Prostate-specific membrane antigen (PSMA) radiolabeling inhibitors [ 18 Improved synthesis of F]DCFPYL

Abstract

This document provides methods and related compositions, including kits, for improving […]. 18 The synthesis, preparation, and / or storage of F]DCFPyL are also provided. [The use of [...] 18 The F]DCFPyL method, for example, is used for imaging.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application Nos. 63 / 508,673, filed June 16, 2023; 63 / 514,480, filed July 19, 2023; and 63 / 514,485, filed July 19, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Prostate cancer is the most common cancer among men and one of the most prevalent cancers worldwide, with an estimated more than one million new cases and 307,000 deaths annually (Mauer et al., 2016). In the United States alone, well over 200,000 new cases are diagnosed each year (Seigel et al., 2014). Partly due to serological diagnostic testing for prostate-specific antigen (PSA) expression in developing prostate cancer, with appropriate diagnosis and treatment, the 5-year survival rate is close to 99% (seer.cancer.gov).

[0004] With increasing frequency, appropriate diagnostic and therapeutic monitoring includes non-invasive molecular imaging. Several radiotracers have been developed for prostate-specific membrane antigen (PSMA) PET imaging in prostate cancer, including 18F-FACBC (fluciclovine), Ga68 PSMA-11, and DCFPyL. The successful use of DCFPyL (Chen et al., 2011; Szabo et al., 2015) and its favorable distribution and imaging characteristics compared to other PSMA-targeting radiotracers (Dietlein et al., 2015) have led to increased demand for this radiotracer. Summary of the Invention

[0005] This article provides methods for improvement. 18 Methods and related compositions for the synthesis, purification, and / or storage of F]DCFPyL (also referred to herein as PyL or PYLARIFY). In one aspect, this disclosure provides any of the methods provided herein.

[0006] In another aspect, this disclosure provides any of the compositions (including kits) as described herein, such as those comprising ascorbic acid and […]. 18 F]DCFPyL (or used to prepare [ 18Compositions of reagents of F]DCFPyL and / or compositions produced by any of the methods described herein.

[0007] In another aspect, this disclosure provides a method for applying any of the compositions described herein to an object in need of such application.

[0008] In another aspect, this disclosure provides methods for detecting 18 The method of F includes steps that are any of the methods provided herein, the method including the use of TEAF.

[0009] This disclosure also provides kits comprising any of the compositions described herein or any of the compositions produced by or used in any of the methods described herein.

[0010] definition

[0011] The term “determine” as used in this article generally refers to, for example, the quantitative or qualitative analysis of a molecule or a group of molecules or a signal or a group of signals, and / or the detection of the presence or absence of one or more molecules.

[0012] As used in this article, the term "diagnostic imaging" refers to the steps used to detect imaging agents that can be used to diagnose symptoms, diseases, and / or disorders.

[0013] As used in this article, the term “diagnosis” encompasses the identification, confirmation, assessment, and / or characterization of a condition, disease, and / or disorder.

[0014] A “kit” contains one or more containers (e.g., vials) of components or a collection of components that can be used by a practicing end-user in a clinical or pharmacy setting. The kits provided herein can be used to synthesize radiopharmaceuticals, such as those for diagnostic purposes. Therefore, practicing end-users in a clinical or pharmacy setting can use the kits to synthesize and / or use radiopharmaceuticals in diagnostics. In some embodiments, the kit may provide all the necessary components for synthesizing and / or using radiopharmaceuticals, in addition to those components typically available to the practicing end-user (e.g., water for injection or saline, radioisotopes, etc.). 18 F) Equipment for handling the kit during the synthesis and handling of the radiopharmaceutical (if necessary), and equipment required for administering the radiopharmaceutical to the subject, such as syringes, shielding, imaging equipment, etc. In some embodiments, the imaging agent may be provided to the end user in its final form, typically in a formulation such as, for example, an aqueous solution contained in one or more containers (e.g., vials or one or more syringes). Thus, in one embodiment, the kit may contain the reagent in its final form.

[0015] In this article, "a part of an object" refers to a specific region of the object, the location of the object, etc. For example, a part of an object could be the brain, heart, vascular system, coronary blood vessels, tumor, etc.

[0016] As used herein, the term "object" refers to a human or non-human mammal or animal. Non-human mammals include livestock, companion animals, laboratory animals, and non-human primates. Non-human objects also specifically include, but are not limited to, horses, cattle, pigs, goats, dogs, cats, mice, rats, guinea pigs, gerbils, hamsters, minks, and rabbits. In some embodiments of the invention, the object is referred to as a "patient." In some embodiments, the patient or object may be under the care of a physician or other healthcare professional (including, but not limited to, those who have consulted a physician or other healthcare professional, received advice from a physician or other healthcare professional, or received prescriptions or other recommendations from a physician or other healthcare professional).

[0017] Any compound described herein may be in various forms, such as, but not limited to, salts, solvates, hydrates, tautomers, and isomers. In some embodiments, the imaging agent is a pharmaceutically acceptable salt of an imaging agent. As used herein, the term "pharmaceutically acceptable salt" means those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, a description which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases, as well as organic acids and bases. Some examples of pharmaceutically usable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or amino salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using anti-charge ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0018] "Pharmaceutical-grade carrier" refers to a biocompatible solution, taking into account sterility, p[Eta], isotonility, stability, etc., and may contain any and all solvents, diluents (including sterile saline, sodium chloride injection, Ringer's injection, dextran injection, dextran and sodium chloride injection, lactated Ringer's injection, and other aqueous buffer solutions), dispersion media, coatings, antibacterial and antifungal agents, isotonics, etc. Pharmaceutical-grade carriers may also contain stabilizers, preservatives, antioxidants, or other additives known to those skilled in the art, or other carriers known in the art.

[0019] In some embodiments, the compound is in the form of a hydrate or a solvate. As used herein, the term "hydrate" refers to a compound that is non-covalently associated with one or more molecules of water. Similarly, the term "solvate" refers to a compound that is non-covalently associated with one or more molecules of an organic solvent.

[0020] The term "about" as used herein with respect to a value or parameter refers to a typical range of error for the corresponding value or parameter that is readily known to those skilled in the art. The term "about" as used herein includes (and describes) aspects relating to the value or parameter itself. For example, a description of "about X" includes a description of "X". In one embodiment of any of the compositions or methods provided herein, "about" refers to a value or parameter and is ±10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment of any of the compositions or methods provided herein, any quantity described herein may refer to a quantity alone and without the term "about". Attached Figure Description

[0021] Figure 1 It shows [ 18 Synthesis method of F]DCFPyL.

[0022] Figure 2 It shows [ 18 F]DCFPyL and free 18 Chromatogram of impurities decomposed by F radiation.

[0023] Figure 3 5 µCi doped with TEAF (44 mg / mL) was shown. 18 Chromatogram of F.

[0024] Figure 4 This shows the free form in the presence of ethanol. 18 The formation of F.

[0025] Figure 5The HPLC radiodetector traces of samples with or without TEAF dopant are shown.

[0026] Figure 6 The HPLC radiodetector trace of the sample in 35% ethanol in saline is shown.

[0027] Figure 7 The presence of 20% ethanol in brine was shown to facilitate the free flow of... 18 F's [ 18 The concentration-dependent formation of F]DCFPyL.

[0028] Figure 8 The results show the concentration of ascorbic acid at 100 mg / mL (pH 2). 18 HPLC radiodetector traces of the T0 and T4 hours samples of F]DCFPyL.

[0029] Figure 9 The results show the concentration of ascorbic acid at 50 mg / mL (pH 5.8). 18 HPLC radiodetector traces of the T0 and T4 hours samples of F]DCFPyL.

[0030] Figure 10 This shows the free form in the presence of ascorbic acid. 18 F's [ 18 The concentration-dependent formation of F]DCFPyL.

[0031] Figure 11 This shows the free form in the presence of sodium ascorbate. 18 F's [ 18 The concentration-dependent formation of F]DCFPyL.

[0032] Figure 12 It shows [ 18 F]DCFPyL drug product manufacturing method.

[0033] Figure 13 A list of AIO reagents and a diagram showing the location of the reagents are provided.

[0034] Figure 14 A flowchart indicating the different points where ascorbic acid is introduced is shown.

[0035] Figure 15 The figure of 110 mCi / mL in ascorbic acid at 50 mg / mL and pH 5.8 is shown. 18 F]DCFPyL 147mCi / mL [ 18 Radiochromatogram of F]DCFPyL radiolysis at T=0 hours.

[0036] Figure 16 The graph shows the RCP versus time for batches 220816PyL, 220817PyL, and 220818PyL.

[0037] Figure 17 The following are examples of batches 220816PyL, 220817PyL, and 220818PyL. 18 A graph showing the formation of F over time.

[0038] Figure 18 The graph shows the peak formation versus time for batches 220816PyL, 220817PyL, and 220818PyL at a retention time of 6.0 minutes.

[0039] Figure 19 The graph shows the peak formation versus time for batches 220816PyL, 220817PyL, and 220818PyL at a retention time of 9.8 minutes.

[0040] Figure 20 The graph shows the peak formation versus time for batches 220816PyL, 220817PyL, and 220818PyL at a retention time of 10.6 minutes.

[0041] Figure 21 The images show batches 220816PyL, 220817PyL, and 220818PyL containing only... 18 A graph of RCP calculated from F degradation products versus time.

[0042] Figure 22 The following is an example of preparations using 5.0 mg / mL ascorbic acid at pH 6 in saline. 18 A representative radiochemical chromatogram of F]DCFPyL.

[0043] Figure 23 The radiochemical chromatogram of batch 220908PyL is shown; the peak cut purified from semi-preparative HPLC was delivered to a collection vial in a SWFI, and then to an FPV containing 0.9% saline, ready for analysis without further processing (166 mCi / mL).

[0044] Figure 24 The radiochemical chromatogram of batch 220909PyL at T=4 hours is shown; 5 mg / mL, pH 6 ascorbic acid in the collection vial and 10 mg / mL, pH 6 ascorbic acid in 0.9% saline in the FPV are also shown.

[0045] Figure 25The radiochemical chromatogram of batch 220914PyL at T=4 hours is shown; 5 mg / mL, pH 2 ascorbic acid in SWFI in collection vials; 5 mg / mL, pH 6 ascorbic acid in saline vials; and 5 mg / mL, pH 6 ascorbic acid in 0.9% saline in FPV.

[0046] Figure 26 The following are radiochemical chromatograms of batch 220927PyL at T=4 hours are shown: 5 mg / mL ascorbic acid at pH 2 in the SWFI collection vial; and 10 mg / mL ascorbic acid at pH 6 in the 0.9% saline vial in the FPV vial.

[0047] Figure 27 The radiochemical chromatogram of batch 220928PyL at T=4 hours is shown; 5 mg / mL of SWFI, pH 2 ascorbic acid in collection vials and 10 mg / mL of ascorbic acid, pH 6 in saline vials are also shown.

[0048] Figure 28 It shows [ 18 Radiochemical chromatogram of F]DCFPyL (batch 221025PyL) at T=10 hours, produced with 10 mg / mL, pH 2 ascorbic acid in the collection vial and pre-loaded with 10 mg / mL, pH 5.5 ascorbic acid in the FPV.

[0049] Figure 29 It shows [ 18 Radiochemical chromatogram of F]DCFPyL (batch 221026PyL) at T=10 hours, produced with 10 mg / mL, pH 2 ascorbic acid in the collection vial and pre-loaded with 10 mg / mL, pH 4.5 ascorbic acid in the FPV.

[0050] Figure 30 It shows [ 18 F]DCFPyL (T=10-hour radiochemical chromatogram of batch 230124PyL, produced in a collection vial loaded with 10 mg / mL, pH 2 ascorbic acid and pre-loaded in an FPV with 10 mg / mL, pH 7.0 ascorbic acid).

[0051] Figure 31 It shows [ 18 Radiochemical chromatogram of F]DCFPyL (batch 230130PyL) at T=10 hours, produced with 10 mg / mL, pH 2 ascorbic acid in the collection vial and 6.6 mg / mL, pH 5.5 ascorbic acid preloaded in the FPV.

[0052] Figure 32 It shows [ 18 Radiochemical chromatogram of F]DCFPyL (batch 230131PyL) at T=10 hours, produced with 10 mg / mL, pH 2 ascorbic acid in the collection vial and 15.6 mg / mL, pH 5.5 ascorbic acid preloaded in the FPV.

[0053] Figure 33 The radiochemical chromatogram of batch 220908PyL is shown; the peak cut from the semi-preparative HPLC purification was delivered to the SWFI in the collection vial, and then to the FPV containing 0.9% saline for analysis without further processing (115 mCi / mL).

[0054] Figure 34 The UV impurity chromatogram for the development batch at T=6 hours is shown.

[0055] Figure 35 The chromatogram of UV impurities at T=5 days for the development batch is shown.

[0056] Figure 36 The generation of ascorbic acid impurity peaks over time is shown.

[0057] Figure 37 It shows the presence and absence of F 18 UV chromatogram of ascorbic acid matrix solution under certain conditions.

[0058] Figure 38 The UV-HPLC / MS chromatograms of the development batch are shown. The green highlighted area in the mass chromatogram represents the background subtraction range. The light blue highlighted area in the mass chromatogram represents the retention time range (3.6 to 3.9 minutes) of unknown impurities.

[0059] Figure 39 It shows 5 mg / mL ascorbic acid + F 18 UV-HPLC / MS chromatogram of solution at T=24 hours. The green highlighted area in the mass chromatogram represents the background subtraction range. The light blue highlighted area in the mass chromatogram represents the retention time range of unknown impurities (3.6 to 4.0 minutes).

[0060] Figure 40 The instructions are shown in [ 18 Flowcharts illustrating examples of different points where ascorbic acid can be introduced in F]-DCFPyL ascorbic acid formulations. Detailed Implementation

[0061] [ 18F]DCFPyL (as shown in the figure below) has been found to be a powerful imaging agent for assessing cancers such as prostate cancer. However, generally speaking, the upper limit of radioactivity concentration at the end of synthesis (EOS) is 80 mCi / mL. Products with higher radioactivity concentrations (e.g., >80 mCi / mL at EOS) may be beneficial to improve drug supply and / or allow for larger doses per batch (batch size may be limited by the vial size of the maximum drug concentration product (e.g., 50 mL)) and / or improve storage. Additionally, the main observed radiodegradation product is free radioactive ions. 18 F, and through [ 18 The radiation of F]DCFPyL is formed. [ 18 It can also be beneficial to minimize the radiolysis at the same time.

[0062]

[0063] This article provides the generation of [ 18 Methods and related compositions for F]DCFPyL that provide higher radioactive concentrations and purity with minimal radiolysis. These methods and compositions help provide patients with better access to imaging agents and purer formulations for improved uses. The methods and related compositions presented herein include the use of ascorbic acid. Ascorbic acid is a buffer with a pKa of 4.2. However, for a particular radiopharmaceutical, the concentration and pH of the ascorbic acid-containing solution that produces the desired characteristics (e.g., maintaining purity at the desired radioactive concentration level) vary and are unique to that particular radiopharmaceutical.

[0064] This document provides compositions and methods, the methods comprising using ascorbic acid at specific concentrations and pH, for example in […]. 18 In the synthesis and / or storage of F]DCFPyL, a formulation can be produced that exhibits high purity maintained at high radioactive concentrations, along with other desired characteristics, which can be the result not only at the end of synthesis (EOS) in any embodiment of the methods or compositions provided herein, but also after synthesis (e.g., 10 hours after synthesis). Such characteristics are for [ 18 The availability and use of F]DCFPyL in imaging patients can be important.

[0065] Surprisingly, it was found that certain concentrations of ascorbic acid within certain pH ranges [ 18 This is particularly beneficial in the production of F]DCFPyL. The present invention generally relates to at least the preparation or synthesis of [ 18Methods for composing F]DCFPyL with ascorbic acid at such concentrations and within such pH ranges, and related compositions and methods. This disclosure advantageously provides methods utilizing ascorbic acid as a stabilizer. 18 F]DCFPyL formulation, which may have improved [ 18 The purity and radioactivity concentration of F]DCFPyL. Additionally, in some embodiments, the pH range can enhance the stability and shelf life of the composition, and can also minimize severe local site reactions after injection. In some embodiments, beneficial characteristics of formulations prepared using the methods provided herein have been found to [ 18 The synthesis of F]DCFPyL was observed at the end of the synthesis and after the synthesis (e.g., 10 hours after synthesis). Therefore, in some embodiments, ascorbic acid at the concentrations provided herein and within certain pH ranges can be […]. 18 The radiopharmaceutical composition of F]DCFPyL, when used as a stabilizer during preparation, transport, and / or storage, has yielded unexpectedly beneficial results.

[0066] Ascorbic acid is used as provided in this article [ 18 F]DCFPyL is a stabilizing component of radiopharmaceutical compositions. Ascorbic acid, also known as vitamin C, has been used as an antioxidant to prevent the radiodegradable degradation of certain radiopharmaceuticals (WO 95 / 33757; Anticancer Res. 1997, 17, 1783-1796; U.S. Patents 5,093,105 and 5,306,482) or radiolabeled peptides (U.S. Patents 5,393,512; 5,384,113 and 5,961,955). The term "ascorbic acid" as used herein includes ascorbic acid itself, as well as analogues and salts of the acid known to those skilled in the art. Ascorbic acid is an readily available FDA-inactive ingredient and can be used in pharmaceutical compositions and other formulations for biological purposes at levels up to 200 mg / mL in the final formulation. Previous compositions containing ascorbic acid were typically kept within a biological pH range (e.g., 6 to 8) throughout substantially all processing steps and during administration to the subject to reduce the risk of irritation and pain associated with acidic solutions. However, within the biological pH range, the ability of ascorbic acid / ascorbate buffer solutions to stabilize radiopharmaceutical solutions can be unexpectedly reduced.

[0067] Ascorbic acid, as described herein, has been found to be a highly effective protectant for PyL. It is important to note that different compounds can be protected differently by different protectants or stabilizers. Furthermore, for any given compound, the effective concentration and pH for a possible protectant can vary, including when combined with other components of the composition, such as ethanol. For example, ethanol in FDG can inhibit defluorination at very low concentrations (Dantas et al. 2012, Fawdry 2007), while in some other products, ethanol can remain stable in 100% EtoH or 50% ethanol (Scott 2009 AV 19). As another example, ascorbic acid stabilizes FDG to prevent defluorination, but only at 10 mg / mL can less than 2% be obtained over 10 hours (Fawdry 2007). Ascorbic acid exhibits pH-dependent inhibition of radiolysis (Castner et al., US9687571), therefore the amount of ascorbic acid required for radiation protection is both compound- and pH-dependent, and prior to the findings described herein, its application to PyL was unknown. Furthermore, impurities at levels described herein, detectable using HPLC, were also unknown or unrecognized.

[0068] The [disclosed in this article] 18 Some advantages of using ascorbic acid or its analogues in F]DCFPyL radiopharmaceutical compositions include: (1) the ability to prepare radiopharmaceutical compositions with a radioactive concentration of at least 80 mCi / mL; (2) the ability to prepare radiopharmaceutical compositions with a radiochemical purity of at least 90% 10 hours after synthesis; and / or (3) the ability to prepare radiopharmaceutical compositions with less than 5% free... 18 F. Radiopharmaceutical compositions. In some embodiments of any of the compositions or methods provided herein, ascorbic acid salts may be added to the formulation. In some embodiments of any of the compositions or methods provided herein, ascorbic acid may be used in an uncharged form or in a composition in which a higher percentage of the ascorbic acid is protonated at a suitable pH. Not bound by any particular theory, in some cases, the potency of an antioxidant may be directly related to the nonionic nature of the hydroxyl bonds in the antioxidant, exhibiting enhanced stability at acidity levels where the majority of the antioxidant is in a protonated form.

[0069] In any of this aspect and other aspects and embodiments of the invention, ascorbic acid may be present in an acidic form (e.g., as ascorbic acid) and / or a basic form (e.g., as ascorbate salt), depending on pH. For example, at pH values ​​greater than about 4.2 (i.e., the pKa of ascorbic acid), the basic form will be more prevalent than the acidic form. The higher the pH, the higher the proportion present in the basic form. Conversely, at pH values ​​less than about 4.2, the acidic form will be more prevalent than the basic form. The lower the pH, the higher the proportion present in the acidic form. Therefore, when the term ascorbic acid is used herein in conjunction with a composition, it should be understood that the composition may comprise ascorbic acid in an acidic form, ascorbic acid in a basic form, or a combination thereof.

[0070] In some embodiments of any of the methods or compositions provided herein, the basic form (i.e., ascorbate) may associate with the counter-charged ion. Those skilled in the art will recognize pharmaceutically acceptable salts suitable for association with ascorbate and use in the compositions described herein. Some non-limiting examples of pharmaceutically acceptable salts are described herein. In some cases of any of the methods or compositions provided herein, the counter-charged ion is sodium (e.g., such that the composition comprises sodium ascorbate).

[0071] In some embodiments of any of the methods or compositions provided herein, the radiopharmaceutical compositions provided herein may contain ascorbic acid as a stabilizer in the absence of other stabilizer compounds. In some embodiments of any of the methods or compositions provided herein, the radiopharmaceutical compositions provided herein may contain ascorbic acid as a stabilizer, and ethanol. In some of these embodiments, ethanol is maintained at any of the specific concentrations provided herein.

[0072] In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 8. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is from about 3 to about 8. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is from about 3 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is from about 3.3 to about 7.8. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 7.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4 to about 7.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 7.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5 to about 7.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 7. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4 to about 6.5.In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 6. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH is from about 5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH is any of the pH values ​​provided herein.

[0073] In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 2.5 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 3.0 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 3.5 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 4.0 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 4.5 to about 7.5. In some embodiments of any of the methods or compositions provided herein, the pH of the composition is about 5.0 to about 7.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.0 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.0 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.0 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 7.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.0 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.0 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.0 to about 6.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 6.5.In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.0 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.0 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.0 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.5 to about 6.0. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 2.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.0 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 3.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.0 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 4.5 to about 5.5. In some embodiments of the methods or compositions provided herein, the pH of the composition is from about 5.0 to about 5.5.

[0074] In any of the aforementioned pH embodiments, the pH is the pH of the solution in the collection vial (e.g., final collection vial, FCV). In any of the compositions or methods provided herein, the collection vial is performed after a semi-preparative process (e.g., semi-preparative HPLC) but before solvent exchange. As used herein, FCV refers to a collection containing a solution that has been prepared or synthesized. 18 The vial containing the solution of F]DCFPyL is such that the solution is considered to be the result of a preparation or synthesis method (e.g., the method provided herein). In one embodiment of any of the methods or compositions provided herein, the solution collected in the FCV is a solution that can be applied to the subject without further processing other than dilution. In one embodiment of any of the compositions or methods provided herein, the collection vial is a Final Product Vial (FPV). In one embodiment of any of the compositions or methods provided herein, the FPV is prepared for application after solvent exchange (e.g., Figure 13 ）。

[0075] In some embodiments of any of the methods or compositions provided herein, ascorbic acid is present at concentrations of about 2 mg / mL, about 2.5 mg / mL, about 3.3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, or about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 2.5 to about 7.5 mg / mL, about 3.5 to about 7.5 mg / mL, about 5 to about 7.5 mg / mL, about 2.5 to about 10 mg / mL, about 3.5 to about 10 mg / mL, about 5 to about 10 mg / mL, about 2.5 to about 15 mg / mL, about 3.5 to about 15 mg / mL, or about 5 to about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 2.5 to about 7.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 3 to about 7.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 3.0 to about 7.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 3.3 to about 7.8 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.0 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.0 to about 7.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 7 mg / mL.In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.0 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.0 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.0 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.5 to about 7 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.5 to about 7.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.0 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4 to about 6.5 mg / mL.In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.0 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.0 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.5 to about 6.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 6 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 6.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3 to about 6 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.0 to about 6.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 6 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 6.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4 to about 6 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.0 to about 6.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 6 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 6.0 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 5 to about 6 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 5.0 to about 6.0 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is about 5.5 to about 6 mg / mL.In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5.5 to about 6.0 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 2.5 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.0 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 3.5 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.0 to about 5.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 4.5 to about 5.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration of the composition is from about 5 to about 5.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is from about 5.0 to about 5.5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is any of the concentrations provided herein.

[0076] In one embodiment of any of the aforementioned ascorbic acid concentrations, the ascorbic acid concentration is the ascorbic acid concentration of the solution in the collection vial (e.g., FCV or FPV).

[0077] In one aspect, it involves the preparation of a mixture containing the following formula [ 18 Method for composing F]DCFPyL:

[0078] .

[0079] In one implementation, such a method includes sending to a container [ 18 F]DCFPyL's first solution is added to a second solution containing ascorbic acid to form [ 18 A third solution comprising [F]DCFPyL and ascorbic acid. The concentration and pH of the ascorbic acid in the second solution may be either of the concentrations and pHes provided herein. Alternatively, the concentration and pH of the ascorbic acid in the second solution may be such that the third solution has either of the concentrations and pHes provided herein. Alternatively, a solution comprising [18 Methods involving compositions containing [F]DCFPyL may include [ 18 The solution of F]DCFPyL is adjusted such that it has either the ascorbic acid concentration and pH provided herein. The resulting solution from any of the foregoing methods may be collected in or transferred to a collection vial (e.g., FCV or FPV). It has been found that specific concentrations of ascorbic acid and pH as provided herein produce […]. 18 Compositions of F]DCFPyL having one or more or all of the desired features provided herein.

[0080] In some embodiments, the solution is purified by chromatography before being added to the second solution or adjusted as provided herein. 18 F]DCFPyL (and any of the methods provided herein may also include such purification). In some embodiments of any of the methods or compositions provided herein, purification is not performed by chromatography before adding the first solution to the second solution or adjusting the solution. 18 F]DCFPyL.

[0081] In some embodiments of any of the methods or compositions provided herein, the solution (e.g., the first solution) further comprises a solvent, such as a solvent eluted from a column (e.g., an HLB column). 18 F]DCFPyL and / or ascorbic acid are substantially soluble in the solvent. In some embodiments of any of the methods or compositions provided herein, the composition comprises water. In some embodiments of any of the methods or compositions provided herein, the composition comprises water and at least one additional solvent, wherein the solvent is substantially miscible with water. Some non-limiting examples of solvents include, but are not limited to, alcohol solvents (e.g., ethanol, methanol, propanol, isopropanol, tert-butanol). Other non-limiting examples of solvents include acetone, acetic acid, formic acid, dimethyl sulfoxide, dimethylformamide, acetonitrile, glycol, triethylamine, methylpyridine, and pyridine. In some embodiments of any of the methods or compositions provided herein, the composition comprises water and a polar solvent that is substantially miscible with water.

[0082] In some embodiments of any of the methods or compositions provided herein, the solvent comprises ethanol. In some embodiments of any of the methods or compositions provided herein, for example when the solvent is eluted from or used to elute from a column (e.g., an HLB column), the solution comprises at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% ethanol (w / v). In some of the foregoing embodiments, the solution comprises 100% ethanol (w / v).

[0083] In some embodiments of the methods or compositions provided herein, for example when the solvent is in a collection vial (e.g., FCV or FPV), the solution contains less than or equal to about 30% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 25% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 20% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 15% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 10% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 5% ethanol (w / v). In some embodiments of the methods or compositions provided herein, the solution contains less than or equal to about 3% ethanol (w / v). In one embodiment of any of the foregoing, the solution contains at least 3% ethanol (w / v). In some embodiments of any of the methods or compositions provided herein, the solution contains any of the values ​​of ethanol (w / v) provided herein.

[0084] In some embodiments of any of the methods or compositions provided herein, the composition comprises acetonitrile. In some embodiments of any of the methods or compositions provided herein, such as in a solution in or transferred to a collection vial (e.g., FCV or FPV), acetonitrile is present at a level not exceeding about 0.05% (w / v), not exceeding about 0.04% (w / v), not exceeding about 0.03% (w / v), not exceeding about 0.02% (w / v), or not exceeding about 0.01% (w / v). In some embodiments of any of the methods or compositions provided herein, the solution comprises acetonitrile (w / v) at any value provided herein.

[0085] In some embodiments, any of the methods provided herein may include or may further include the steps of applying any of the solutions provided herein to a solvent exchange column and / or eluting from a solvent exchange column with any of the solutions provided herein. In one embodiment, any of the solutions having any of the ascorbic acid concentrations and pH values ​​provided herein are applied to a solvent exchange column, such as an HLB column. In another embodiment, […] 18 Any of the solutions of F]DCFPyL were adjusted to have any of the ascorbic acid concentrations and pH values ​​provided herein and then applied to a solvent exchange column.

[0086] In any of the foregoing embodiments, the concentration of ascorbic acid in the applied solution is or is adjusted to about 3 mg / mL to about 50 mg / mL, about 3 mg / mL to about 45 mg / mL, about 3 mg / mL to about 40 mg / mL, about 3 mg / mL to about 35 mg / mL, about 3 mg / mL to about 30 mg / mL, about 3 mg / mL to about 25 mg / mL, about 3 mg / mL to about 20 mg / mL, about 3 mg / mL to about 15 mg / mL, about 3 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the concentration of ascorbic acid is about 3.3 to about 7.8 mg / mL. In any of the foregoing embodiments, the concentration of ascorbic acid in the applied solution is or is adjusted to about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, about 25 mg / mL to about 50 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 50 mg / mL, about 40 mg / mL to about 50 mg / mL, or about 55 mg / mL to about 50 mg / mL. In any of the foregoing embodiments, the concentration of ascorbic acid in the applied solution is or is adjusted to about 5 mg / mL to about 45 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 35 mg / mL, or about 20 mg / mL to about 30 mg / mL. In any of the foregoing embodiments, the concentration of ascorbic acid in the applied solution is or is adjusted to about 5 mg / mL, about 8 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is about 2.5 to about 7.5, about 3.5 to about 7.5, about 5 to about 7.5, about 2.5 to about 10, about 3.5 to about 10, about 5 to about 10, about 2.5 to about 15, about 3.5 to about 15, or about 5 to about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is any value provided herein.

[0087] In any of the foregoing embodiments, the pH of the applied solution is or is adjusted to about 4 or lower, about 3.5 or lower, about 3 or lower, about 2.5 or lower, about 2 or lower, about 1.5 or lower, or about 1 or lower. In any of the foregoing embodiments, the pH of the applied solution is or is adjusted to about 1 to about 4, about 1.5 to about 4, about 2 to about 4, about 2.5 to about 4, about 3 to about 4, or about 3.5 to about 4. In any of the foregoing embodiments, the pH of the applied solution is or is adjusted to about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, or about 1 to about 1.5. In any of the foregoing embodiments, the pH of the applied solution is or is adjusted to about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, or about 1.5 to about 2. In some embodiments of the methods or compositions provided herein, any pH provided herein is used.

[0088] In any of the foregoing embodiments, the solution further comprises ethanol. In some embodiments, the solution comprises less than or equal to about 30% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 25% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 20% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 15% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 10% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 5% ethanol (w / v). In some embodiments, the solution comprises less than or equal to about 3% ethanol (w / v). In any of the foregoing embodiments, the solution comprises at least 3% ethanol (w / v). In some embodiments of any of the methods or compositions provided herein, the solution comprises any value of ethanol (w / v) provided herein.

[0089] In one implementation of any of the methods provided herein, the application may include [ 18 The solvent exchange column is then washed with a solution of F]DCFPyL. In one embodiment of any of the methods provided herein, [ 18 F]DCFPyL remains substantially on the solvent exchange column during washing. In one embodiment or any of the methods provided herein, the washing solution is any of the solutions provided herein with any of the ascorbic acid concentrations and pH values ​​provided herein.

[0090] In one embodiment of any of the methods provided herein, the method further includes eluting from the solvent exchange column with a solvent solution. 18[F]DCFPyL. In one embodiment or any of the methods provided herein, the solvent solution comprises an alcohol. In some embodiments, the solvent solution comprises ethanol in any of the amounts provided herein, for example, at least 90% ethanol (w / v). In some embodiments, the solvent solution comprises 100% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 30% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 25% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 20% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 15% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 10% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 5% ethanol (w / v). In some embodiments, the solvent solution comprises less than or equal to about 3% ethanol (w / v). In any of the foregoing embodiments, the solvent solution comprises at least 3% ethanol (w / v). In some embodiments of any of the methods or compositions provided herein, the solution contains any of the values ​​of ethanol (w / v) provided herein.

[0091] In one embodiment of any of the foregoing embodiments, the ascorbic acid concentration of the solvent solution is about 3 mg / mL to about 50 mg / mL, about 3 mg / mL to about 45 mg / mL, about 3 mg / mL to about 40 mg / mL, about 3 mg / mL to about 35 mg / mL, about 3 mg / mL to about 30 mg / mL, about 3 mg / mL to about 25 mg / mL, about 3 mg / mL to about 20 mg / mL, about 3 mg / mL to about 15 mg / mL, about 3 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 5 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is about 3.3 to about 7.8 mg / mL. In any of the foregoing embodiments, the ascorbic acid concentration of the solvent solution is about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, about 25 mg / mL to about 50 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 50 mg / mL, about 40 mg / mL to about 50 mg / mL, or about 55 mg / mL to about 50 mg / mL. In any of the foregoing embodiments, the ascorbic acid concentration of the solvent solution is about 5 mg / mL to about 45 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 35 mg / mL, or about 20 mg / mL to about 30 mg / mL. In any of the foregoing embodiments, the ascorbic acid concentration of the solvent solution is about 5 mg / mL, about 8 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is about 2.5 to about 7.5, about 3.5 to about 7.5, about 5 to about 7.5, about 2.5 to about 10, about 3.5 to about 10, about 5 to about 10, about 2.5 to about 15, about 3.5 to about 15, or about 5 to about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is any value provided herein. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is any value provided herein.

[0092] In one embodiment of any of the foregoing embodiments, the pH of the solvent solution is about 4 or lower, about 3.5 or lower, about 3 or lower, about 2.5 or lower, about 2 or lower, about 1.5 or lower, or about 1 or lower. In one embodiment of any of the foregoing embodiments, the pH of the solvent solution is about 1 to about 4, about 1.5 to about 4, about 2 to about 4, about 2.5 to about 4, about 3 to about 4, or about 3.5 to about 4. In one embodiment of any of the foregoing embodiments, the pH of the solvent solution is about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, or about 1 to about 1.5. In one embodiment of any of the foregoing embodiments, the pH of the solvent solution is about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, or about 1.5 to about 2. In some embodiments of any method or composition provided herein, the pH is any pH provided herein.

[0093] In one embodiment of any of the methods provided herein, the method further includes [ 18 The eluent of F]DCFPyL is collected in a collection vial (e.g., FCV or FPV). In one embodiment of any of the methods provided herein, the method further includes maintaining or adjusting the ascorbic acid concentration and pH of the collected solution to either of the ascorbic acid concentration and pH provided herein.

[0094] In some embodiments of any of the methods provided herein, the pH is maintained or adjusted to about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 3 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 4 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 7. In some embodiments, the pH is maintained or adjusted to about 3 to about 7. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 7. In some embodiments, the pH is maintained or adjusted to about 4 to about 7. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 7. In some embodiments, the pH is maintained or adjusted to about 5 to about 7. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 7. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 3 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 4 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 6. In some embodiments, the pH is maintained or adjusted to about 3 to about 6. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 6. In some embodiments, the pH is maintained or adjusted to about 4 to about 6. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 6. In some embodiments, the pH is maintained or adjusted to about 5 to about 6. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 6. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 3 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 4 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 5 to about 5.5.In some embodiments of any of the methods or compositions provided herein, pH is any of the pH values ​​provided herein.

[0095] In some embodiments of any of the methods provided herein, the pH is maintained or adjusted to about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 3.0 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 4.0 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 5.0 to about 7.5. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 3.0 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 4.0 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 5.0 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 7.0. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 3.0 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 4.0 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 5.0 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 6.5. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 3.0 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 4.0 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 4.5 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 5.0 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 5.5 to about 6.0. In some embodiments, the pH is maintained or adjusted to about 2.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 3.0 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 3.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 4.0 to about 5.5.In some embodiments, the pH is maintained or adjusted to about 4.5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 5.0 to about 5.5. In some embodiments of any of the methods or compositions provided herein, the pH is any of the pH values ​​provided herein.

[0096] In some embodiments of any of the methods provided herein, ascorbic acid is maintained or adjusted to about 2 mg / mL, about 2.5 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL. In some embodiments of any of the methods provided herein, ascorbic acid is maintained or adjusted to about 2 mg / mL, about 2.5 mg / mL, about 3.5 mg / mL, about 4.0 mg / mL, about 4.5 mg / mL, about 5.0 mg / mL, about 5.5 mg / mL, about 6.0 mg / mL, about 6.5 mg / mL, about 7.0 mg / mL, about 7.5 mg / mL, about 8.0 mg / mL, about 8.5 mg / mL, about 9.0 mg / mL, about 9.5 mg / mL, about 10 mg / mL, or about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.3 to about 7.8 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 7.5, about 3.5 to about 7.5, about 5 to about 7.5, about 2.5 to about 10, about 3.5 to about 10, about 5 to about 10, about 2.5 to about 15, about 3.5 to about 15, or about 5 to about 15 mg / mL. In some embodiments of any of the methods or compositions provided herein, the ascorbic acid concentration is any of the values ​​provided herein.

[0097] In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.0 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.0 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.0 to about 7.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.0 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.0 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 7.0 mg / mL.In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.0 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.5 to about 7 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.5 to about 7.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.0 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.0 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.0 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.5 to about 6.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.0 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 6 mg / mL.In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.0 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.0 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.5 to about 6 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.5 to about 6.0 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 2.5 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.0 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 3.5 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.0 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 4.5 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5 to about 5.5 mg / mL. In some embodiments of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to about 5.0 to about 5.5 mg / mL. In some embodiments of the methods or compositions provided herein, the ascorbic acid concentration is any of the values ​​provided herein.

[0098] Not wishing to be bound by theory, the exemplary methods provided in this paper can also be used to extract from [...] 18 Impurities and / or exchanges are removed from the composition of F]DCFPyL where [ 18 The solvent of F]DCFPyL allows for the formation of imaging or diagnostic compositions. For example, the solution can be, for instance, from [ 18 F]DCFPyL is obtained through purification (e.g., via HPLC or another purification method) and may contain solvents and / or impurities unsuitable for application to a target. Therefore, the methods provided herein can be used to remove impurities and / or exchange the solvent.

[0099] As another example, solutions of any of the methods or compositions provided herein may contain ascorbic acid, [ 18 F]DCFPyL and one or more solvents and / or impurities. In one embodiment of any of the methods provided herein, the solution may be applied to a solvent exchange column, wherein substantially [ 18 F]DCFPyL, and other components (e.g., solvents, such as acetonitrile and / or impurities) can be removed by elution (e.g., in a resin washing step). In one embodiment of any of the methods provided herein, [ 18 F]DCFPyL can be recovered by elution with a solvent solution. In any embodiment of the methods provided herein, the resulting solution containing [ 18 A solvent solution of F]DCFPyL is used to form an imaging or diagnostic composition suitable for application to a subject.

[0100] In another example, the solution of any of the methods or compositions provided herein may contain acetonitrile (or another solvent, for example, one unsuitable for application to the object). In one embodiment of any of the methods provided herein, acetonitrile (and / or impurities) may not adhere to the solvent exchange column and may therefore be eluted or washed through. Thus, in one embodiment of any of the methods provided herein, by eluting from the resin... 18 The solution formed by F]DCFPyL may be substantially free of acetonitrile (or other solvents). In some embodiments of any of the methods or compositions provided herein, the first solution may be a composition according to any aspect or embodiment of the invention described herein.

[0101] Therefore, in some embodiments of any of the methods or compositions provided herein, the solution contains acetonitrile at levels not exceeding about 0.05% (w / v), not exceeding about 0.04% (w / v), not exceeding about 0.03% (w / v), not exceeding about 0.02% (w / v), or not exceeding about 0.01% (w / v). In some embodiments of any of the methods or compositions provided herein, the solution contains acetonitrile (w / v) at any value provided herein.

[0102] The elution solvent for any of the methods or compositions provided herein may be permissible for elution. 18 F]DCFPyL in any solvent. Generally speaking, [ 18 F]DCFPyL is substantially soluble in the elution solvent. In some embodiments of any of the methods or compositions provided herein, the solvent in the elution solution is an alcohol, such as ethanol, which may be an alcohol contained in the final imaging or diagnostic composition. The ethanol in such embodiments may be at the concentrations of any of the embodiments provided herein. Suitable columns, etc., are known to those skilled in the art, including HLB and SEP-PAK.

[0103] Radiochemical purity, stability and radioactivity concentration

[0104] Compositions described herein and / or prepared according to the methods described herein may have high radiochemical purity and / or maintain high radiochemical purity for a considerable period of time. Radiochemical purity as used herein refers to the proportion of radioactivity (from a given radioisotope) present in a particular radiopharmaceutical to the total amount of radioactivity (from the same radioisotope) in a composition containing that particular radiopharmaceutical. Radiochemical purity can be a measure of the extent to which a particular radiopharmaceutical degrades and / or decomposes and / or transforms into other compounds that may or may not contain radioisotopes. Radiochemical purity can be the distribution of radioactivity of a parent material relative to other radioactive materials.

[0105] In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 90%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 95%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 96%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 97%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 98%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 98.5%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 98.9%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 99%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 99.5%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is at least about 99.9%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 98%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 98.5%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 98.9%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 99%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 99.5%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 99.9%. In some embodiments of the methods or compositions provided herein, the radiochemical purity of the composition is about 95% to about 100%. In some embodiments of any of the methods or compositions provided herein, the radiochemical purity of the composition is any of the values ​​provided herein.

[0106] Those skilled in the art will be familiar with the techniques and systems used to determine the radiochemical purity of a composition. In some cases, HPLC associated with a radioactive detector is used to determine radiochemical purity. Typically, radiochemical purity is determined under environmental conditions (e.g., ambient temperature, ambient humidity, ambient light, etc.), such as in samples stored under these conditions.

[0107] In some embodiments of any of the methods or compositions provided herein, the composition maintains high radiochemical purity for a considerable period of time. It is not desirable to be bound by theory; this may be due to the selection of suitable compositional components and conditions that contribute to the stability of the developer. For example, the presence of ascorbic acid and / or ethanol, and / or the selection of a suitable composition pH, can significantly influence the radiostability of the developer.

[0108] In some embodiments of the methods or compositions provided herein, the composition has the radiochemical purity as provided herein at the end of synthesis (EOS). In some embodiments of the methods or compositions provided herein, the composition has a radiochemical purity of at least about 90% over a time period of at least about 6 hours, at least 8 hours, or at least 10 hours. In some embodiments of the methods or compositions provided herein, the composition has a radiochemical purity of at least about 95% at about 10 hours. In some embodiments of the methods or compositions provided herein, the composition has a radiochemical purity of at least about 97% at about 10 hours. In some embodiments of the methods or compositions provided herein, the composition has a radiochemical purity of at least 99% for at least 10 hours. In such embodiments, the time is measured after synthesis (i.e., beyond the end of synthesis (EOS)).

[0109] In some embodiments of any of the methods or compositions provided herein, the compositions provided herein exhibit little or no radiolysis, for example, at least about 6, 7, 8, 9, or 10 hours after synthesis. In any embodiment, the compositions provided herein have less than about 5% free radiolysis. 18 F. Less than approximately 4.5% free 18 F. Less than approximately 4% free 18 F, less than approximately 3.5% free 18 F. Less than approximately 3% free 18 F, less than approximately 2.5% free 18 F. Less than approximately 2% free 18 F. Less than approximately 1.5% free 18 F. Less than approximately 1% free 18 F or less than about 0.5% free 18F, for example, at least about 6, 7, 8, 9, or 10 hours after synthesis. In some embodiments of any of the methods or compositions provided herein, the composition has the free radicals provided herein. 18 Any of the F levels.

[0110] In one embodiment of any of the compositions or methods provided herein, the incorporation of ascorbate into the collection vial prevents radiolysis during transfer to and attachment to the solvent exchange column. This can result in a reduction of impurities in the pharmaceutical product at T0. In one embodiment of any of the compositions or methods provided herein, the presence of ascorbate in the FCV or FPV can stabilize the product for 10 hours during storage.

[0111] In one aspect, this paper provides methods for detecting free [elements] in samples. 18 Method F. In any of such methods, TEAF is used, for example, at any of the concentrations provided herein. In any of such methods, the composition may be comprising a radiopharmaceutical, for example [ 18 The composition of F]DCFPyL. Such a method includes adding tetraethylammonium fluoride to the composition to be evaluated; and measuring the sample to determine the free fluoride of the composition. 18 The level of F, for example, by chromatography, such as HPLC.

[0112] In some embodiments of any of the methods or compositions provided herein, the radioactive concentration of the composition is at least about 80 mCi / mL, at least about 85 mCi / mL, at least about 90 mCi / mL, at least about 95 mCi / mL, at least about 100 mCi / mL, at least about 105 mCi / mL, at least about 110 mCi / mL, at least about 115 mCi / mL, at least about 120 mCi / mL, at least about 125 mCi / mL, at least about 130 mCi / mL, at least about 135 mCi / mL, at least about 140 mCi / mL, at least about 145 mCi / mL, at least about 150 mCi / mL, at least about 155 mCi / mL, at least about 160 mCi / mL, at least about 165 mCi / mL, at least about 166 mCi / mL, at least about 167 mCi / mL, at least about 168 ... mCi / mL, at least about 169 mCi / mL, or at least about 170 mCi / mL. In some embodiments of any of the methods or compositions provided herein, the radioactivity concentration of the composition is any of the values ​​provided herein.

[0113] In some embodiments of any of the methods or compositions provided herein, the radioactive concentration of the composition is about 80 mCi / mL to about 170 mCi / mL, about 80 mCi / mL to about 165 mCi / mL, about 80 mCi / mL to about 160 mCi / mL, about 80 mCi / mL to about 155 mCi / mL, about 80 mCi / mL to about 150 mCi / mL, about 80 mCi / mL to about 145 mCi / mL, about 80 mCi / mL to about 140 mCi / mL, about 80 mCi / mL to about 135 mCi / mL, about 80 mCi / mL to about 130 mCi / mL, about 80 mCi / mL to about 125 mCi / mL, or about 80 mCi / mL to about 120 mCi / mL. In some embodiments of any of the methods or compositions provided herein, the radioactive concentration of the composition is about 85 mCi / mL to about 170 mCi / mL, about 90 mCi / mL to about 170 mCi / mL, about 95 mCi / mL to about 170 mCi / mL, about 100 mCi / mL to about 170 mCi / mL, about 105 mCi / mL to about 170 mCi / mL, about 110 mCi / mL to about 170 mCi / mL, about 115 mCi / mL to about 170 mCi / mL, about 120 mCi / mL to about 170 mCi / mL, about 125 mCi / mL to about 170 mCi / mL, about 130 mCi / mL to about 170 mCi / mL, about 135 mCi / mL to about 170 mCi / mL, about 140 mCi / mL to about 170 mCi / mL, about 145 ... mCi / mL to about 170 mCi / mL, about 150 mCi / mL to about 170 mCi / mL, about 155 mCi / mL to about 170 mCi / mL, about 160 mCi / mL to about 170 mCi / mL, or about 165 mCi / mL to about 170 mCi / mL.In some embodiments of any of the methods or compositions provided herein, the radioactive concentration of the composition is about 85 mCi / mL to about 165 mCi / mL, about 90 mCi / mL to about 165 mCi / mL, about 95 mCi / mL to about 165 mCi / mL, about 100 mCi / mL to about 165 mCi / mL, about 105 mCi / mL to about 165 mCi / mL, about 110 mCi / mL to about 165 mCi / mL, about 115 mCi / mL to about 165 mCi / mL, about 120 mCi / mL to about 165 mCi / mL, about 125 mCi / mL to about 165 mCi / mL, about 130 mCi / mL to about 165 mCi / mL, about 135 mCi / mL to about 165 mCi / mL, about 140 mCi / mL to about 165 mCi / mL, about 14 ... mCi / mL to about 165 mCi / mL, about 150 mCi / mL to about 165 mCi / mL, about 155 mCi / mL to about 165 mCi / mL, or about 160 mCi / mL to about 165 mCi / mL.

[0114] In some embodiments of any of the methods or compositions provided herein, the radioactivity concentration of the composition is equal to or less than or equal to about 170 mCi / mL. In some embodiments of any of the methods or compositions provided herein, the radioactivity concentration of the composition is equal to or less than about 169 mCi / mL, equal to or less than about 168 mCi / mL, equal to or less than about 167 mCi / mL, equal to or less than about 166 mCi / mL, or equal to or less than about 165 mCi / mL.

[0115] As an example, it provides [ 18 A composition comprising F]DCFPyL and one or more of the following characteristics. In one embodiment, the composition has ≥ 95% [ 18F]DCFPyL (radiochemical purity), pH 4.5 to 7.0, and ascorbic acid 5 to 15 mg / mL. In any of the embodiments of the foregoing compositions, the radioactivity concentration of the composition at the end of synthesis (EOS) is 1 to 125 mCi / mL (e.g., at least 80 mCi / mL, at least 85 mCi / mL, at least 90 mCi / mL, at least 95 mCi / mL, at least 100 mCi / mL, at least 105 mCi / mL, at least 110 mCi / mL, at least 115 mCi / mL, at least 120 mCi / mL, at least 125 mCi / mL, at least 80 mCi / mL to 125 mCi / mL, at least 85 mCi / mL to 125 mCi / mL, at least 90 mCi / mL to 125 mCi / mL, at least 95 mCi / mL to 125 mCi / mL, at least 100 mCi / mL to 125 mCi / mL, at least 105 mCi / mL to 125 mCi / mL, at least 110 mCi / mL, at least 110 mCi / mL, at least 125 ... The specific activity (based on EOS) at the expiration date is ≥ 1000 mCi / μmol (from mCi / mL to 125 mCi / mL, at least 115 mCi / mL to 125 mCi / mL, or at least 120 mCi / mL to 125 mCi / mL). In any embodiment of the foregoing composition, the composition comprises ≤ 7.89% w / v ethanol and / or ≤ 0.04% w / v acetonitrile. In any embodiment of the foregoing composition, the composition comprises a total of ≤ 1.5 μg / mL of unknown impurities and / or ≤ 5.0 μg / mL of ascorbic acid-related impurities, for example, at a relative retention time (RRT) of 0.607. In any embodiment of the foregoing composition, radioactivity consistency is calculated within ±10% and / or by half-life (T0). 1 / 2 The radionuclide identity of the sample is 105 to 115 minutes. The aforementioned characteristics, as well as those in the table below, can be determined, measured, or evaluated using methods known to those skilled in the art or the methods provided in the table below.

[0116] Table 32

[0117]

[0118]

[0119] 1 Equal portions of samples taken from the same vial can be tested.

[0120]

[0121] 1 Equal portions of samples taken from the same vial can be tested.

[0122]

[0123]

[0124] Developers and related methods

[0125] Imaging agents allow for the detection, imaging, and / or monitoring of the presence and / or progression of symptoms, pathological disorders, and / or diseases. Typically, an imaging agent is applied to a subject (e.g., a person) to provide information relevant to at least a portion of the subject. In some cases, imaging agents can be used to highlight specific areas of a subject, making organs, blood vessels, tissues, and / or other parts easier to detect and / or more clearly imaged. By improving the detectability and / or image quality of the subject under study, the presence and extent of diseases and / or symptoms can be determined.

[0126] The developing agent provided in this article is [ 18 F]DCFPyL, in which radioactive isotopes 18 F stands for imaging, specifically positron emission tomography (PET) imaging in one embodiment. The compositions provided herein can be used for nuclear medicine imaging. In some embodiments, the provided compositions may be pharmaceutically acceptable. The phrase "pharmaceutically acceptable" as used herein means compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues within a reasonable medical judgment without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0127] [ 18F]DCFPyL may also be present as a pharmaceutically acceptable salt in the compositions provided herein. Pharmaceutically acceptable salts can be derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its acidic or basic salt. Some examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); and basic or organic salts of acidic residues (e.g., carboxylic acids). Pharmaceutically acceptable salts include, for example, conventional nontoxic salts or quaternary ammonium salts of parent compounds formed from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethylsulfonic acid.

[0128] In some implementation schemes, [ 18 F]DCFPyL can be synthesized using an automated synthesis module. Automated synthesis modules will be known to those skilled in the art. In some cases, the developer can be synthesized according to the teachings of the automated synthesis module described in International Patent Publication No. WO2011 / 097649, published August 11, 2011, the teachings of which are incorporated herein by reference.

[0129] In some embodiments, the imaging or diagnostic compositions described herein may be applied to imaging methods, including methods for imaging a subject, comprising administering the imaging or diagnostic compositions described herein and imaging a target region of the subject. The target region may include, but is not limited to, cancerous tissue, tissues and organs with tumors and / or metastases, the prostate, and blood vessels (e.g., arteries, veins). Methods for imaging one or more types of cells, organs, or tissues are also provided herein, comprising contacting the cells, organs, or tissues with an effective amount of the compounds provided herein or administering an effective amount of the compounds provided herein to the subject. In some embodiments, one or more organs or tissues include prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue. In some embodiments, the subject is a human subject.

[0130] In some embodiments, the imaging method is suitable for imaging via targeted PSMA. In some embodiments, the imaging method is suitable for imaging cancer, tumors, or growths. In some embodiments, the cancer is selected from ocular cancer or eye cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, gastric cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer (e.g., glioma), laryngeal cancer, melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oropharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

[0131] The imaging methods provided herein are suitable for imaging any physiological process or feature involving PSMA. In some embodiments, the imaging methods are suitable for identifying tissues or target regions expressing high concentrations of PSMA. Exemplary applications include imaging glutamatergic neurotransmission, presynaptic glutamatergic neurotransmission, PSMA-expressing malignancies or cancers, prostate cancer (including metastatic prostate cancer), and angiogenesis. Solid tumors express PSMA in neovascularization. Therefore, the methods and compositions provided herein can be used to image solid tumors, including lung, kidney cells, glioblastoma, pancreas, bladder, sarcoma, melanoma, breast, colon, germ cells, pheochromocytoma, esophagus, and stomach. PSMA is commonly expressed in the endothelial cells of capillaries in the peritumoral and intratumoral regions of various malignancies, making the provided methods and compositions suitable for imaging such malignancies. Furthermore, certain benign lesions and tissues, including endometrium, schwannomas, and Barrett's esophagus, can be imaged according to the provided methods and compositions.

[0132] The provided methods and compositions for imaging angiogenesis are suitable for imaging a variety of diseases and conditions in which angiogenesis occurs. Illustrative, non-limiting examples include tumors, collagen vascular diseases, cancer, stroke, vascular malformations, and retinal diseases. The provided methods and compositions for imaging angiogenesis are also suitable for the diagnosis and observation of normal tissue development.

[0133] In some implementations, any of the methods provided herein may include diagnosing or assisting in the diagnosis of a disease or condition, evaluating and / or selecting and / or altering treatment for a disease or condition, assessing the efficacy of treatment for a disease or condition, or imaging an object suffering from a known or suspected disease or condition.

[0134] In some embodiments of any of the methods provided herein, the imaging method includes (a) administering an imaging or diagnostic composition comprising a developer to the subject, and (b) acquiring at least one image of at least a portion of the subject. In some embodiments, any of the acquisition methods provided herein employs positron emission tomography (PET) to visualize the distribution of the developer within at least a portion of the subject. As will be understood by those skilled in the art, imaging may include whole-body imaging of the subject, or imaging of a specific target body region or tissue of the subject. For example, if the subject is known to have or suspected of having cancer, such as prostate cancer, the method may be used to image organs of the subject with primary tumors, such as the prostate, and / or organs with (or suspected of having) metastases.

[0135] In one embodiment of any of the compositions or methods provided herein, the amount of PyL is 8 to 10 mCi. In one embodiment of any of the compositions or methods provided herein, the amount of PyL administered to the patient is 8 to 10, or 8, 9, or 10 mCi from an FPV prepared at any of the concentrations provided herein (e.g., 80 to 170 mCi / mL) and containing any of the concentrations provided herein, such as 5.6 mg / mL ascorbate. In one embodiment of any of the compositions or methods provided herein, the amount of PyL administered to the patient is 8 to 10 or 8, 9 or 10 mCi from an FPV prepared at any of the concentrations provided herein (e.g., 80 to 125, 80 to 130, 80 to 135, 80 to 140, 80 to 145, 80 to 150, 80 to 155, 80 to 160 or 80 to 165 mCi / mL), and contains any of the concentrations of ascorbate provided herein, such as 5.6 mg / mL ascorbate, has a pH of any of the pH provided herein, such as 4.5 to 7 or 7.0, and has any of the radiochemical purities provided herein, such as at least 90% (e.g., up to 10 hours after EOS), and / or any of the specific activities provided herein at the time of administration, such as at least 1000 mCi / μmol. In one embodiment of any of the foregoing embodiments, the composition contains ≤ 78.9 mg of ethanol in 0.9% sodium chloride (USP for injection). In one embodiment of any of the foregoing embodiments, imaging is performed using a PET camera 1 hour after administration.

[0136] In some embodiments of any of the methods or compositions provided herein, radiolabeled compounds are detected by positron emission tomography (PET) or PET / CT. Images can be generated by means of differences in the spatial distribution of the imaging agent accumulated at the site. Any means suitable for a particular label can be used to measure the spatial distribution, such as a gamma camera, PET device, PET / CT device, etc. The degree of imaging agent accumulation can be quantified using known methods for quantifying radioactivity.

[0137] Generally, a detectable effective amount of the composition for imaging provided herein can be administered to the subject. According to the invention, a “detectable effective amount” is defined as an amount sufficient to produce acceptable images using a clinically usable device. The composition for a detectable effective amount provided herein can be administered in one or more injections. The detectable effective amount can vary depending on factors such as individual susceptibility, individual age, sex, and weight, individual idiosyncratic response, and dosing. The detectable effective amount can also vary depending on instrument and film-related factors. Optimization of such factors is entirely within the scope of the art. The amount of imaging agent used for diagnostic purposes and the duration of the imaging study will depend on the imaging agent, the patient's weight, the nature and severity of the condition being treated, the nature of the patient's existing therapeutic treatments, and the patient's idiosyncratic response. Ultimately, the attending physician can determine the amount administered to each individual patient and the duration of the imaging study.

[0138] In one embodiment of any of the methods or compositions provided herein, the object is a human, rat, mouse, cat, dog, horse, sheep, cattle, monkey, bird, or amphibian. In another embodiment of any of the methods or compositions provided herein, the cells are in vivo or in vitro. Typical objects to which the compounds of the present invention can be applied are mammals, such as primates and humans. For veterinary applications, a wide variety of objects include, for example, livestock such as cattle, sheep, goats, dairy cows, pigs, etc.; poultry such as chickens, ducks, geese, turkeys, etc.; and domesticated animals, especially pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals are suitable objects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs, such as inbred pigs, etc. Furthermore, for in vitro applications, such as in vitro diagnostic and research applications, body fluid and cell samples from any of the above-mentioned objects are suitable for use, such as human, blood, urine, or tissue samples.

[0139] Reagent test kit

[0140] Kits comprising any of the compositions, reagents, or combinations of reagents provided herein are also provided. In some embodiments, the kit provides a packaged pharmaceutical composition comprising the compositions of the present invention and a pharmaceutically acceptable carrier. In other embodiments, the kit provides the compounds and reagents necessary to carry out any of the methods provided herein. Thus, in some embodiments, the kits provided herein comprise a combination of reagents of any of the methods provided herein. In one embodiment of any of the provided kits, the kit further comprises a label comprising at least one of: instructions for carrying out any of the methods provided herein, instructions for preparing any of the compositions provided herein, and / or instructions for using the final composition provided herein in a method of use (e.g., any of the methods of use provided herein). In one embodiment of any of the provided kits, the kit comprises a combination of any of the compositions provided herein with a pharmaceutically acceptable carrier. The compositions of any of the provided kits may be in solution. In one embodiment of any of the provided kits, the final composition is provided in a syringe or vial, or the kit further comprises a syringe or vial, such as an administration syringe or vial, for example, an FCV or FPV.

[0141] In one embodiment of any of the kits provided herein, the kit is used to synthesize PyL. In one embodiment of any of the kits provided herein, the kit contains ascorbic acid, for example at any of the concentrations provided herein, or in an amount sufficient to prepare ascorbic acid salt at any of the concentrations provided herein. In one of the foregoing embodiments, the kit also contains a PyL precursor, saline, and / or phosphate. In one of the foregoing embodiments, the kit also contains one or more collection vials and / or one or more FCVs and / or FPVs. In one embodiment of any of the kits provided herein, the kit contains a cassette for automated synthesis (e.g., all-in-one synthesis). In one embodiment of any of the provided kits, automated synthesis is used to synthesize PyL for PET imaging.

[0142] Example

[0143] To provide a more complete understanding of the disclosure described herein, the following embodiments are illustrated. The synthetic and biological embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting their scope in any way.

[0144] Example 1. [ 18 Synthesis of F]DCFPyL

[0145] The precursor of 5-(((S)-6-(tert-butoxy)-5-(3-(((S)-1,5-ditert-butoxy-1,5-dioxopentan-2-yl)ureo)-6-oxohexyl)carbamoyl)-N,N,N-trimethylpyridin-2-ammonium trifluoromethanesulfonate was custom-synthesized with reference standard ((2S)-2-[(1S)-1-carboxy-5-[(6-fluorylpyridin-3-carbonyl)-amino]-pentyl]-carbamoyl-amino]glutaric acid. The synthetic reagents were from the FDA-approved Trasis kit. Ascorbic acid and citric acid were USP. The synthesis of 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridin-3-carbonyl)-amino]-pentyl}ureo)-glutaric acid was performed on a one-step module (Trasis). A cyclotron-generated... 18 F was captured.

[0146] All chemicals and components are loaded into a one-step synthesis chamber, where a cyclotron generates […]. 18 F]fluoride ions are captured on the SPE box. The resin column is eluted into the reaction vessel and dried. The reaction vessel is cooled, and [ 18 A solution of F]DCFPyL precursor was added to a solution containing dried [ 18 The reaction vessel containing the fluoride was heated. After the labeled reaction was complete, phosphoric acid (85%) was added to the reaction to promote the removal of the tert-butoxy protecting group. Sodium hydroxide was then added to quench the deprotection reaction. The reaction mixture was purified by semi-preparative HPLC. 18 F]DCFPyL. Based on radioactive detection collection [ 18 The F]DCFPyL product peak was observed, and the solvent was subsequently exchanged using a retention and elution separation column. Elution was performed in ethanol, followed by dilution to a separate brine solution or a brine solution containing an additional radiation shielding agent. Figure 1 ).

[0147] Stability was assessed using reversed-phase HPLC on a C18 column with a phosphate-buffered saline / acetonitrile gradient mobile phase, and elution profiles were monitored using both UV and radiochemical detectors. Samples were analyzed by direct injection into the HPLC, dilution and injection, or by adding tetraethylammonium fluoride (TEAF) to the sample prior to injection.

[0148] The pH of the solution is determined by spotting the sample on a pH paper strip or by using a pH probe and pH meter. The ascorbic acid concentration is verified by spotting the sample on an ascorbic acid test strip.

[0149] Example 2. Radiolysis Assessment Method

[0150] [ 18F]DCFPyL is generally radiometrically stable, but an exception was observed in an early running peak on the analytical method during process validation (PV) batches. This early running peak exhibited significant tailing and was associated with free... 18 F co-elution. Poor peak shape leads to free ions in the RCP chromatogram. 18 The integral of the difference between the F peaks, and there is a risk of underestimating impurities ( Figure 2 ).

[0151] It can be used to improve the free in the analytical sample 18 Quantitative analysis of potassium fluoride (15 mg / mL) incorporated by F using an HPLC radiometric detector to sharpen free radicals. 18 The F-peak method (Journal of Pharmaceutical and Biomedical Analysis 111 2015 209–214). However, using tetraethylammonium fluoride (TEAF, 44 mg / mL) ( Figure 3 Studies have shown that peak shape is improved. Potassium fluoride leads to [ 18 The peak shape of F]DCFPyL deteriorated, so TEAF was chosen.

[0152] Known amounts of free TEAF, either alone or mixed with TEAF 18 F was injected onto the analytical column, and the eluent from the column was collected during chromatography. Radioactivity was then determined using Capintec. The results showed that the isolated free... 18 F and free TEAF-doped 18 The recoveries of F were 90.9% and 101.3%, respectively. This indicates that when the sample is doped with TEAF, in addition to the aforementioned peak shape improvement, free TEAF... 18 The F recovery rate also improved. TEAF was added to the analytical sample and subsequently examined. 18 In the study of the potential radiolysis of F]DCFPyL, in order to overcome free 18 Some limitations in F quantification.

[0153] Example 3. Ethanol as a radiation protectant

[0154] Synthesize as described in Example 1. 18 F]DCFPyL sample. The final product was 325 mCi / mL at the end of the synthesis and was maintained in 100% ethanol. As in Example 1, samples were taken hourly over 10 hours to determine radiochemical and chemical purity by HPLC radiometric detection or UV detection, respectively. Free 18 The time dependence of F formation is obvious. Figure 4 (as shown in Table 1), with no other radioactive impurities.

[0155] Table 1. Formation of free 18F in the presence of ethanol

[0156]

[0157] free 18 The estimation of F is influenced by the HPLC column. 18 The poor peak shape of F was a limitation. Adding TEAF improved the peak shape. This indicates an underestimation of free... 18 The probability of F (Table 2).

[0158] Table 2. Effects of adding TEAF to the sample prior to HPLC analysis

[0159]

[0160] Example 4. Formation of radioactive impurities in the presence of ethanol and water

[0161] Synthesize as described in Example 1. 18 F]DCFPyL sample. At the end of the synthesis, the final product was 146.76 mCi / mL and was maintained in 36% ethanol brine. Samples were taken every 30 minutes over 4 hours as in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18 The time dependence of F formation is evident (Table 3), with several other unidentified radioactive impurities.

[0162] Table 3. Percentage of total radioactivity detected in 35% ethanol saline solution

[0163]

[0164] RT = Retention time of radioactive impurities

[0165] Example 5. Formation of radioactive concentration-related impurities in the presence of ethanol and water

[0166] Synthesize as described in Example 1. 18 F]DCFPyL sample. At the end of the synthesis, the final product had a radioactivity concentration ranging from 52 to 85 mCi / mL and was maintained in a saline solution containing 20% ​​ethanol. Samples were taken every 30 minutes over 4 hours as in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18 The formation of F is clearly time- and concentration-dependent, and it contains several other unidentified radioactive impurities (Table 4).

[0167] Table 4. Percentage of total activity detected in 20% ethanol saline solution

[0168]

[0169] RT = Retention time of radioactive impurities

[0170] Example 6. Formation of radioactive impurities in ethanol and 100 mg / mL ascorbic acid

[0171] Synthesize as described in Example 1. 18 F]DCFPyL sample. However, the peak collected from HPLC was added to ascorbic acid at pH 2.0 to obtain a final concentration of 100 mg / mL. Solvent exchange was performed with ascorbic acid added to the washing solution at 100 mg / mL, and the final ethanol eluent was diluted to a final ascorbic acid concentration of 100 mg / mL. At the end of the synthesis, the radioactivity concentration of the final product was 256 mCi / mL and remained in ethanol. As in Example 1, samples were taken every 30 minutes over 4 hours, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. The formation of free 18F was significantly suppressed, accumulating only 0.08% over 4 hours (Table 5). However, in the presence of ascorbic acid, radioactive impurities accumulated over time at retention times (RT) of 12 and 12.2 minutes. Figure 8 ).

[0172] Table 5 shows that this differs from samples collected in ethanol alone or in saline solution, where free ethanol was observed within 4 hours. 18 High formation of F. However, in the presence of ascorbic acid, radioactive impurities accumulate over time at retention times (RT) of 12 and 12.2 minutes. Figure 8 ).

[0173] Table 5. Percentage of total activity detected in 100 mg / mL ascorbic acid

[0174]

[0175] Example 7. Formation of radioactive impurities in ethanol and 50 mg / mL ascorbic acid

[0176] Synthesize as described in Example 1. 18 F]DCFPyL sample. However, the final ethanol eluent was diluted to a final ascorbic acid concentration of 50 mg / mL, pH 5.8. At the end of the synthesis, the final product had a radioactivity concentration of 111 mCi / mL and was maintained in 20% ethanol. Samples were taken every 30 minutes over 4 hours as in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18The formation of F was significantly inhibited, accumulating only 0.26% within 4 hours (Table 6). This differs from samples collected in ethanol alone or in ethanol in saline solution, where free F was observed within 4 hours. 18 High formation of F. In addition, impurities are not obvious at RT 12 and 12.2, and there are also few impurities at RT 5 and 5.9 (Table 6).

[0177] Table 6. Percentage of total activity detected in 50 mg / mL ascorbic acid in the final product vial

[0178]

[0179] Example 8. Formation of radioactive impurities in ethanol and the concentration range of ascorbic acid.

[0180] Synthesize as described in Example 1. 18 F]DCFPyL sample. However, the final ethanol eluent was diluted to a final ascorbic acid concentration of 0.5 to 50 mg / mL, pH 5.8. At the end of the synthesis, the final product had a radioactivity concentration of 99 to 139 mCi / mL and was maintained in 20% ethanol. Samples were taken at times 0, 2, 4, 6, and 10 hours as in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18 F formation was inhibited in a concentration-dependent manner, but was significantly inhibited at all ascorbic acid concentrations tested over 10 hours (Table 7 and 10). Figure 10 This differs from samples collected in ethanol alone or in saline solution, where free ethanol is observed within 4 hours. 18 High formation of F. In addition, impurities are not obvious at RT 12, 12.2 and 5.9, and there are also very few impurities at RT 5.

[0181] Table 7. Percentage of total radioactivity detected in HPLC-separated samples with ascorbic acid concentrations ranging from 0.5 to 50 mg / mL in the final product vials.

[0182]

[0183]

[0184] Example 9. Formation of radioactive impurities and concentration range of sodium ascorbate in the presence of ethanol.

[0185] As outlined in Example 1, synthesize [ 18F]DCFPyL sample. However, the final ethanol eluent was diluted to a final sodium ascorbate concentration of 1, 2.5, or 5 mg / mL. The radioactivity concentration of the final product was measured at the end of the synthesis and maintained in 20% ethanol. Samples were taken at times 0, 2, 4, 6, and 10 hours as described in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18 The formation of F was inhibited in a concentration-dependent manner and at all ascorbic acid concentrations tested over 10 hours. This differs from samples collected in ethanol alone or in saline solution, where free F was observed within 4 hours. 18 F forms highly.

[0186] A comparison between sodium ascorbate and ascorbic acid showed that ascorbic acid inhibited... 18 F-DCFPyL is more effective at defluorination. Furthermore, impurities at RT 12, 12.2, 5.9, and 5.0 are not noticeable (Table 8).

[0187] Table 8. Percentage of total radioactivity detected in final product vials when sodium ascorbate concentration is 1 or 5 mg / mL.

[0188]

[0189]

[0190] Example 10. Formation of radioactive impurities in the presence of ethanol and sodium citrate

[0191] As outlined in Example 1, synthesize [ 18 F]DCFPyL sample. However, the final ethanol eluent was diluted to a final sodium citrate concentration of 20 mg / mL. At the end of the synthesis, the final product had a radioactivity concentration of 104.8 mCi / mL and was maintained in 20% ethanol. Samples were taken at times 0, 2, and 4 hours as described in Example 1, and radiochemical and chemical purity were determined by HPLC radiometric detection or UV detection, respectively. Free 18 The formation of F occurs rapidly, with 10.22% present at time 0 and increasing to 20.65% at 4 hours (Table 9). This is similar to samples collected in ethanol alone or in ethanol in saline solution, where free F is observed within 4 hours. 18 The formation of F is high. Most of the radioactive impurities formed are free. 18 F.

[0192] Table 9. Percentage of total radioactivity detected in HPLC-separated samples with a sodium citrate concentration of 20 mg / mL in the final product vials

[0193]

[0194] Example 11. pH of ascorbic acid and pH of sodium ascorbate as a function of concentration

[0195] Solutions of varying concentrations were prepared, ranging from 50 mg / mL to 0.5 mg / mL of Ascor USP ascorbic acid in SWFI and from 50 mg / mL to 0.5 mg / mL of sodium ascorbate from Spectrum in saline. pH was measured using a Corning pH meter (calibrated with 4.0 and 7.0 pH buffers) and Macherey-Nagel pH paper (range 2.0 to 9.0). Since the Ascor USP ascorbic acid solutions used had a pH range of 5.6 to 6.6, aliquots of sodium ascorbate from Spectrum in saline at concentrations of 50 mg / mL, 5 mg / mL, 2.5 mg / mL, and 1 mg / mL were adjusted to pH close to this range using concentrated hydrochloric acid (Table 10). On a different day, another set of sodium ascorbate in pure saline at a concentration of 2.5 mg / mL was also prepared and its pH adjusted with concentrated hydrochloric acid. The pH of this group was measured using a Corning pH meter (calibrated with 4.0 and 7.0 pH buffers), Macherey-Nagel pH paper (range 2.0 to 9.0), and EMD pH paper (range 2.0 to 9.0) (Table 11).

[0196] Table 10. pH results measured using a pH meter and pH paper

[0197]

[0198] Table 11. pH results measured using a pH meter and pH paper

[0199]

[0200] Example 12. 18 F]DCFPyL formulation

[0201] Table 12 provides [ 18 The desired formulation of F]DCFPyL is 0.9% sodium chloride (USP) with up to 7.89% ethanol (w / v), for example, 3% ethanol. Figure 13The diagram provides a schematic of a Trasis One-Step (AIO) synthesis module with reagents and reagent positions. Typically, the upper limit for radioactive concentration at the end of synthesis (EOS) can be 80 mCi / mL. To improve drug supply and / or allow for larger doses per batch (batch size may be limited by the vial size of the maximum drug concentration product (e.g., 50 mL)), products with higher radioactive concentrations (e.g., >120 mCi / mL at EOS) can be beneficial. Furthermore, the main observed radiodegradation product is free radioactive... 18 F, and through [ 18 The radiolysis of F]DCFPyL is formed. Minimizing the radiolysis can be beneficial.

[0202] Table 12. [18F]DCFPyL formulation

[0203]

[0204] a TOA = Time of application

[0205] b Depends on the specific activity of the batch at the end of synthesis (EOS) and the hysteresis time between EOS and TOA.

[0206] c After production, the product is diluted with physiological saline to achieve a radiochemical concentration ≤ 80 mCi / mL at EOS. The degree of dilution varies depending on the initial batch size (1 Ci to 10 Ci) and process yield.

[0207] Research was conducted to examine the direction [ 18 The formulation of F]DCFPyL has achieved success in adding radiation shielding agents and minimizing the radiolysis of the drug substance. While ascorbic acid has been shown to quench radiolysis induced by high radioactivity concentrations in certain PET products (e.g., US20200222562), its application regarding specific desired characteristics... 18 The effectiveness of preparing F]DCFPyL has not been previously evaluated. [Ascorbic acid stabilization] 18 The capabilities of F]DCFPyL (e.g., at higher radioactive concentrations (e.g., > 120 mCi / mL)) and the impact on such desired characteristics of its formulations were comprehensively analyzed.

[0208] Figure 14 A flowchart illustrating the introduction of ascorbic acid during the production process is shown. In one embodiment, ascorbic acid may be included as part of the product delivery from the HLB solvent exchange column (ascorbic acid added to the delivery solution vial; position F on AIO,). Figure 13This can be achieved by direct introduction into the final product vial (FPV) and / or by adding ascorbic acid directly into the FPV. In another embodiment, adding ascorbic acid to a collection vial for receiving peak cuts from semi-preparative purification also provides a pathway to stabilize the product prior to the solvent exchange step. In another embodiment, ascorbic acid can be used to pretreat the column used for solvent exchange, such as an HLB column.

[0209] HPLC radiochemistry and chemical impurity determination

[0210] An analytical HPLC method was used. This method employed UV detection at 264 nm for chemical impurities and radiochemical analysis using an Eckert & Ziegler B-FC-1000 gamma detector.

[0211] [ 18 F]DCFPyL Specifications

[0212] Table 15 provides the expected [ 18 Specifications for the F]DCFPyL product are also provided. A general test plan (Table 16) is also provided, although in some cases the test timings have been modified as instructed.

[0213] Table 15. [18F]DCFPyL Product Specifications

[0214]

[0215] a TOA = Time of application

[0216] b Depends on the specific activity of the batch at the end of synthesis (EOS) and the hysteresis time between EOS and TOA.

[0217] c Formulation A (ascorbate) drug product is undiluted.

[0218] Table 16. Test Plan

[0219]

[0220] The experiment was conducted at an 18F initiation activity of approximately 2 Ci. 18 F]DCFPyL Research

[0221] The use of ascorbic acid in the following steps was evaluated to stabilize […]. 18Feasibility of F]DCFPYL: 1) Addition to a collection vial for receiving the product peak cut from the semi-preparative purification step, 2) Addition to a pretreatment vial for solvent exchange using an HLB column, and 3) The final product vial. To achieve a radioactivity concentration of approximately 120 mCi / mL, the labeled product was eluted from the HLB column for solvent exchange and delivered using nitrogen pusher to a receiving vial pre-loaded with at least 1.3 mL of formulation matrix (0.9% sodium chloride (USP) or ascorbic acid (USP)). The product was then measured by Capintec and diluted to achieve the desired radioactivity concentration. This resulted in a product with a higher ethanol level (approximately 20%) than clinically used (e.g., approximately 3%). While ethanol is known to provide some protection against radiolysis, it provides a preliminary assessment of the stability effects of ascorbic acid compared to an ethanol control.

[0222] The control batch produced did not contain ascorbic acid, and its final radiochemical purity was 147 mCi / mL with an ethanol level of 29.8%. Product samples were taken every 30 minutes, and an extended gradient was added for assay to allow for the detection of hydrophobic impurities. The product was delivered from the HLB to vials containing 1.3 mL of 0.9% sodium chloride (USP). The product was assayed and diluted with 0.9% sodium chloride (USP) to achieve the desired radiochemical purity. The initial radiochemical purity (RCP) was 94%, and the RCP at T=4 hours was 89%, significantly lower than the expected ≥95% RCP product specification. Besides free... 18 Besides F, there are two other radioactive impurities in the initial time point chromatogram [ 18 The F]DCFPYL peak eluted before the others but showed no increase over time. These could be process impurities rather than ongoing radiolytic degradation. There were also two additional peaks below the reportable limit of 0.3% w / w at [ 18 The product peak of F]DCFPYL was eluted afterward. Data are provided in Table 17. Figure 15 The chromatogram for T=0 hours is provided.

[0223] One batch was produced using 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution pre-loaded into a collection vial. The HLB column was also washed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. [The remaining text appears to be incomplete and requires further context.] 18F]DCFPYL was delivered from HLB to a vial containing 1.3 mL of 0.9% sodium chloride (USP). The product was determined and diluted with 0.9% sodium chloride (USP) to the desired radioactive concentration. Samples were taken and determined every 30 minutes. For HPLC analysis of radiochemical purity, 44 mg / mL of tetraethylammonium fluoride was added to the sample to reduce column retention and sharpen free radicals. 18 The F peak allows for better quantification. The product has a radiochemical concentration of 256 mCi / mL. The initial RCP is 99.7%, and free... 18 The F impurity level was 0.29%. This was observed in the control batch. 18 Of the two impurities eluted prior to the F]DCFPYL peak, only one was occasionally present, ranging from < LLQ to 0.35%, but not consistently observed at reportable levels (> 0.3%). At T=4 h, RCP was 98.0%. Data for this batch are provided in Table 18. This clearly demonstrates that radiolysis was significantly reduced when ascorbic acid was added to the collection vial.

[0224] A batch was produced using 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution pre-loaded into a collection vial. The HLB column was also washed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. Finally, [ 18 F]DCFPYL was collected in vials pre-loaded with 50 mg / mL ascorbic acid solution at pH 5.8, and analyzed by Capintec, with dilution to the desired concentration using 50 mg / mL ascorbic acid solution at pH 5.8. Samples were taken and analyzed every 30 minutes. For HPLC analysis of radiochemical purity, 44 mg / mL tetraethylammonium fluoride was added to the sample to reduce column retention and sharpen free radicals. 18 The F peak allows for better quantification. The product has a radiochemical concentration of 110 mCi / mL and an ethanol level of 24% (w / w). The initial RCP is 99.7%, and 18 The F impurity is <LLQ. The impurity observed in the control batch is [ 18 The levels of the two impurities eluted prior to the F]DCFPYL peak ranged from <LLQ to 0.37%, but were not always at reportable levels (>0.3%). At T=4 hours, RCP remained above 99%. Data for this batch are provided in Table 19. This clearly demonstrates that the use of ascorbic acid in the collection vessel, wash solution, and FPV significantly reduced radiolysis. However, ethanol... 18 The contribution of F]DCFPYL to stability is unknown.

[0225] Table 17. 0.9% Sodium Chloride (USP) at 147 mCi / mL 18 F]DCFPYL's radiolysis

[0226]

[0227] Table 18. 0.9% Sodium Chloride (USP) a ) of 256 mCi / mL 18 F]DCFPYL's radiolysis

[0228]

[0229] a Collect vials pre-loaded with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid, and receive approximately 5 mL at the peak cut-off point. Wash the HLB column with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid to protect it with a free radical scavenging solution, and transfer the product from the HLB column to a vial containing 1.3 mL of 0.9% sodium chloride (USP). Assay the product and dilute with 0.9% sodium chloride (USP) to the desired radioactive concentration.

[0230] Table 19. Ascorbic acid at 50 mg / mL, pH 5.8 a 110 mCi / mL 18 F]DCFPYL's radiolysis

[0231]

[0232] a Collect vials pre-loaded with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid, and collect approximately 5 mL at the peak cut. Wash the HLB column with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid to protect it with a free radical scavenging solution, and transfer the product from the HLB column to a vial containing 1.3 mL of 50 mg / mL, pH 5.8 ascorbic acid. Assay the product and dilute to the desired radioactive concentration with 50 mg / mL, pH 5.8 ascorbic acid.

[0233] exist 18 The [initial activity (> 10 Ci) was conducted at the following conditions] 18 F]DCFPyL Research

[0234] The activity was studied at levels exceeding the current product limit by 80 mCi / mL. 18 Stability of F]DCFPYL injection solution. Add ascorbic acid as a radioprotective agent to FPV and / or to the "delivery solution vial" (position F, Figure 13 (or, as shown in Table 20, not included in batch production.) A list of solution compositions for these studies is provided in Table 21. The initial activity target for the labeled reaction was 15 Ci, with the aim of producing products with a radioactivity concentration > 120 mCi / mL.

[0235] Ascorbic acid at pH 6.0 was incorporated into three batches of final product vials (FPV). Three batches were produced using 17.6 Ci, 13.5 Ci, and 13.4 Ci. 18 These batches were prepared with initial activity F to achieve final activity concentrations of 166 mCi / mL, 120 mCi / mL, and 127 mCi / mL, respectively. The samples were determined using radiochemical HPLC at 0, 2, 4, 6, and 10 hours after the end of synthesis (EOS). Table 22 provides the results for batches 220816 PyL, 220817 PyL, and 220818 PyL at T=0, T=4, and T=10 hours. Figures 16 to 20 The RCP and other protocols are provided respectively. 18 F. Results plots of peaks at retention times (RT) of 6.0, 9.8, and 10.6 minutes, including additional time point data not listed in Table 22.

[0236] Data and graphs of total RCP as a function of time indicate that when the ascorbic acid level is 5.6 mg / mL, [ 18 F]DCFPYL is more stable at lower radioactive concentrations (RCP of 95.5% and 96.9% at 166 and 120 mCi / mL, respectively, at T=10 hours), while for formulations with approximately the same radiochemical concentrations (120 to 127 mCi / mL), reducing the ascorbic acid concentration to 2.8 mg / mL results in a lower RCP (96.9% vs. 96.9% RCP). Figure 16 When compared to a batch prepared in ascorbic acid at 5.6 mg / mL, pH 6.0 (165 mCi / mL), the batch prepared at 2.8 mg / mL, pH 6.0, with a concentration of 127 mCi / mL, showed slightly better stability (approximately 0.5% RCP difference), consistent with greater radiolysis at higher radioactive concentrations. Figure 16 When compared to batches formulated in ascorbic acid at 5.6 mg / mL, pH 6.0 but with a similar radioactivity concentration (120 mCi / mL), the stability of the same batch was slightly worse (approximately 0.5% difference). This is consistent with the lower concentration of ascorbic acid in the formulation providing less radiation protection, and is also evident from the 18F formation plots of these batches. Figure 17 .

[0237] The peaks at retention times of 6.0, 9.8, and 10.6 minutes ranged from 0.4% to 0.6% at T=0 minutes and showed minimal changes (< 0.2%) from their initial levels over the 10-hour study period. Figure 22 Representative chromatograms are provided. The lack of significant change from T=0 to T=10 hours suggests that these three peaks are process impurities. Overall, all three batches did not achieve the expected RCP (>99%) at T=0 hours, and the lower RCP results are likely due to the presence of process impurities. However, these batches do demonstrate that adding both 2.8 and 5.6 mg / mL of ascorbic acid to the FPV stabilizes the product even at concentrations up to 165 mCi / mL. 18 Degradation of F]DCFPYL.

[0238] Table 20. Location of ascorbic acid addition in FPV ascorbic acid study

[0239]

[0240] Table 21. Addition of ascorbic acid (pH 6) to FPV

[0241]

[0242] a 16 mL saline plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0243] b 16 mL saline plus 20 mL of 5 mg / mL ascorbic acid = (20 mL × 5 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0244] Table 22. Check the addition of ascorbic acid to [ 18 Results of the initial batch of F]DCFPYL formulation

[0245]

[0246] a n / a = Not applicable

[0247] b nt = Untested

[0248] In addition to adding ascorbic acid (5 mg / mL) to the 20 mL saline pre-filled into the final product vial (FPV), ascorbic acid (5 mg / mL) was also added to the saline vial (position F) used to deliver the product from the HLB column to the FPV. Figure 13), and put it in high [ 18 The results for RCP and free 18F were examined under the condition of F]DCFPyL. Batch 220819PyL was produced with an initial activity of 13.7 Ci and the radioactivity concentration of the product at EOS was 134 mCi / mL. The results for RCP and free 18F of batch 220819PyL (5 mg / mL ascorbic acid in both FPV and delivery solution) and batch 220817PyL (10 mg / mL ascorbic acid in FPV only, diluted to 5 mg / mL with delivery solution) were similar, at 97.9% vs. 97.8% and 0.52% vs. 0.6%, respectively, and indicated that using ascorbic acid (5 mg / mL) at pH 6.0 to deliver the product from HLB did not provide additional stabilizing effect, Table 22.

[0249] Production batch 220908PyL (HCI) was used to determine the presence of impurities with RTs of approximately 6.0, 9.8, and 10.6 in the peak slices from the semi-preparative HPLC purification. The peak slices were delivered to collection vials containing 35 mL of SWFI. The contents of the collection vials were immediately delivered to an FPV containing 16 mL of 0.9% saline and analyzed immediately without further processing. This provided an assessment of whether the observed impurities were process impurities. The RC impurities at the peaks with RTs of 6.0, 9.8, and 10.6 min were 2.13%, 1.42%, and 0.72%, respectively, and were consistent with levels observed in batches produced in FPV using ascorbic acid (Table 22). This further supports the conclusion that the peaks with RTs of 6.0, 9.8, and 10.6 are process impurities. Figure 23 Radiochemical chromatograms are provided.

[0250] Add ascorbic acid (position I) to the collection vial. Figure 13 )

[0251] Further studies were designed to determine whether stabilizing the purified product could increase [the effectiveness] prior to the solvent exchange step on the HLB column. 18 The initial RCP of F]DCFPyL. As shown in Table 23, ascorbic acid was added to the collection vial (position I, Figure 13 ) and / or add to "delivery solution vial" (position F, Figure 13 Table 24 provides a list of the solution compositions used in these studies.

[0252] Ascorbic acid was used to produce batch 220909Pyl(HCI) loaded into the collection vial and FPV at pH 6.0. The concentration of ascorbic acid in the FPV was 5.6 mg / mL after product delivery from the HLB column. The pH of the product in the collection vial was 4.7 after peak cut. The radiochemical concentration in the FPV was 89 mCi / mL, significantly lower than the expected >120 mCi / mL. The initial RCP was 99% and remained >97% at 4 hours (Table 25). Although this study shows […] 18 The F]DCFPyL exhibited good stability, but the radioactivity concentration was not high enough to support a stability assessment at high radioactivity concentrations. At T=4 hours, process impurities were below reportable levels (< 0.3%). Figure 24 The results from this study, combined with the analysis results from peak cuts analyzed without further treatment (batch 220908PyL), indicate that the impurity is a degradation product rather than a process impurity, as it can be reduced by stabilizing the product with ascorbic acid prior to solvent exchange. High levels of radioactivity were detected by the AIO waste pipeline radioactivity detector during solvent exchange, indicating that the product was not well retained on the HLB column. Hypothesis [ 18 The retention of F]DCFPyL on an HLB column decreased with increasing pH, which is consistent with the increase in [[] with increasing pH. 18 The ionization phase of F]DCFPyL is consistent.

[0253] Batch 220914PyL (HCI) was produced using delivery solution vials and 5.0 mg / mL ascorbic acid at pH 6 in FPV. Vials containing 5.0 mg / mL ascorbic acid at pH 2 were collected to test whether the pH of the sample loaded onto the HLB column affected […]. 18 F]DCFPyL retained. The product's radioactivity concentration is 159 mCi / mL, with RCP of 99.0% and 97.6% at T=0 and T=4 hours, respectively. Radiochemical impurities did not reach reportable levels (Table 25). Figure 25 Radiochromatograms at T=4 hours are provided. RCP results were similar to those of the product produced without the addition of ascorbic acid to the saline vials (batch 220909 PyL; 99.6% and 98.8% at T=0 and T=4 hours, respectively, Table 25). Lowering the pH of the collection vials to 2 resulted in product retention, which was barely observed in the HLB column wash buffer. 18 F]DCFPyL (based on low radioactivity detected by the AIO waste pipeline radioactivity detector).

[0254] Batch 220927 (HCI) was prepared using 10.0 mg / mL, pH 6.0 ascorbic acid in an FPV vial and 5.0 mg / mL, pH 2 ascorbic acid loaded into a collection vial. The radiochemical concentration of this batch was 127 mCi, and the RCP was 99.0% and 98.1% at T=0 and T=10 hours, respectively (Table 25). Although the radiochemical impurities were close to the limit (0.3%), they did not reach reportable levels. Figure 26 Radiochromatograms are provided. The results for this batch are similar to those for batch 220914PyL (99.0 and 98.6 at T=0 and T=4 hours, respectively [no ascorbic acid in the delivery vial], Table 26), indicating that the presence of ascorbic acid in the saline vial does not improve stability compared to simply adding it to the collection vial.

[0255] Batch 220928PyL (HCl) was prepared by delivering 10 mg / mL ascorbic acid (pH 6.0) in vials, collecting 5 mg / mL ascorbic acid (pH 2.0) in vials from the SWFI, and preparing saline in the FPV. The radiochemical concentration was 138 mCi / mL, with RCPs of 99.7%, 98.3%, and 97.8% at T=0, T=4, and T=10 hours, respectively, reproducing the results of batch 220927PyL at T=0, T=4, and T=10 hours (99.0%, 98.0%, and 98.0%, respectively). (Table 25) No reportable radiochemical impurities were found. Figure 27 The radiochemical chromatogram is provided. Adding ascorbic acid to a saline vial offers no advantage over simply placing ascorbic acid directly into the saline vial.

[0256] Table 23. Location of Ascorbic Acid Addition in the Initial Collection of Vial Ascorbic Acid Study

[0257]

[0258] Table 24. Studies on the addition of ascorbic acid to collection vials (Location I, Figure 13 )

[0259]

[0260] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0261] bThe concentration of ascorbic acid is calculated as follows: 5.0 mg / mL ascorbic acid in 16 mL of 0.9% sodium chloride (USP) plus 5 mg / mL ascorbic acid in 20 mL of 0.9% sodium chloride (USP) = [(16 mL × 5 mg / mL) + (20 mL × 5 mg / mL) / 36 mL = 5.0 mg / mL ascorbic acid].

[0262] c The concentration of ascorbic acid (10.0 mg / mL) in 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 0.9% sodium chloride (USP) equals [(16 mL × 5 mg / mL) + (20 mL × 5 mg / mL) / 36 mL = 4.4 mg / mL ascorbic acid].

[0263] Table 25. Adding ascorbic acid to the collection vial

[0264]

[0265] nt = Untested

[0266] LLQ = below the limit of quantitation

[0267] Table 26. Adding ascorbic acid to the collection vial

[0268]

[0269] a nt = Untested

[0270] b LLQ = below the limit of quantitation

[0271] Effects of FPV pH and ascorbic acid concentration on formulation stability

[0272] Based on studies showing a pH drift to approximately pH 6.8 at T=10 hours, a formulation pH target of 5.5 was selected for ascorbic acid preparations. Production involved loading collection vials with 35 mL of 10 mg / mL ascorbic acid at pH 2 in 0.9% sodium chloride (USP), and preloading 20 mL of 10 mg / mL ascorbic acid at pH 5.5 in 0.9% sodium chloride (USP) into the FPV. After delivering the purified product from an HLB solvent exchange column to the FPV, the resulting concentration of ascorbic acid in the product was 5.6 mg / mL.

[0273] The effect of FPV pH on [the target pH and pH limits of 4.5 and 7.0] was investigated. 18The effect of F]DCFPyL stability. Batches were prepared at pH 4.5, 5.5, and 7.0, and RCP and pH analyses were performed on samples at 0, 2, 4, 6, and 10 hours. A summary of the composition of delivery vials, collection vials, and FPV is provided in Table 27.

[0274] Batch 221025Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from a collection vial and 10.0 mg / mL ascorbic acid at pH 5.5 from an FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 98.9% at 0 hours and 97.4% at 10 hours (Table 28). One radiochemical impurity was present at approximately 0.5% within 4 hours, but was absent after 4 hours. No other impurities were found at reportable levels. Figure 28 The chromatogram for T=10 hours is provided.

[0275] Batch 221026Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 4.5 from the FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 99.4% at 0 hours and 98.0% at 10 hours (Table 28). No reportable radiochemical impurities were found throughout the study. Figure 29 The chromatogram for T=10 hours is provided.

[0276] Batch 230124Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 7.5 from the FPV. The radiochemical concentration of the product was 162 mCi / mL. The RCP was 99.2% at 0 hours and 97.4% at 10 hours (Table 28). No reportable radiochemical impurities were found throughout the study. Figure 30 The chromatogram for T=10 hours is provided.

[0277] Table 27. Study of [18F]DCFPyL products at different pH levels

[0278]

[0279] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0280] Table 28. Data on [18F]DCFPyL produced at different pH values

[0281]

[0282] a LLQ = below the limit of quantitation

[0283] The highest radiochemical concentration produced at the pH limits (4.5 and 7.0) was 165 mCi / mL. 18 [F]DCFPyL, expected to meet RCP and related chemical impurity product specifications within 10 hours after EOS. The lowest actual RCP value is 97.4%, which is also at the highest pH (7.5) and highest radioactive concentration (162 mCi / mL). In one embodiment, this study supports the use of an ascorbic acid formulation at 5.5 mg / mL, pH 5.5, and provides the following confirmation: products at or near the pH specification acceptance limit of 4.0 to 7.0 will meet ≥96% RCP specifications at concentrations up to 165 mCi / mL.

[0284] The effects of ascorbic acid on [target ascorbic acid levels and at specification limits of 3.0 and 7.0 mg / mL] were investigated. 18 The effect of F]DCFPyL on stability. Preparation batches were analyzed, and RCP and pH of samples were performed at 0, 2, 4, 6, and 10 hours. Table 29 provides a summary of the composition of delivery vials, collection vials, and FPV.

[0285] Batch 230130 PyL was prepared using 10 mg / mL ascorbic acid (pH 2.0) from a collection vial and 3.3 mg / mL ascorbic acid (pH 5.5) from an FPV. The radiochemical concentration of the product was 150 mCi / mL. The RCP was 99.0% at 0 hours and 96.7% at 10 hours (Table 30). No other radiochemical impurities were found at reportable levels. Figure 31 The chromatogram for T=10 hours is provided.

[0286] Batch 221026 PyL was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 5.5 from the FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 99.4% at 0 hours and 98.0% at 10 hours (Table 30). No reportable radiochemical impurities were found throughout the study. Figure 29 The chromatogram for T=10 hours is provided.

[0287] Batch 230131 PyL was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 14.0 mg / mL ascorbic acid at pH 5.5 from the FPV. The radiochemical concentration of the product was 165 mCi / mL. The RCP was 99.0% at 0 hours and 97.3% at 10 hours (Table 30). No reportable radiochemical impurities were found throughout the study. Figure 32 The chromatogram for T=10 hours is provided.

[0288] Table 29. Study of [18F]DCFPyL products at different ascorbic acid levels

[0289]

[0290] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 6 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 3.3 mg / mL ascorbic acid

[0291] b 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0292] 5.5c 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 14 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 7.8 mg / mL ascorbic acid

[0293] Table 30. Data on [18F]DCFPyL produced at different ascorbic acid concentrations

[0294]

[0295] a LLQ = below the limit of quantitation

[0296] Radiochemical concentrations up to 165 mCi / mL were produced at target and specification levels of ascorbic acid (3.0, 5.0, and 7.0 mg / mL). 18[F]DCFPyL, expected to meet RCP and related chemical impurity product specifications within 10 hours after EOS. The minimum practical RCP value for batches with an ascorbic acid concentration of 3.0 mg / mL and a radioactivity concentration of 150 mCi / mL is 96.7%. In one embodiment, this study supports an ascorbic acid formulation of 5.5 mg / mL, pH 5.5, and provides the following confirmation: products at or near the ascorbic acid specification acceptance limit of 3.0 to 7.0 mg / mL will meet ≥95% RCP specifications at concentrations up to 165 mCi / mL.

[0297] pH affects HLB column [ 18 The impact of F]DCFPyL retention

[0298] The aim of this study was to characterize the effect of pH on HLB solvent exchange columns. 18 The effect of F]DCFPyL retention. Three different 10 mg / mL ascorbic acid solutions were prepared. The pH of one solution was adjusted to 2 by adding 1N HCl, and the pH of the second solution was adjusted to 4. The third solution was used without adjusting its initial pH of 7.2. Using a BD syringe, 0.5 mL of 100 μg / mL stock solution was added to 10 mL of each solution to spike [ 19 [F]DCFPyL (50 μg). Each spiking solution was loaded onto an HLB column at a rate of approximately 2 mL / min. The eluent from each HLB column was collected separately and labeled “Loading Solution”. Each HLB column was then washed with 10 mL of water at a rate of approximately 2 mL / min. The eluent from each HLB column was collected separately and labeled “Wash Solution”. Each HLB column was then eluted separately with 1 mL of ethanol, and the sample was collected and labeled “Product Sample”. The loading and wash solutions were analyzed using a pharmaceutical product chemical impurity assay after diluting 1 mL to 10 mL with saline, while the ethanol product sample was analyzed after diluting 0.5 mL to 10 mL with saline.

[0299] Loading and recovering samples 19 The concentration of F]DCFPyL varies as a function of pH. At pH 7.2, 19 F-DCFPYL was not retained by the HLB column but was recovered into the loaded sample. A small amount of [[ was recovered in the washed sample]] 19 F]DCFPyL (3.8 μg / mL) was not recovered in the product sample. A portion was recovered in the loaded sample in the sample at pH 4. 19F]DCFPyL (approximately 31% < 1 μg), and a larger amount was recovered in the product sample (approximately 68% of the total recovered from all samples). No [F] was detected in the loaded or washed samples at pH 2. 19 F]DCFPyL. Recover [in product solution] 19 F]DCFPyL. The HLB column at pH 2 was eluted with a second volume of ethanol, with a recovery rate of 98%. [Observed] 19 Additional recovery of F]DCFPyL (approximately 25% of the amount recovered in the first elution).

[0300] Recovery rates are based on the concentration in the sample and the volume of the solution used. Volume loss in the dead space or adsorption of [19F]DCFPyL on the surface may explain why the overall recovery rate is less than 100%. Nevertheless, it is clear that retention at a lower pH (e.g., pH 2) is optimal. These studies suggest that, in one embodiment, the pH of the collection vial solution (the solution loaded onto the HLB solvent exchange column) can be set to pH 2.

[0301] Table 31. Recovery rates of loaded, rinsed, and product samples from solvent-exchange HLB columns

[0302]

[0303] Example 13. 18 F]DCFPyL formulation

[0304] Table 33 provides the composition of PYLARIFY. The formulation is 0.9% sodium chloride (USP) with up to 7.89% ethanol (w / v) (typical batch contains about 3% ethanol). Figure 13 The process solution is provided in the document. Figure 14 A schematic diagram of the Trasis One-Step (AIO) synthesis module with indicated reagents or reagent locations is provided. The upper limit of radioactivity concentration at the end of synthesis (EOS) for this product is 80 mCi / mL. The main observed radiodegradation product is free radioactive. 18 F, and it is through 18 F-DCFPyL is formed by radiolysis. The rapid commercialization of PYLARIFY has led to some commercial PMFs requiring multiple batches to be produced daily.

[0305] To ensure unrestricted drug supply, products with higher radioactive concentrations (>120 mCi / mL) at EOS are desirable, as this will provide more doses per batch. Several studies were conducted to examine the addition of radioprotective agents to drug products to minimize potential radiolysis of the drug substances, thereby achieving higher radioactive concentrations. The ability of ascorbic acid to stabilize PYLARIFY at radioactive concentrations >120 mCi / mL was examined. A flowchart indicating the different locations of ascorbic acid in the production process is presented to protect the product at high radioactive points. Ascorbic acid can be used as part of the product delivery from the HLB solvent exchange column (ascorbic acid added to the delivery solution vial; position F on the AIO, ...). Figure 14 Ascorbic acid is introduced into the final product vial (FPV) via direct introduction into the FPV. In any of the methods provided herein, ascorbic acid is introduced at any of the concentrations provided herein in such a step. Adding ascorbic acid to a collection vial for receiving peak cuts from semi-preparative purification also provides a potential pathway for stabilizing the product prior to the solvent exchange step. In any of the methods provided herein, ascorbic acid is introduced at any of the concentrations provided herein in such a step.

[0306] Table 33: Exemplary Formulation Composition of PYLARIFY

[0307]

[0308] a TOA = Time of application

[0309] b Depends on the specific activity of the batch at the end of synthesis (EOS) and the hysteresis time between EOS and TOA.

[0310] c After production, the product is diluted with physiological saline to achieve a radiochemical concentration ≤ 80 mCi / mL at EOS. The degree of dilution varies depending on the initial batch size (1 Ci to 10 Ci) and process yield.

[0311] Table 34 provides exemplary PYLARIFY product specifications. Table 35 provides a general test plan as an example. In some implementations, the test timing can be modified.

[0312] Table 34: PYLARIFY Product Specifications

[0313]

[0314] a Radiochemical consistency = (1 - [RT of hot peak] / [RT of cold peak]) 100%

[0315] b Due to the specific activity and shelf life of less than 10 hours, this does not preclude the use of this batch for the purposes of this program.

[0316] Table 35: Test Plan

[0317]

[0318] Preliminary studies were conducted at an 18F initiation activity of approximately 2 Ci.

[0319] Feasibility studies were conducted on stabilizing PYLARIFY using ascorbic acid by adding it to 1) a collection vial for receiving product peak cuts from a semi-preparative purification step, 2) a pretreatment step using an HLB column for solvent exchange, and / or 3) a final product vial. In any of the methods provided herein, ascorbic acid is introduced in such steps at any of the concentrations provided herein.

[0320] The first experiment was conducted to understand the product's stability in ethanol, serving as a benchmark for measuring improvements. It also provided information on radiochemical impurities that could form at very high radioactive concentrations before the product was exposed to an aqueous medium. The product was collected in 10 mL GRACE headspace vials, which were then capped and crimped. The final product volume was 1.41 mL, with a final product activity of 514 mCi at the end of synthesis and a final radioactive concentration (RAC) of 364.5 mCi / mL for the production batch. To analyze the product at each time point, the vials were unsealed, aliquots were taken using a pipette, and diluted with saline (at this point, the product was no longer in a nitrogen atmosphere but exposed to air). The results are presented in the table.

[0321] Table 36: At high activity concentrations 18 Forced radiolysis of F-DCFPyL

[0322]

[0323] All times are in hours.

[0324] b. Add TEAF to sharpen the 18F peak – 44 mg TEAF plus 1 mL of product (44 mg / mL)

[0325] c All values ​​are area percentages.

[0326] The data shows that the only radioactive impurity formed in ethanol is 18 F. 18Fluorine (F) is displaced over time, with levels initially rising and then stabilizing over time. Ethanol is a free radical scavenger, but in this study, fluorine was primarily displaced within 4 hours after EOS, indicating that this occurs in the presence of ethanol as a free radical scavenger. It is known that halogens undergo displacement from the pyridine ring under harsh alkaline conditions (e.g., with sodium methoxide or sodium ethoxide solutions). These are only present in aqueous media. In the case of eluting an HLB column during treatment, any water remaining in the HLB can be incorporated into the elution band.

[0327] Examination of the chromatogram confirmed that it was difficult to determine the width. 18 Integrating the F peak, and 18 The plateau in F formation can be caused by challenges associated with its integration. When TEAF (tetraethylammonium fluoride) was added to the product at the 10-hour time point, the peak was sharper and easier to integrate. The level of radiolytic impurities was 7.35% at this point, compared to 4.55% when TEAF was not added to the sample. Notably, the ethanol eluting the HLB column contained 2 to 3 Ci of impurities upon exiting the HLB column. 18 F-DCFPyL indicates that the likelihood of radiolysis is much higher in ethanol alone than in a batch of product solution. Figure 5 The chromatograms of injectable products with and without TEAF are presented at the 10-hour time point.

[0328] Preliminary studies were then conducted, among which the largest 18 The F-process was limited to approximately 2 Ci to minimize radiation exposure. To achieve a radioactive concentration of approximately 120 mCi / mL, the labeled product was eluted from an HLB column used for solvent exchange and delivered using nitrogen pusher to a receiving vial pre-loaded with at least 1.3 mL of formulation matrix (0.9% sodium chloride (USP) or ascorbic acid (USP)). The product was then measured using a Capintec dosimeter and diluted to achieve the desired radioactive concentration. This resulted in a product with a higher ethanol level (approximately 20%). While ethanol is known to provide some protection against radiolysis, this study at high ethanol levels still provides a method for preliminary evaluation using ascorbic acid stabilization.

[0329] The control batch produced did not contain ascorbic acid, and its final radiochemical concentration was 147 mCi / mL with an ethanol level of 29.8%. Product samples were taken every 30 minutes, and an extended gradient was added for assay to allow for the detection of hydrophobic impurities. The product was delivered from the HLB to a vial containing 1.3 mL of 0.9% sodium chloride (USP). The product was assayed and diluted with 0.9% sodium chloride (USP) to achieve the desired radiochemical concentration. The initial radiochemical purity (RCP) was 94%, and the RCP at T=4 hours was 89%, well below the ≥95% RCP specification. (Except for free...)18 Besides F, there are two other radioactive impurities in the initial time point chromatogram. 18 The F-DCFPyL peaks eluted earlier but showed no increase over time. These could be process impurities rather than ongoing radiolytic degradation. There were also two additional peaks below the reportable limit of 0.3% w / w. 18 Elution followed by the F-DCFPyL product peak. Data are provided in Table 37. Chromatograms at T=0 hours are shown in... Figure 6 Provided by China.

[0330] One batch was produced using 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution pre-loaded into a collection vial. The HLB column was also washed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. Then, 25 mL of 100 mg / mL, pH 2.0 ascorbic acid was filled into the original delivery solution vial (position F). Figure 13 Once the product is captured on the HLB, the ascorbic acid solution is used to wash the HLB and replace the SWFI for solvent exchange. Then... 18 F-DCFPyL was delivered from HLB to an empty product vial in 100% ethanol. The product was then analyzed. To analyze the sample, 12.5 μL of the required amount of product in 100% ethanol was diluted with 237.5 μL of saline. Sampling and analysis were performed every 30 minutes. 44 mg / mL of tetraethylammonium fluoride was added to the sample for radiochemical purity HPLC analysis to reduce column retention and sharpen the column. 18 The F peak allows for better quantification. The product has a radiochemical concentration of 256 mCi / mL. The initial RCP is 99.7%, and... 18 The F impurity level was 0.29%. This was observed in the control batch. 18 Of the two impurities eluted prior to the F-DCFPyL peak, only one was occasionally present, ranging from <LLQ to 0.35%, but was not consistently observed at reportable levels (>0.3%). The RCP was 98.0% at T=4 hours. Data for this batch are provided in Table 38. This clearly demonstrates that radiolysis was significantly reduced when ascorbic acid was added to the collection vial. Figure 8 The chromatograms at T=0 and T=4 hours are shown in the superimposed image.

[0331] A batch was produced using 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution pre-loaded into a collection vial. The HLB column was also washed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. Finally, the... 18F-DCFPyL was collected in final product vials pre-loaded with 50 mg / mL ascorbic acid solution at pH 5.8, determined by Capintec, and diluted to the desired concentration with 50 mg / mL ascorbic acid solution at pH 5.8. Product samples were taken and determined every 30 minutes, with 44 mg / mL of tetraethylammonium fluoride added. The radiochemical concentration of the product was 110 mCi / mL, and the ethanol level was 24% (w / w). The initial RCP was 99.7%, and... 18 Impurity F is < LLQ. This was observed in the control batch. 18 The levels of the two impurities eluted prior to the F-DCFPyL peak ranged from <LLQ to 0.37%, but were not always at reportable levels (>0.3%). At T=4 hours, RCP remained above 99%. Data for this batch are provided in Table 39. Figure 9 The chromatograms at T=0 and T=4 hours are shown in superimposed view. This clearly demonstrates that the use of ascorbic acid in the collection vessel, washing solution, and FPV significantly reduces radiolysis. However, ethanol has a negative effect on... 18 The stabilizing effect of F-DCFPyL is unknown.

[0332] Table 37: 147 mCi / mL sodium chloride in 0.9% sodium chloride (USP) 18 Radiolysis of F-DCFPyL

[0333]

[0334] All times are in hours.

[0335] b represents all values ​​as a percentage of area.

[0336] Table 38: Ethanol at 256 mCi / mL 18 Radiolysis of F-DCFPyL

[0337]

[0338] a Collect vials pre-loaded with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid, and receive approximately 5 mL at the peak cut-off point. Wash the HLB column with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid to protect it with a free radical scavenging solution, and transfer the product from the HLB column to the vial in ethanol. Assay the product.

[0339] b All times are in hours.

[0340] c All values ​​are area percentages.

[0341] Table 39: 110 mCi / mL of ascorbic acid at 50 mg / mL and pH 5.8 18 Radiolysis of F-DCFPyL

[0342]

[0343] A collection vial is pre-loaded with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid, and approximately 5 mL is collected at the peak cut-off point. The HLB column is washed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid to protect it with a free radical scavenging solution, and the product is transferred from the HLB column to a vial containing 1.3 mL of 50 mg / mL, pH 5.8 ascorbic acid. The product is analyzed and diluted with 50 mg / mL, pH 5.8 ascorbic acid to the desired radioactive concentration.

[0344] All times are in hours.

[0345] All values ​​for c represent area percentage.

[0346] Inspect the initial batch of PYLARIFY formulation containing ascorbic acid.

[0347] The activity was studied at levels above the currently approved product limit of 80 mCi / mL. 18 The stability of F-DCFPyL injection was assessed. Ascorbic acid was added to the FPV as a radioprotective agent to demonstrate the feasibility of stabilizing the product, and subsequently added to the delivery solution vial to determine the effectiveness of adding ascorbic acid salt to the saline solution (position F) used to deliver the product from the HPB column to the FPV. Figure 13 Whether additional stability can be achieved in the sample is shown in Table 40. The last batch in this sequence was examined for peak shaving stability in the collection vials (not delivered to FPVs containing ascorbate). A list of solution compositions for these studies is provided in Table 41. The initial activity target for the labeling reaction was 15 Ci, with the goal of producing a product with a radioactivity concentration > 120 mCi / mL.

[0348] Ascorbic acid at pH 6.0 was incorporated into three batches of final product vials (FPV). Three batches were produced using 17.6 Ci, 13.5 Ci, and 13.4 Ci. 18These batches were prepared with initial activity F to achieve final activity concentrations of 166 mCi / mL, 120 mCi / mL, and 127 mCi / mL, respectively. The samples were determined using radiochemical HPLC at 0, 2, 4, 6, and 10 hours after the end of synthesis (EOS). Table 42 provides the results for batches 220816 PyL, 220817 PyL, and 220818 PyL at T=0, T=4, and T=10 hours. Figures 16 to 20 The RCP and other protocols are provided respectively. 18 F. Results plots of peaks at retention times (RT) of 6.0, 9.8, and 10.6 minutes, including additional time point data not listed in Table 42.

[0349] Data and graphs of total RCP as a function of time indicate that when the ascorbic acid level is 5.6 mg / mL, 18 F-DCFPyL is more stable at lower radioactive concentrations (RCP of 95.5% and 96.9% at 10 hours T=10, respectively, at 166 and 120 mCi / mL), while for formulations with approximately the same radiochemical concentrations (120 to 127 mCi / mL), reducing the ascorbic acid concentration to 2.8 mg / mL results in a lower RCP (96.9% vs. 96.1% RCP). When compared to batches formulated in ascorbic acid at 2.8 mg / mL, pH 6.0 (165 mCi / mL), batches formulated at 127 mCi / mL have slightly better stability (approximately 0.5% RCP difference), consistent with the greater radiolysis at higher radioactive concentrations. The same batch exhibited slightly worse stability (approximately 0.5% difference) compared to batches formulated in ascorbic acid at 5.6 mg / mL, pH 6.0 but with a similar radioactive concentration (120 mCi / mL). This is consistent with the lower concentrations of ascorbic acid in formulations providing less radiation protection, and is also consistent with the stability observed in these batches. 18 The formation of F is also evident in the diagram.

[0350] The peaks with retention times of 6.0, 9.8, and 10.6 minutes ranged from 0.4% to 0.6% at T=0 minutes and showed minimal changes (< 0.2%) from their initial levels over the 10-hour study period. Figure 20Representative chromatograms are provided. The lack of significant change from T=0 to T=10 hours suggests that these three peaks are process impurities or formed before transfer to FPV. Overall, all three batches did not achieve the expected RCP (>99%) at T=0 hours, and the lower RCP results are likely driven by the presence of process impurities. However, these batches do demonstrate that adding both 2.8 and 5.6 mg / mL of ascorbic acid to FPV stabilized the process. 8 F-DCFPyL degradation occurs even at concentrations as high as 165 mCi / mL.

[0351] In addition to adding ascorbic acid (5 mg / mL) to the 20 mL saline pre-filled into the final product vial (FPV), ascorbic acid (5 mg / mL) was also added to the saline vial (position F) used to deliver the product from the HLB column to the FPV. Figure 13 ), use high 18 The concentration of F-DCFPyL was examined. Batch 220819PyL was produced with an initial activity of 13.7 Ci, and the radioactivity concentration of the product at EOS was 134 mCi / mL. The RCP of batches 220819PyL (5 mg / mL ascorbic acid in both FPV and delivery solution) and 220817PyL (10 mg / mL ascorbic acid in FPV only, diluted to 5 mg / mL by adding delivery solution) was also examined. 18 The F results were similar, at 97.9% vs. 97.8% and 0.52% vs. 0.6%, respectively, and indicated that using ascorbic acid (5 mg / mL) at pH 6.0 to deliver the product from HLB did not provide additional stability, Table 42.

[0352] Production batch 220908PyL (HCI) was used to determine the presence of impurities with RTs of approximately 6.0, 9.8, and 10.6 in the peak cut from the semi-preparative HPLC purification. The peak cut was delivered to a collection vial containing 35 mL of SWFI. The contents of the collection vial were immediately delivered to an FPV containing 16 mL of 0.9% saline and analyzed immediately without further processing. This provided an assessment of whether the observed impurities were process or degradation impurities. The peaks at RTs of 6.0, 9.8, and 10.6 min were present at 2.13%, 1.42%, and 0.72%, respectively, and were consistent with levels observed in batches produced in FPV using ascorbic acid (Table 42). Figure 22 Radiochemical chromatograms are provided.

[0353] Table 40: Location of Ascorbic Acid Addition in Initial FPV Ascorbic Acid Study

[0354]

[0355] a This batch is designed to examine radiochemical impurities in semi-preparative HPLC peak cuts and is not subjected to solvent exchange or loaded into FPV.

[0356] Table 41: Addition of ascorbic acid, pH 6 to FPV

[0357]

[0358] a This batch is designed to examine radiochemical impurities in semi-preparative HPLC peak cuts and is not subjected to solvent exchange or loaded into FPV.

[0359] a 16 mL saline plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0360] b 16 mL saline plus 20 mL of 5 mg / mL ascorbic acid = (20 mL × 5 mg / mL) / 36 mL = 2.8 mg / mL ascorbic acid

[0361] Table 42: Results of examining the initial batches of PYLARIFY formulation with ascorbic acid added.

[0362]

[0363] a n / a = Not applicable

[0364] b All times are in hours.

[0365] c All values ​​are area percentages.

[0366] d nt = Untested

[0367] e nd = Not detected

[0368] d Degradation is greater in saline when activity > 80 mCi / mL. Therefore, this sample showed greater degradation. To maintain dataset consistency, the peak at RT 6.4 at T=0 h was not tabulated. The level was 0.61%. At T=4 h, additional peaks were observed at RT 5.0 (0.29%), RT 6.4 (1.99%), RT 8.0 (0.45%), and RT 9.2 (0.55%).

[0369] Add ascorbic acid to the collection vial (position I). Figure 13 )

[0370] Further studies were designed to determine whether the initial RCP of PYLARIFY could be improved by stabilizing the purified product prior to the solvent exchange step on the HLB column. Based on previously completed studies, this appears to be a method of stabilizing the product before loading it into the HLB. As shown in Table 43, in addition to FPV (position F, Figure 13 In addition to ), ascorbic acid will be added to the collection vial (position I, Figure 13 (and / or delivery solution vials). The last batch in this sequence examined adding ascorbic acid to the formulation solely via delivery solution vials, thus eliminating pre-loading of ascorbic acid into the FPV. A list of solution compositions for these studies is provided in Table 44.

[0371] Production batch 220909Pyl(HCI) was prepared using ascorbic acid loaded at pH 6.0 into both the collection vial and the FPV. The concentration of ascorbic acid in the FPV was 5.6 mg / mL after product delivery from the HLB column. The pH of the product in the collection vial was 4.7 after peak cut. The radiochemical concentration in the FPV was 89 mCi / mL, significantly lower than the expected >120 mCi / mL. The initial RCP was 99%, and >97% at 4 hours (Table 45). Although this study demonstrates… 18 F-DCFPyL exhibits good stability, but the radioactivity concentration is not high enough to support a stability assessment at high radioactivity concentrations. At T=4 hours, impurities are below reportable levels (< 0.3%). Figure 24 The results from this study indicate that impurities can be reduced by stabilizing the product with ascorbic acid prior to solvent exchange. High levels of radioactivity were detected by an AIO waste pipeline radioactivity detector during batch 220909Pyl(HCl) production, during solvent exchange, indicating that the product was not well retained on the HLB column. Hypothesis 18 The retention of F-DCFPyL on an HLB column decreased with increasing pH, which contrasts with the increase in retention with increasing pH. 18 The ionization phase of F-DCFPyL is consistent.

[0372] Batch 220914PyL (HCI) was produced in delivery solution vials and FPV using 5.0 mg / mL ascorbic acid at pH 6. Vials containing 5.0 mg / mL ascorbic acid at pH 2 were collected to test whether the pH of the sample loaded onto the HLB column affected the concentration of the ascorbic acid. 18F-DCFPyL retained. The product's radioactivity concentration is 159 mCi / mL, with RCP of 99.0% and 97.6% at T=0 and T=4 hours, respectively. Radiochemical impurities did not reach reportable levels (Table 45). Figure 25 Radiochromatograms at T=4 hours are provided. RCP results were similar to those of products produced without the addition of ascorbic acid to the delivery solution vials (batch 220909 PyL; 99.6% and 98.8% at T=0 and T=4 hours, respectively, Table 45). Lowering the pH of the collection vials to 2 resulted in product retention, which was barely observed in the HLB column wash buffer. 18 F-DCFPyL (based on low radioactivity detected by the AIO waste pipeline radioactivity detector).

[0373] Batch 220927 PyL (HCl) was prepared using 10.0 mg / mL, pH 6.0 ascorbic acid in an FPV vial and 5.0 mg / mL, pH 2 ascorbic acid loaded into a collection vial. The radiochemical concentration of this batch was 127 mCi, and the RCP was 99.0% and 98.1% at T=0 and T=10 hours, respectively (Table 45). Although the radiochemical impurities were close to the limit (0.3%), they did not reach reportable levels. Figure 26 Radiochromatograms are provided. The results for this batch are similar to those for batch 220914PyL (99.0 and 98.6 at T=0 and T=4 hours, respectively [no ascorbic acid in the delivery vial], Table 45), indicating that the presence of ascorbic acid in the delivery vial does not improve stability compared to simply adding it to the collection vial.

[0374] Batch 220928PyL (HCl) was prepared using 10 mg / mL ascorbic acid (pH 6.0) in the delivery solution vial, 5 mg / mL ascorbic acid (pH 2.0) in the collection vial (SWFI), and saline in the FPV. The radiochemical concentration was 138 mCi / mL, with RCPs of 99.7%, 98.3%, and 97.8% at T=0, T=4, and T=10 hours, respectively. This results were reproduced for batch 220927Pyl at T=0, T=4, and T=10 hours, with RCPs of 99.0%, 98.0%, and 98.0%, respectively (Table 45). No reportable radiochemical impurities were found. Figure 27 The radiochemical chromatogram is provided. Adding ascorbic acid to the delivery vial offers no advantage over placing ascorbic acid in the FPV (Final Product Vial) vial.

[0375] Table 43: Location of Ascorbic Acid Addition in Initial Collection of Vial Studies

[0376]

[0377] Table 44: Studies on the addition of ascorbic acid to collection vials (Location I, Figure 13 )

[0378]

[0379] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0380] b The concentration of ascorbic acid is calculated as follows: 5.0 mg / mL ascorbic acid in 16 mL of 0.9% sodium chloride (USP) plus 5 mg / mL ascorbic acid in 20 mL of 0.9% sodium chloride (USP) = [(16 mL × 5 mg / mL) + (20 mL × 5 mg / mL) / 36 mL = 5.0 mg / mL ascorbic acid].

[0381] c The concentration of ascorbic acid (10.0 mg / mL) in 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 0.9% sodium chloride (USP) equals [(16 mL × 5 mg / mL) + (20 mL × 5 mg / mL) / 36 mL = 4.4 mg / mL ascorbic acid].

[0382] Table 45: Adding ascorbic acid to the collection vial

[0383]

[0384] All times are in hours.

[0385] b. All values ​​are area percentages.

[0386] nt = Untested

[0387] d nd = Not detected

[0388] Effects of FPV pH and ascorbic acid concentration on the stability of the target formulation

[0389] Based on the aforementioned studies showing a pH drift from an initial target pH of 6.0 at EOS to approximately pH 6.8 at T=10 hours, the target pH for the ascorbic acid formulation is reduced to 5.5. Production may include loading collection vials with 35 mL of 10 mg / mL ascorbic acid at pH 2 in 0.9% sodium chloride (USP), and preloading 20 mL of 10 mg / mL ascorbic acid at pH 5.5 in 0.9% sodium chloride (USP) into the FPV. After delivering the purified product from an HLB solvent exchange column to the FPV, the concentration of ascorbic acid in the product can be 5.6 mg / mL.

[0390] The effect of FPV pH on FPV was investigated at the target pH and pH limits of 4.5 and 7.0. 18 The effect of F-DCFPyL stability. Batches were prepared at pH 4.5, 5.5, and 7.0, and RCP analysis was performed on samples at 0, 2, 4, 6, and 10 hours, as well as pH analysis at 0 and 10 hours. A summary of the composition of delivery vials, collection vials, and FPV is shown in Table 46.

[0391] Batch 221025Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from a collection vial and 10.0 mg / mL ascorbic acid at pH 5.5 from an FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 98.9% at 0 hours and 97.4% at 10 hours (Table 47). One radiochemical impurity was present at approximately 0.5% within 4 hours, but was absent after 4 hours. No other impurities were found at reportable levels. Figure 28 The chromatogram for T=10 hours is provided.

[0392] Batch 221026Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 4.5 from the FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 99.4% at 0 hours and 98.0% at 10 hours (Table 47). No reportable radiochemical impurities were found throughout the study. Figure 29 The chromatogram for T=10 hours is provided.

[0393] Batch 230124Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 7.5 from the FPV. The radiochemical concentration of the product was 162 mCi / mL. The RCP was 99.2% at 0 hours and 97.4% at 10 hours (Table 47). No reportable radiochemical impurities were found throughout the study. Figure 30 The chromatogram for T=10 hours is provided.

[0394] Table 46: Study of PYLARIFY products at different pH levels

[0395]

[0396] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0397] Table 47: Data on PYLARIFY generated at different pH levels

[0398]

[0399] a All times are in hours. b All values ​​are area percentages. c nd = Not detected

[0400] Discussion of pH studies

[0401] The highest radiochemical concentration produced at the limits of the pH specifications (4.5 and 7.0) was 165 mCi / mL. 18 F-DCFPyL is expected to meet RCP and related chemical impurity product specifications within 10 hours after EOS. The lowest actual RCP value is 97.4%, which is also at the highest pH (7.5) and highest radioactive concentration (162 mCi / mL). This study supports examples of ascorbic acid formulations targeting 5.5 mg / mL at pH 5.5 and provides the following confirmation: products at or near the pH specification acceptance limit of 4.0 to 7.0 will meet ≥95% RCP specifications at concentrations up to 165 mCi / mL.

[0402] Ascorbic acid concentration study

[0403] The effects of ascorbic acid on the target ascorbic acid level and at limits of 3.0 and 7.0 mg / mL were investigated. 18 The effect of F-DCFPyL on stability. Preparation batches were analyzed, and RCP analysis was performed on samples at 0, 2, 4, 6, and 10 hours, as well as pH analysis at 0 and 10 hours. The composition of delivery vials, collection vials, and FPV is summarized in Table 48.

[0404] Batch 230130Pyl was prepared using 10 mg / mL ascorbic acid (pH 2.0) from a collection vial and 3.3 mg / mL ascorbic acid (pH 5.5) from an FPV. The radiochemical concentration of the product was 150 mCi / mL. The RCP was 99.0% at 0 hours and 96.7% at 10 hours (Table 49). No other radiochemical impurities were found at reportable levels. Figure 31 The chromatogram for T=10 hours is provided.

[0405] Batch 221026Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 10.0 mg / mL ascorbic acid at pH 5.5 from the FPV. The radiochemical concentration of the product was 133 mCi / mL. The RCP was 99.4% at 0 hours and 98.0% at 10 hours (Table 49). No reportable radiochemical impurities were found throughout the study.

[0406] Batch 230131Pyl was prepared using 10 mg / mL ascorbic acid at pH 2.0 from the collection vial and 14.0 mg / mL ascorbic acid at pH 5.5 from the FPV. The radiochemical concentration of the product was 165 mCi / mL. The RCP was 99.0% at 0 hours and 97.3% at 10 hours (Table 49). No reportable radiochemical impurities were found throughout the study. Figure 32 The chromatogram for T=10 hours is provided.

[0407] Table 48: Study of PYLARIFY products at different ascorbic acid levels

[0408]

[0409] a 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 6 mg / mL ascorbic acid = (20 mL × 6 mg / mL) / 36 mL = 3.3 mg / mL ascorbic acid

[0410] b 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 10 mg / mL ascorbic acid = (20 mL × 10 mg / mL) / 36 mL = 5.6 mg / mL ascorbic acid

[0411] c 16 mL of 0.9% sodium chloride (USP) plus 20 mL of 14 mg / mL ascorbic acid = (20 mL × 14 mg / mL) / 36 mL = 7.8 mg / mL ascorbic acid

[0412] Table 49: Data on PYLARIFY produced at different ascorbic acid concentrations

[0413]

[0414] a All times are in hours. b All values ​​are area percentages. c nd = Not detected

[0415] Radiochemical concentrations up to 165 mCi / mL were produced at example target and specification levels of ascorbic acid (3.3, 5.5, and 7.8 mg / mL). 18 F-DCFPyL is expected to meet RCP and related chemical impurity product specifications within 10 hours after EOS. The minimum practical RCP value for a batch with an ascorbic acid concentration of 3.3 mg / mL and a radioactivity concentration of 150 mCi / mL is 96.7%. This study supports an example target of 5.6 mg / mL, pH 5.5 ascorbic acid formulations and provides the following confirmation: products at or near the ascorbic acid specification acceptance limit of 3.3 to 7.8 mg / mL will meet ≥95% RCP specifications at concentrations up to 165 mCi / mL.

[0416] pH on HLB column 18 Study on the impact of F-DCFPyL retention

[0417] The aim of this study was to characterize the effect of pH on HLB solvent exchange columns. 18 The effect of F-DCFPyL retention. Three different 10 mg / mL ascorbic acid solutions were prepared. The pH of one solution was adjusted to 2 by adding 1N HCl, and the pH of the second solution was adjusted to 4. The third solution was used without adjusting its initial pH of 7.2. At this pH, the solution would be predominantly sodium ascorbate. Using a BD syringe, 0.5 mL of 100 μg / mL stock solution was added to 10 mL of each solution. 19 F-DCFPyL (50 μg). Each spiking solution was loaded onto an HLB column at a rate of approximately 2 mL / min, and the solution collected after the HLB column was labeled as the loading solution. Each HLB column was then washed with 10 mL of water at a rate of approximately 2 mL / min, and the solution collected after the HLB column was labeled as the wash solution. Each HLB column was then eluted individually with 1 mL of ethanol, and the solution collected after the HLB column was labeled as the product sample. After diluting 1 mL to 10 mL with saline, the loading and wash solutions were analyzed using a drug product chemical impurity assay, while the ethanol product sample was analyzed after diluting 0.5 mL to 10 mL with saline.

[0418] Loading and recovering samples 19 The concentration of F-DCFPYL varies as a function of pH. At pH 7.2, 19 F-DCFPyL was not meaningfully retained by the HLB column but was recovered during sample loading (collected post-column). Small amounts... 19 F-DCFPyL (3.8 μg / mL) was recovered in the wash sample but not in the product sample. At pH 4, a portion... 19 F-DCFPyL (approximately 31%; <1 μg) was recovered in the loaded sample, and a larger amount was recovered in the product sample (approximately 68% of the total recovered from all samples). It was not detected in the loaded or washed samples at pH 2. 19 F-DCFPYL. 19 F-DCFPYL was recovered in the product solution. Because the overall recovery (concentration) was significantly lower than the amount applied to the HLB column, a second ethanol elution volume was used. [The following is a separate, unrelated observation:] It was observed that... 19 Additional recovery of F-DCFPyL (approximately 25% of the amount recovered in the first elution). Results are summarized in Table 50.

[0419] The volumes of different solutions were determined to allow for the calculation of mass recoveries. The results clearly show that at pH 4 and higher, only [the following is observed] on the HLB column. 19 Partial retention of F-DCFPyL. Retention on the HLB column is evident at lower pH levels (e.g., pH 2). These studies suggest that the pH for collecting vials (solutions loaded onto the HLB solvent exchange column) can be set to pH 2.

[0420] Table 50: Recovery rates from solvent-exchange HLB columns for loaded, washed, and product samples.

[0421]

[0422] Research on chemical impurities in ascorbic acid

[0423] Prepared at 163.0 mCi / mL [ 18 During the batch development of F]-DCFPyL, a chemical impurity of 0.9 μg / mL was observed on the UV trace at a retention time of approximately 4.6 minutes. Figure 34 Since this peak was not previously observed in formulations lacking ascorbic acid, it was suspected to be ascorbic acid-related, and further investigation was conducted. Further analysis of decay samples from the manufactured batch confirmed the presence of the peak. Figure 35 To exclude impurities involved in PLYLARIFY and to demonstrate that it is formed from ascorbic acid, free... 18F (129 mCi / mL) was incubated for different times in ascorbic acid solution at 5 mg / mL, pH 6. Chemical impurities in the samples were determined at T = 0, 4, 10, and 24 hours while kept inverted under ambient conditions. The 4.6 min RT peak, assessed by HPLC-UV detection, was absent at T = 0 hours and increased in a time-dependent manner over 24 hours, reaching a concentration of approximately 1.75 μg / mL at T = 24 hours (assuming a concentration similar to […]). 19 The relative response factor of the F]-DCFPyL standard is 1 (see [reference]). Figure 36 This impurity only forms when there is radioactive exposure, and does not form when stored under ambient conditions in light or darkness (see [link]). Figure 37 Because ascorbic acid-related UV impurity peaks can be detected in the absence of PYLARIFY, they can be detected by... 18 The peak formed when F was incubated together did not match the radioactive peak and was not formed by exposure to light or darkness. Therefore, it was concluded that it was formed by radiolysis of ascorbic acid.

[0424] The degradation of ascorbic acid has been studied (Analytical Biochemistry, 265, 238–245 (1998), Journal of Chromatography A, 881 299–307 (2000). The oxidation of ascorbic acid to dehydroascorbic acid (DHA) is a key component in the degradation process. DHA was obtained from Apollo Scientific (catalog number BIB6039) and analyzed using HPLC-UV chemical impurity methods. DHA did not elute simultaneously with other impurities.

[0425] The decayed development sample was analyzed by HPLC / MS. For mass spectrometry compatibility, 0.1% formic acid was used instead of 0.1% TFA as a modifier. The modified mobile phase was used, except for the […] at approximately 7.5 minutes. 19 Beyond the F]-DCFPyL peak, the decayed sample exhibits a UV peak at 264 nm with a retention time of approximately 3.8 minutes. The mass spectrometry chromatogram at the corresponding retention time shows a peak at m / z 346.9. Figure 38 At T = 24 hours, the reaction was also carried out with approximately 120 mCi / mL of F. 18 Samples added to a 5 mg / mL, pH 6 ascorbic acid solution were analyzed by HPLC / MS (see [reference]). Figure 39 ).

[0426] 5 mg / mL ascorbic acid + F 18The solution sample showed a UV peak at 264 nm with a retention time of approximately 3.8 minutes. A mass spectrometry chromatogram at the corresponding retention time showed a peak at m / z 347.1, confirming that the mass of the impurity peak formed by ascorbic acid was the same as that present in the development batch. DHA at m / z 175 was not detected in this sample. An m / z of approximately 347 was identified in two separate samples, one a decaying PYLARIFY sample, and the other via ascorbic acid and F... 18 Produced through incubation.

[0427] In both positive and negative modes, fragmentation of unknown impurity peaks from decaying PYLARIFY samples was performed using LC / MS / MS within the collision energy range. Literature indicates that a common degradation product of ascorbic acid is dehydroascorbic acid monomer (DHA), which may bind to another DHA molecule or an alternative form of ascorbic acid. The fragment mass observed from the 347 m / z impurity is comparable to […]. 19 None of the major fragments in the F]-DCFPyL standard matched, thus further confirming that the impurity was related to ascorbic acid, rather than PYLARIFY.

[0428] Preparation of final formulation containing ascorbic acid

[0429] Data generated during these research processes led to the selection of an exemplary formulation for PYLARIFY containing 5.6 mg / mL ascorbic acid at pH 5.5. This also led to the use of a 10 mg / mL ascorbic acid solution at pH 2 (position I) in the collection vials. Figure 13 The final formulation can be obtained by delivering 1.3 mL of ethanol to the FPV, followed by 15 mL of saline. The FPV can be preloaded with 20 mL of a 10 mg / mL ascorbic acid solution at pH 5.5. The final product volume can be 36 mL, and therefore the ascorbic acid concentration is 5.6 mg / mL. The formulation has been shown to be stable at RAC (Radioactive Concentration) ≤ 165 mCi / mL. Figure 40 The instructions are shown in [ 18 A flowchart illustrating the preloading of ascorbic acid before the start of F-DCFPyL production to protect the product at a high radioactivity point. In embodiments of any of the methods or compositions provided herein, any one or more, or all of the foregoing steps and / or features may be included as part of the method or composition, respectively.

[0430] Research was conducted to develop a PYLARIFY formulation with a higher concentration of radioactivity. 18 The main degradation of F]-DCFPyL is the release of 18Radiolysis of F. Incorporating 5 mg / mL ascorbate at pH 6 as ascorbic acid into the final product provides 96% RCP at 10 hours. Adding 10 mg / mL ascorbate at pH 6 as ascorbic acid to the collection vial receiving the peak cut from the semi-preparative HPLC purification step, in addition to loading the final product vial with 5 mg / mL ascorbic acid at pH 6, provides a product with 99% RCP at 4 hours; however, a significant portion (approximately 40%) of the product is not retained on SepPak. Lowering the pH of the ascorbate in the collection vial to pH 2 while maintaining 5 mg / mL ascorbate at pH 6 in the FPV provides additional stability, yielding 98% RCP at 10 hours, while retaining >98% of the product on SepPak. In embodiments of any of the methods or compositions provided herein, any one or more, or all of the foregoing steps and / or features may be included as part of the method or composition, respectively.

[0431] For collecting vials, pH 2 was chosen based on the HLB column pair [ 18 The improved retention of F]-DCFPyL was driven by 98% and 81% at pH 2 and 4, respectively. The optimal pH for product binding to HLB is pH 2; therefore, an ascorbic acid solution at pH 2 was chosen for prefilling collection vials. 5 or 10 mg / mL of ascorbic acid is sufficient for stability; however, for ease of preparation, a 10 mg / mL ascorbic acid stock solution was chosen and then used for prefilling FPV vials or collection vials after pH adjustment. It is feasible to supply kits containing ascorbic acid solution using 5 mg / mL of ascorbic acid. In embodiments of any of the methods or compositions provided herein, any one or more or all of the foregoing steps and / or features may be included as part of the method or composition, respectively.

[0432] Finally, using 5 mg / mL ascorbate at pH 6 as a 20 mL FPV prefiller and 16 mL of 6 mg / mL ascorbate at pH 6 as the formulation delivery solution for HLB instead of saline did not provide additional stability compared to using saline for HLB formulation delivery, with an RCP of 98% at 4 hours. During the stability assay, a slight increase in pH was observed over 10 hours, indicating that products produced at pH 6 or 7 were close to the upper limit of specification 7. Based on the pH change observed during the stability studies, the target pH was changed from 6 to 5.5 to ensure that the product was fully within the upper limit of specification 7 at 10 hours. These studies established example target solutions: 16 mL of 5.6 mg / mL ascorbate at pH 5.5 in the FPV, 35 mL of 10 mg / mL ascorbate at pH 2 in the collection vial, and 0.9% sodium chloride as the HLB formulation delivery solution. In any embodiment of the methods or compositions provided herein, any one or more or all of the foregoing steps and / or features may be included as part of the method or composition.

[0433] Studies were then conducted at three ascorbic acid levels in the FPV while maintaining 10 mg / mL ascorbic acid at pH 2 in the collection vials. The %RCP results for 3.3, 5.6, and 7.8 mg / mL ascorbic acid at 10 hours were 97, 98, and 97%, respectively. Studies were also conducted at the pH specification limits and at the target pH to confirm product compliance with specifications within the pH specification range. The results at 10 hours at pH 4.5, 5.5, and 7.0 were 98%, 97%, and 97%, respectively. These studies establish that the exemplary proposed product preparation solution produces specifications compliant at the limits of ascorbic acid concentration and pH. 18 F]-DCFPyL. Data generated during these studies led to the selection of an exemplary final formulation for PYLARIFY with 5.6 mg / mL ascorbic acid at pH 5.5. This formulation has been shown to be stable at RAC (radioactive concentration) ≤ 160 mCi / mL. In embodiments of any of the methods or compositions provided herein, any one or more, or all of the foregoing steps and / or features may be included as part of the method or composition, respectively.

[0434] Equivalent schemes and scope

[0435] In the claims, nouns not limited by a quantifier may mean one or more than one / a, unless the contrary is indicated or is otherwise apparent from the context. A claim or description containing "or" between one or more members of a group is deemed to satisfy the following: for a given product or process, one, more than one, or all of the group members are present, used, or otherwise associated with it, unless the contrary is indicated or is otherwise apparent from the context. This disclosure includes embodiments in which exactly one group member is present in, used in, or otherwise associated with a given product or method. This disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or method.

[0436] Furthermore, this disclosure covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. When elements are presented in list form, such as in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, generally speaking, when referring to the disclosure or aspects described herein as containing specific elements and / or features, certain embodiments or aspects described herein consist of or are substantially composed of such elements and / or features. For simplicity, these embodiments are not explicitly given in the language herein. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or are obvious from the context or as understood by one of ordinary skill in the art, values ​​expressed as ranges in the various embodiments described herein may be assumed to be any particular value or subrange within the range, up to one-tenth of the lower limit unit of the range, unless the context explicitly states otherwise.

[0437] This application relates to numerous granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of this disclosure that falls within the scope of the prior art is expressly excluded from any one or more claims. Because such embodiments are considered known to one of ordinary skill in the art, they may be excluded even if not expressly stated herein. Any particular embodiment described herein may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0438] Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments described herein using only conventional experiments. The scope of the embodiments of the invention described herein is not intended to be limited to the foregoing description, but is set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of this disclosure as defined by the appended claims.

Claims

1. A composition comprising the following formula: 18 F]DCFPyL: ， It is in solution, optionally in ethanol solution, the solution further comprising ascorbic acid at a concentration of 3 to 15 mg / mL, 3 to 8 mg / mL or 5 to 15 mg / mL, and wherein the pH of the solution is in the range of 4 to 7.

5.

2. The composition of claim 1, wherein the ascorbic acid concentration is 3.5 to 8 mg / mL, 3.5 to 7.5 mg / mL, 3.5 to 7 mg / mL, 4 to 8 mg / mL, 4 to 7.5 mg / mL, 4 to 7 mg / mL, 4.5 to 8 mg / mL, 4.5 to 7.5 mg / mL, 4.5 to 7 mg / mL, 5 to 8 mg / mL, 5 to 7.5 mg / mL, 5 to 7 mg / mL, 5.5 to 8 mg / mL, 5.5 to 7.5 mg / mL, 5.5 to 7 mg / mL, 6 to 8 mg / mL, 6 to 7.5 mg / mL, 6 to 7 mg / mL, 6.5 to 8 mg / mL, 6.5 to 7.5 mg / mL, 6.5 to 7 mg / mL, 7 to 8 mg / mL, 7 to 7.5 mg / mL, or 7.5 to 8 mg / mL.

3. The composition of claim 1, wherein the ascorbic acid concentration is 3 to 6.5 mg / mL, 3 to 6 mg / mL, 3 to 5.5 mg / mL, 3 to 5 mg / mL, 3 to 4.5 mg / mL, 3 to 4 mg / mL or 3 to 3.5 mg / mL.

4. The composition of claim 1, wherein the ascorbic acid concentration is 3.5 to 6.5 mg / mL, 4 to 6 mg / mL, or 4.5 to 5.5 mg / mL.

5. The composition of any one of claims 1 to 4, wherein the pH of the solution is in the range of 3.5 to 7.5, 4 to 7.5, 4.5 to 7.5, 5 to 7.5, 5.5 to 7.5, 6 to 7.5, 6.5 to 7.5, or 7 to 7.

5.

6. The composition of any one of claims 1 to 4, wherein the pH of the solution is in the range of 3.5 to 7, 4 to 7, 4 to 6.5, 4 to 6, 4 to 5.5, 4 to 5, or 4 to 4.

5.

7. The composition of any one of claims 1 to 4, wherein the pH of the solution is in the range of 4.5 to 7, 5 to 6.5, or 5.5 to 6.

8. The composition of any one of claims 1 to 7, wherein the solution has a radiochemical purity (RCP) of at least 90% 10 hours after synthesis.

9. The composition of claim 8, wherein the RCP of the solution is at least 91%, 92%, 93%, 94% or 95% 10 hours after synthesis.

10. The composition of any one of claims 1 to 9, wherein the solution has an RCP of at least 95% at the end of synthesis (EOS).

11. The composition of claim 10, wherein the RCP of the solution in EOS is at least 96%, 97%, 98% or 99%.

12. The composition of any one of claims 1 to 11, wherein the radioactivity concentration of the solution in EOS is at least 80 mCi / mL.

13. The composition of claim 12, wherein the radioactivity concentration of the solution in EOS is at least 85 mCi / mL, 90 mCi / mL, 95 mCi / mL, 100 mCi / mL, 105 mCi / mL, 110 mCi / mL, 115 mCi / mL, 120 mCi / mL, 125 mCi / mL, 130 mCi / mL, 135 mCi / mL, 140 mCi / mL, 145 mCi / mL, 150 mCi / mL, 160 mCi / mL, 165 mCi / mL, 166 mCi / mL, or 167 mCi / mL.

14. The composition of claim 12 or 13, wherein the radioactivity concentration of the solution at EOS is equal to or less than 155 mCi / mL, 160 mCi / mL, 161 mCi / mL, 162 mCi / mL, 163 mCi / mL, 164 mCi / mL, 165 mCi / mL, 166 mCi / mL, 167 mCi / mL, 168 mCi / mL, 169 mCi / mL or 170 mCi / mL.

15. The composition of any one of claims 1 to 14, wherein the solution has less than 5% free radicals. 18 F.

16. The composition of claim 15, wherein the solution has less than 4.5% free... 18 F.

17. The composition of claim 16, wherein the solution has less than 4% free radicals. 18 F.

18. The composition of claim 17, wherein the solution has less than 3.5% free... 18 F.

19. The composition of claim 18, wherein the solution has less than 3% free... 18 F.

20. The composition of any one of claims 1 to 19, wherein the solution comprises ethanol and the ethanol content is less than 30% w / v.

21. The composition of claim 20, wherein the ethanol content of the solution is less than 25% w / v.

22. The composition of claim 21, wherein the ethanol content of the solution is less than 20% w / v.

23. The composition of claim 22, wherein the ethanol content of the solution is less than 15% w / v.

24. The composition of claim 23, wherein the ethanol content of the solution is less than 10% w / v.

25. The composition of claim 24, wherein the ethanol content of the solution is less than 5% w / v.

26. The composition of any one of claims 20 to 25, wherein the ethanol in the solution is at least 3% w / v.

27. The composition of any one of claims 1 to 26, wherein the solution contains less than or equal to 2 µg / mL of total unknown impurities.

28. The composition of claim 27, wherein the solution contains less than or equal to 1.5 µg / mL of total unknown impurities.

29. The composition of claim 28, wherein the unknown impurity is not detectable by HPLC at RT 6.0, RT 9.8 or RT 10.

6.

30. The composition of any one of claims 1 to 29, wherein the solution contains ascorbic acid-related impurities ≤ 5.0 μg / mL.

31. The composition of claim 30, wherein the RRT of the ascorbic acid-related impurities as detected by HPLC UV is 0.

607.

32. The composition of any one of claims 1 to 31, wherein the solution comprises less than or equal to ≤ 0.04% w / v acetonitrile.

33. The composition of any one of the preceding claims, wherein the ascorbic acid concentration of the solution is 5.5 mg / mL or 5.6 mg / mL.

34. The composition of any one of the preceding claims, wherein the pH of the solution is 5.

5.

35. Used to prepare a mixture containing the following formula [ 18 Method for composing F]DCFPyL: ， The method includes sending to a container [ 18 F]DCFPyL's first solution is added to a second solution containing ascorbic acid to form a solution containing [ 18 F]DCFPyL and a third solution of ascorbic acid, wherein the third solution has an ascorbic acid concentration as defined in any of the preceding claims or as otherwise defined herein, and a pH as defined in any of the preceding claims or as otherwise defined herein, and wherein the third solution is collected in or transferred to a collection vial, such as a final collection vial (FCV) or a final product vial (FPV).

36. Used to prepare a mixture containing the following formula [ 18 Method for composing F]DCFPyL: ， The method includes containing [ 18 The F]DCFPyL solution is adjusted to have an ascorbic acid concentration as defined in any of the preceding claims or as otherwise defined herein, and a pH as defined in any of the preceding claims or as otherwise defined herein, wherein the adjusted solution is collected in or transferred to a collection vial, such as a final collection vial (FCV) or a final product vial (FPV).

37. The method of claim 35 or 36, wherein the third solution or the adjusted solution further comprises ethanol.

38. The method of claim 37, wherein the %w / v of ethanol is as defined in any of the preceding claims or as otherwise defined herein.

39. The method of any one of claims 35 to 38, wherein the third solution or the adjusted solution has a radiochemical purity (RCP) as defined in any of the preceding claims or as otherwise defined herein.

40. The method of any one of claims 35 to 39, wherein the third solution or the adjusted solution has a radioactive concentration as defined in any of the preceding claims or as otherwise defined herein.

41. The method of any one of claims 35 to 40, wherein the third solution or the adjusted solution has the free concentration as defined in any of the preceding claims or as otherwise defined herein. 18 F%.

42. The method of any one of claims 35 to 41, wherein the third solution or the adjusted solution contains a total unknown impurity as defined in any of the preceding claims or as otherwise defined herein.

43. The method of any one of claims 35 to 42, wherein the third solution or the adjusted solution contains ascorbic acid-related impurities as defined in any of the preceding claims or as otherwise defined herein.

44. The method of any one of claims 35 to 43, wherein the third solution or the adjusted solution comprises %w / v acetonitrile as defined in any of the preceding claims or as otherwise defined herein.

45. Used to prepare a mixture containing the following formula [ 18 Method for composing F]DCFPyL: ， The method includes sending to a container [ 18 A first solution of F]DCFPyL is added to a second solution containing ascorbic acid at a concentration of 3 to 50 mg / mL and a pH of 4 or lower to form a solution containing [ 18 The third solution of F]DCFPyL and ascorbic acid.

46. ​​Used to prepare a mixture containing the following formula [ 18 Method for composing F]DCFPyL: ， The method includes containing [ 18 The solution of F]DCFPyL was adjusted to an ascorbic acid concentration of 3 to 50 mg / mL and a pH of 4 or lower.

47. The method of claim 45 or 46, wherein the ascorbic acid concentration is 3 to 45, 3 to 40, 3 to 35, 3 to 30, 3 to 25, 3 to 20, 3 to 15 or 3 to 10 mg / mL.

48. The method of claim 45 or 46, wherein the ascorbic acid concentration is 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, or 45 to 50 mg / mL.

49. The method of claim 45 or 46, wherein the ascorbic acid concentration is 5 to 45, 10 to 40, 15 to 35, or 20 to 30 mg / mL.

50. The method of claim 47, wherein the ascorbic acid concentration is 3 to 15 mg / mL or 5 to 15 mg / mL.

51. The method of claim 50, wherein the ascorbic acid concentration is 8 or 10 mg / mL.

52. The method of any one of claims 45 to 51, wherein the pH of the third solution or the adjusted solution is 3 or lower.

53. The method of claim 52, wherein the pH of the third solution or the adjusted solution is 2 or lower.

54. The method of claim 53, wherein the pH of the third solution or the adjusted solution is 2.

55. The method of claim 52, wherein the pH of the third solution or the adjusted solution is in the range of about 1.5 to 2.

5.

56. The method of any one of claims 45 to 55, wherein the third solution or the adjusted solution further comprises ethanol.

57. The method of claim 56, wherein the %w / v of ethanol is as defined in any one of claims 20 to 26 or as otherwise defined herein.

58. The method of any one of claims 45 to 57, wherein the addition of the second solution or the addition of […] 18 Before adjusting the solution containing [F]DCFPyL, the solution was subjected to chromatography. 18 The solution of F]DCFPyL was purified.

59. The method of claim 58, wherein the chromatography is HPLC.

60. The method of any one of claims 45 to 59, wherein the method further comprises loading the third solution or the adjusted solution onto a solvent exchange column and eluting with a solvent solution. 18 F]DCFPyL.

61. The method of claim 60, wherein the solvent exchange column is an HLB solvent exchange column.

62. The method of claim 60 or 61, wherein the solvent solution comprises ethanol.

63. The method of claim 62, wherein the solvent solution comprises %w / v ethanol as defined in any one of claims 20 to 26 or as otherwise defined herein.

64. The method of any one of the preceding claims, wherein the solvent solution comprises ascorbic acid.

65. The method of claim 64, wherein the concentration of ascorbic acid is as defined in any of the preceding claims or as otherwise defined herein.

66. The method of any of the preceding claims, wherein the pH of the solvent solution is as defined in any of the preceding claims or as otherwise defined herein.

67. The method of any one of the preceding claims, wherein the method further comprises collecting the eluent and maintaining or adjusting the ascorbic acid concentration to the level defined in any one of the preceding claims or as otherwise defined herein, while the pH is as defined in any one of the preceding claims or as otherwise defined herein.

68. The method of claim 67, wherein the eluent is collected in a collection vial, such as a final collection vial (FCV) or a final product vial (FPV).

69. Used to prepare a mixture containing the following formula [ 18 Method for composing F]DCFPyL: ， The method includes containing [ 18 The F]DCFPyL solution was loaded onto a solvent exchange column and eluted with a solvent solution. 18 F]DCFPyL, wherein the ascorbic acid concentration of the solvent solution is 3 to 50 mg / mL and the pH is 4 or lower.

70. The method of claim 69, wherein the solvent exchange column is an HLB solvent exchange column.

71. The method of claim 69 or 70, wherein the solvent solution comprises ethanol.

72. The method of claim 71, wherein the solvent solution comprises %w / v ethanol as defined in any of the preceding claims or as otherwise defined herein.

73. The method of any one of claims 69 to 72, wherein the solvent solution comprises ascorbic acid at a concentration as defined in any of the preceding claims or as otherwise defined herein.

74. The method of any one of claims 69 to 73, wherein the pH of the solvent solution is as defined in any of the preceding claims or as otherwise defined herein.

75. The method of any one of claims 69 to 74, wherein the method further comprises collecting the eluent and maintaining or adjusting the ascorbic acid concentration to the level defined in any of the preceding claims or as otherwise defined herein, while the pH is as defined in any of the preceding claims or as otherwise defined herein.

76. The method of claim 75, wherein the eluent is collected in a collection vial, such as a final collection vial (FCV) or a final product vial (FPV).

77. The method of any one of the preceding claims, wherein the method further comprises collecting [ 18 The solution of F]DCFPyL and ascorbic acid is sterile filtered beforehand or as part of the collection.

78. The method of any one of the preceding claims, wherein the collected solution has a radiochemical purity (RCP) as defined in any one of the preceding claims or as otherwise defined herein.

79. The method of any of the preceding claims, wherein the collected solution has a radioactive concentration as defined in any of the preceding claims or as otherwise defined herein.

80. The method of any one of the preceding claims, wherein the collected solution has the free radicals as defined in any one of the preceding claims or as otherwise defined herein. 18 F%.

81. The method of any one of the preceding claims, wherein the collected solution contains total unknown impurities as defined in any one of the preceding claims or as otherwise defined herein.

82. The method of any one of the preceding claims, wherein the collected solution contains ascorbic acid-related impurities as defined in any one of the preceding claims or as otherwise defined herein.

83. The method of any one of the preceding claims, wherein the collected solution comprises %w / v acetonitrile as defined in any one of the preceding claims or as otherwise defined herein.

84. The method of any one of the preceding claims, wherein the collected solution comprises %w / v ethanol as defined in any one of the preceding claims or as otherwise defined herein.

85. The method of any of the preceding claims, wherein the solution is collected in a collection vial, such as an FCV or FPV.

86. A composition comprising [18F]DCFPyL and ascorbic acid, said composition being produced by any one of the preceding claims.

87. A method of applying the composition of any one of the preceding claims to an object.

88. The method of claim 87, wherein the method is used for imaging.

89. The method of claim 88, wherein the imaging is used for cancer.

90. The method of claim 89, wherein the cancer is prostate cancer.

91. The method of any one of the preceding claims, wherein the method is an automated synthesis method, such as a one-step synthesis method.

92. The composition of any one of the preceding claims, wherein the composition is used in an automated synthesis method, such as a one-step synthesis method.

93. The method or composition of any of the preceding claims, wherein the automated synthesis method is used in an automated PET synthesizer.

94. A composition comprising any of the compositions provided herein.

95. Methods, including any of the methods provided herein.

96. A kit comprising any of the compositions provided herein, such as a composition comprising a PyL precursor or a composition comprising ascorbic acid or ascorbate.

97. The kit of claim 96, wherein the kit comprises a cartridge for automated synthesis, such as a one-step synthesis.

98. The kit of claim 96 or 97, comprising ascorbic acid, such as any concentration of ascorbic acid provided herein, or comprising ascorbate salt in an amount sufficient to prepare any concentration of ascorbic acid provided herein.

99. The kit according to any one of claims 96 to 98, comprising a PyL precursor.

100. The kit of any one of claims 96 to 99, further comprising phosphoric acid, such as phosphoric acid of any concentration provided herein, or phosphoric acid in an amount sufficient to prepare a composition comprising phosphoric acid of any concentration provided herein.

101. The kit according to any one of claims 96 to 100, further comprising saline solution.

102. The kit according to any one of claims 96 to 101, further comprising one or more collection vials.

103. The kit of claim 102, wherein one or more collection vials are FCV or FPV.

104. The kit of claim 102, wherein the one or more collection vials are used to collect the solution immediately after semi-preparation (e.g., semi-preparation HPLC).

105. The kit of any one of claims 102 to 104, comprising one or more collection vials for collecting the solution immediately after semi-preparation (e.g., semi-preparation HPLC), and one or more FCVs or FPVs.

106. The kit according to any one of claims 96 to 105, further comprising acetonitrile.

107. The kit according to any one of claims 96 to 106, further comprising ethanol, such as any concentration of ethanol provided herein.

108. The kit according to any one of claims 96 to 107, further comprising sodium hydroxide.

109. The kit according to any one of claims 96 to 108, including the eluent vial and / or the precursor vial.

110. The kit according to any one of claims 96 to 109, further comprising sterile water, such as an SWFI bag.

111. The kit according to any one of claims 96 to 110, comprising a PyL precursor in a vial, phosphoric acid in a vial, acetonitrile in a vial, ascorbic acid or ascorbate in a vial, and ethanol in a vial.

112. The kit according to any one of claims 96 to 111, further comprising sodium hydroxide in a vial.

113. The kit according to any one of claims 96 to 112, wherein the ascorbic acid or ascorbate is in a collection vial.

114. The kit according to any one of claims 96 to 113, further comprising FCV or FPV.

115. The kit according to any one of claims 96 to 114, further comprising saline and / or sterile water, for example in an SWFI bag.

116. A composition comprising the corresponding amounts of components provided in any of the tables provided herein, such as Table 15 or Table 32.

117. The composition of claim 116, wherein the pH of any one or more or all of the components is any of the pH values ​​provided herein.

118. An imaging method comprising administering to a patient any of the compositions provided herein.

119. The method of claim 118, wherein the composition is the composition of claim 116 or 117.

120. The method of claim 118 or 119, wherein the composition is a composition comprising 8 to 10 mCi of PyL.

121. The method of claim 120, wherein the composition is a composition comprising 9 mCi of PyL.

122. The method of any one of claims 118 to 121, wherein the PyL is derived from FPV and is prepared at 80 to 165 or 170 mCi / mL.

123. The method of any one of claims 118 to 122, wherein the composition further comprises ascorbic acid or ascorbate, such as any concentration of ascorbic acid or ascorbate provided herein.

124. The method of claim 123, wherein the composition comprises 5.6 mg / mL ascorbate.

125. The method of any one of claims 118 to 124, wherein the patient has prostate cancer.

126. The method of any one of claims 118 to 125, wherein imaging is performed with a PET camera 1 hour after application.

127. Used for detecting radiopharmaceutical compositions 18 F's method, the method comprising: (a) Preparing or obtaining any of the compositions provided herein, said compositions comprising, for example, the following formula [ 18 Compositions of F]DCFPyL or salts thereof, optionally produced according to any of the methods provided herein; ， (b) Add tetraethylammonium fluoride to the composition; as well as (c) The composition was determined to be... 18 The level of F is determined, for example, by chromatography, such as HPLC.

128. The method of claim 127, wherein the HPLC is an analytical HPLC.

129. The method of claim 127 or 128, wherein the amount or concentration of said tetraethylammonium fluoride is any of the amounts or concentrations provided herein.

130. The method of any one of claims 1 to 126, further comprising any one or more or all of the steps of any one of claims 127 to 129.

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