agent, enrolled patients are not expected to derive any direct benefit. It is hoped that distant disease will be identified in some patients as a result of this study, and that these patients may benefit from a more appropriate management plan not based on the investigational procedure alone, but confirmed by the SoC diagnostic procedure. The risk-benefit ratio is [ 18It is expected that the [F]CTT1057 imaging agent will be preferred.

[0209] Any risk to participants in this trial will be minimized by compliance with the eligibility criteria and study procedures, as well as close clinical monitoring. Appropriate eligibility criteria will be included in this protocol.

[0210] Investigational and control drugs Description and composition Pharmaceuticals 18 F]CTT1057 370MBq / mL solution for injection has a volume activity of 370MBq / mL at baseline and time (calibration time) and is 18 It is a sterile, ready-to-use, multi-dose solution containing [F]CTT1057. The natural decay of the radionuclide results in a continuing decrease in the specific activity, total radioactivity, and radioactivity concentration of the pharmaceutical over time.

[0211] The radioactive drug substance is prepared as a concentrated aqueous solution (so-called mother liquor) in an automated continuous process using fluorine( 18 F) A labeled PSMA agent [ 18 F]CTT1057. Departure 18 Taking into account the F activity, the obtained radiochemical yield, and the targeted radioactivity concentration of 370 MBq / mL at the calibration time, the mother liquor is further diluted to a ready-to-use injection solution of the final product [18F]CTT1057. The composition of the final product is shown in Table 2 below.

[0212] [Table 4]

[0213] NOTE: NaCl and WFI are components of NaCl 0.9% solution for injection, and NaH2PO4 is used as the hydrated salt form.

[0214] Storage conditions Store below 25° C. The shelf life is 10 hours after T0 (T0: time of activity measurement of the first quality control vial). 10 hours after T0 is the calibration time [Tc ] 6 hours later (T c =T 0+4h ).

[0215] PET contrast agents for clinical trials

[0216] [Table 5]

[0217] [ 18 The [F]CTT1057 radiopharmaceutical is administered intravenously at a dose of approximately 370 MBq (range 266-407 MBq).

[0218] [ 68 The [Ga]Ga-PSMA-11 radiopharmaceutical is administered as a single intravenous (iv) dose of approximately 150 MBq. The administered dose should in any case be no lower than 111 MBq or higher than 185 MBq. The exact dose administered to each patient is recorded on the CRF after measuring the syringe both before and after administration with a dose calibrator.

[0219] Investigational contrast agent [ 18 F]CTT1057 is provided as follows: As a ready-to-use radiopharmaceutical injection solution in a single single-dose syringe (for the US) or a single multi-dose vial (for Europe (EU)) with a volume activity of 370 (±10%) MBq / mL at the reference date and time (calibration time (Tc)).

[0220] Natural decay of the radionuclide results in a continuous decrease in specific activity, total radioactivity, and radioactivity concentration (volumetric activity) over time. Therefore, the volume of the injected solution is varied to provide the required amount of radioactivity on the day and time of injection.

[0221] component[ 68 Ga]Ga-PSMA-11 is provided as follows: As a kit for the preparation of radiopharmaceuticals: Approved 68 Ge / 68Gallium chloride-68( 68 A single vial containing a white lyophilized powder to be locally reconstituted with a solution of GaCl3 (approved 68 Ge / 68 for clinical sites equipped with Ga generators). As a single-dose ready-to-use radiopharmaceutical solution: vials or syringes containing the radiopharmaceutical solution provided by Partners Radiopharmacy (approved 68 Ge / 68 (for clinical sites not equipped with Ga generators).

[0222] Equivalent to the administered radioactive dose [ 68 The volume of the [Ga]Ga-PSMA-11 injection solution is calculated according to the estimated time of injection based on the current activity and physical decay of the radionuclide produced by the generator (half-life = 68 min). After reconstitution, [ 68 The 1,2-Dimethylpyrrolidin-2-(Ga)-PSMA-11 solution can be used according to the instructions provided in the pharmacy manual.

Claims

1. 1. A radioligand imaging agent for use in a diagnostic method for determining the presence and / or localization of a PSMA positive tumor in a subject, particularly wherein said subject has prostate cancer, said PSMA positive tumor is prostate cancer, said subject has been diagnosed with biochemical recurrence, particularly wherein said biochemical recurrence is following radical prostatectomy or radiation therapy, said radioligand imaging agent comprising a phosphoramidate group and [ １８ F]-A radioligand imaging agent that is a PSMA binding compound that contains a fluoro group.

2. The agent has the formula (I): 【Chemistry 1】 [In the formula, each R is independently hydrogen or a protecting group, preferably t-butyl or benzyl; each R2 is independently hydrogen or C1-C6 alkyl; R3 is each [ １８ F]-fluoro group, and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro; L1 is a linker preferably comprising one or more groups selected from one or more amino acids, C1-C18 alkylene, and heteroalkylene containing 1-35 carbon atoms and 1-15 heteroatoms, said heteroalkylene being optionally substituted with one or more substituents selected from oxo and C1-C6 alkyl, more preferably L1 is a linker selected from 1-6 amino acids. or any pharma- ceutically acceptable salt thereof.

3. Formula (II): 【Chemistry 2】 [In the formula, L is a group of the formula -NH-CH ２ CH ２ - (OCH ２ CH ２ -) y-C(O)- moiety, or the formula 【Chemistry 3】 wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 1, 2, 3, or 4; Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. is a linker comprising the group R1 is each [ １８ F]-fluoro group, and optionally substituted with a second group selected from the group consisting of halo, cyano, and nitro, is phenyl or pyridyl; Each R2 is independently hydrogen or C1-C6 alkyl; each R is independently hydrogen or a protecting group (e.g., t-butyl or benzyl); However, L is a group represented by the formula 【Chemistry 4】 When the group The combination of m and n results in a linear linker length of 3 to 21 atoms.

2. The radioligand imaging agent for use according to claim 1, which is a PSMA binding compound of the formula:

4. Formula (III): 【Chemistry 5】 or any pharma- ceutically acceptable salt thereof.

5. 2. The radioligand imaging agent for use according to claim 1, wherein the subject has been diagnosed with biochemical recurrence following radical prostatectomy or radiation therapy.

6. 2. A radioligand contrast agent for use according to claim 1, formulated as an injection or infusion solution in a concentration that provides a volumetric radioactivity of 150-1000 MBq / mL, for example 370 MBq / mL±10%, at a calibration time.

7. A radioligand imaging agent for use according to claim 1, administered intravenously in an effective dose comprised between 250 and 450 MBq, typically around 370 MBq.

8. 7. The radioligand imaging agent for use according to claim 6, wherein the first PET scan of the subject is performed between 60 and 120 minutes after injection and optionally the second scan is performed up to 180 minutes after injection.

9. The method further comprising: [i] administering to the subject an effective dose of the radioligand imaging agent according to any one of claims 1 to 8; [ii] imaging the subject by either a PET scan, a PET / CT or a PET / MRI scan; [iii] analyzing images obtained from the PET scan; and [iv] determining the presence and / or localization of a PSMA-positive tumor in the subject.

9. A radioligand contrast agent for use according to any one of claims 1 to 8, comprising:

10. 6. A solution for injection or infusion which is an aqueous solution comprising the radioligand contrast agent according to any one of claims 1 to 5 at a concentration resulting in a volumetric activity of between 150 and 1000 MBq / mL, for example about 370 MBq / mL, and one or more pharma- ceutically acceptable excipients.

11. Formula (IV) 【Chemistry 6】 11. The solution of claim 10, wherein the precursor compound of is present at a concentration of 5.0 μg / mL or less, preferably 4.0 μg / mL or less, more preferably 3.0 μg / mL or less, even more preferably 2.0 μg / mL or less, and even more preferably 1.0 μg / mL or less.

12. 11. The solution according to claim 10, further comprising a buffer for a pH between 5.0 and 8.0, preferably 6.0 and 8.0, more preferably 6.5 and 7.5, and an isotonicity agent, preferably sodium chloride, preferably said buffer is a phosphate buffer.

13. 11. The solution according to claim 10, further comprising a stabilizer against radiolysis, preferably a stabilizer suitable as an eluent during preparation of said solution, preferably said stabilizer and / or eluent is an alcohol, preferably ethanol.

14. [i] NaCl, at a concentration of 8.0 to 9.5 mg / mL; preferably 8.6 to 8.9 mg / mL; [ii] NaH at a concentration of 0.03 to 0.3 mg / mL; preferably 0.1 to 0.2 mg / mL ２ P.O. ４ , [iii] Na, at a concentration of 0.2 to 1.2 mg / mL; preferably 0.3 to 1.1 mg / mL. ２ H.P.O. ４ , [iv] ethanol, at a concentration of 5 to 50 mg / mL; preferably 10.0 to 39.5 mg / mL; and [v] the precursor compound at a concentration of 5.0 μg / mL or less, preferably 4.0 μg / mL or less, more preferably 3.0 μg / mL or less, even more preferably 2.0 μg / mL or less, even more preferably 1.0 μg / mL or less; 14. The solution of claim 13 comprising:

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