Improved synthesis of the prostate-specific membrane antigen (PSMA) radiolabeling inhibitor [18F]DCFPYL

Abstract

[ 18 Methods and related compositions containing kits for improved synthesis, preparation and / or storage of F]DCFPyL are provided herein. For imaging and other purposes [ 18 A method using F]DCFPyL is also provided.

Description

[Technical Field]

[0001] Related applications This application claims priority under § 119(e) of the U.S. Patent Act to U.S. Provisional Applications No. 63 / 508,673 filed on 16 June 2023; No. 63 / 514,480 filed on 19 July 2023; and No. 63 / 514,485 filed on 19 July 2023; the entire contents of each of these are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Prostate cancer is the most common cancer in men and one of the most frequent cancers worldwide, with an estimated incidence of over one million cases and an estimated death rate of 307,000 men per year (Mauer et al., 2016). In the United States alone, well over 200,000 new cases are diagnosed each year (Seigel et al., 2014). In some cases, thanks to serological diagnostic tests for prostate-specific antigen (PSA) expression in the development of prostate cancer, the five-year survival rate is nearly 99% with appropriate diagnosis and treatment (seer.cancer.gov).

[0003] More frequently, monitoring for appropriate diagnosis and treatment involves non-invasive molecular imaging. Numerous radiotracers have been developed for prostate-specific membrane antigen (PSMA) PET imaging of prostate cancer, including 18F-FACBC (fluciclovine), Ga68 PSMA-11, and DCFPyL. The successful use of DCFPyL (Chen et al., 2011; Szabo et al., 2015), as well as its favorable distribution and imaging characteristics compared to other PSMA-targeted radiotracers (Dietlein et al., 2015), have led to increased demand for this radiotracer. [Overview of the Initiative]

[0004] Summary of the Invention [ 18Methods and related compositions for improved synthesis, purification and / or storage of F]DCFPyL (also referred to herein as PyL or PYLARIFY) are provided herein. In one aspect, this disclosure provides one of the methods provided herein.

[0005] In another respect, this disclosure contains ascorbic acid and [ 18 F]DCFPyL(or[ 18 The present invention provides one of the kit-containing compositions as described herein, such as a composition comprising a reagent for preparing F]DCFPyL and / or a composition produced by any one of the methods described herein.

[0006] In another aspect, this disclosure provides a method for administering any one of the compositions described herein to a subject requiring it.

[0007] In another respect, this disclosure includes, as one of the steps of any of the methods provided herein, 18 We provide a method for detecting F, the method including the use of TEAF.

[0008] Further provided by this disclosure is a kit comprising any one of the compositions described herein, or any one of the compositions produced by or used in any one of the methods described herein.

[0009] definition As used herein, the term “determine” generally refers to, for example, quantitative or qualitative analysis of a molecule or set of molecules or a signal or set of signals, and / or detection of the presence or absence of a molecule or more molecules.

[0010] As used herein, the term “diagnostic imaging” refers to procedures used to detect imaging agents that may be used in the diagnosis of a condition, disease, and / or disorder.

[0011] As used herein, the term “diagnosis” encompasses the identification, confirmation, evaluation, and / or characterization of a condition, disease, and / or disorder.

[0012] A “kit” comprises components or a set of components in one or more containers, such as vials, and can be used by an end user operating in a clinical or pharmacy setting. Kits provided herein may be used to synthesize radiopharmaceuticals for diagnostic purposes, etc. Therefore, kits may be used by an end user operating in a clinical or pharmacy setting to synthesize and / or use radiopharmaceuticals in diagnostics. In some embodiments, the kit may contain water or saline for injection, radioisotopes (for example, 18 F) The kit may provide all components necessary for synthesizing and / or using the radiopharmaceutical, except for those generally available to the end user performing the procedure, such as equipment for handling the kit during the synthesis and manipulation of the radiopharmaceutical, and, if necessary, equipment required for administering the radiopharmaceutical to a 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 contained in one or more containers such as vials or one or more syringes, for example, as an aqueous solution. Thus, in one embodiment, the kit may contain the drug in its final form.

[0013] As used herein, “part of the subject” refers to a specific area of ​​the subject, its location, etc. For example, part of the subject may be the brain, heart, vascular system, cardiovascular system, tumor, etc.

[0014] As used herein, the term “subject” refers to a human or non-human mammal or animal. Non-human mammals include domestic animals, companion animals, laboratory animals, and non-human primates. Non-human subjects also include, but are not limited to, horses, dairy cows, pigs, goats, dogs, cats, mice, rats, guinea pigs, gerbils, hamsters, minks, and rabbits. In some embodiments of the present invention, a subject is referred to as a “patient.” In some embodiments, a patient or subject may be under the care of a physician or other healthcare professional, including, but not limited to, a person who has consulted with, received advice from, or received a prescription or other recommendation from a physician or other healthcare professional.

[0015] Any of the compounds described herein, but not limited to them, may be in various forms such as salts, solvates, hydrates, tautomers, and isomers. In certain embodiments, the imaging agent is a pharmaceutically acceptable salt of the imaging agent. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, and such description is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable and non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfons, It contains lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, 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 N. + (C 1~4 It contains alkyl) tetrasalts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts may contain non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0016] "Pharmacologically acceptable carriers" refer to biocompatible solutions that take into account sterility, p[Eta], isotonicity, stability, etc., and may contain any solvent, diluent (including sterile saline, sodium chloride injection, Ringer's solution injection, dextrose injection, dextrose and sodium chloride injection, Ringer's lactate injection, and other aqueous buffers), dispersion medium, coating, antimicrobial and antifungal agents, isotonic agents, etc. Pharmaceutically acceptable carriers may also include stabilizers, preservatives, antioxidants, or other additives known to those skilled in the art, or other media known in the art.

[0017] In certain embodiments, the compounds are in the form of hydrates or solvates. As used herein, the term “hydrate” refers to a compound non-covalently associated with one or more water molecules. Similarly, the term “solvate” refers to a compound non-covalently associated with one or more molecules of an organic solvent.

[0018] In this specification, any reference to a value or parameter with respect to it refers to the normal range of error for that value or parameter, which is readily known to those skilled in the art. Any reference to a value or parameter with respect to it with respect to it includes (and describes) aspects relating to that value or parameter per se. For example, a statement of “X” includes a statement of “X”. In any embodiment of the compositions or methods provided herein, “about” refers to a value or parameter and ±10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In any embodiment of the compositions or methods provided herein, any quantity listed herein may refer to a single quantity or a quantity without “about”. [Brief explanation of the drawing]

[0019] Brief explanation of the drawing [Figure 1] The synthesis method for [18F]DCFPyL is shown. [Figure 2] The chromatograms of [18F]DCFPyL and free 18F radiolysis impurities are shown. [Figure 3] The chromatogram of 5μCi18F spiked with TEAF (44 mg / mL) is shown. [Figure 4] This shows the formation of free 18F in the presence of ethanol. [Figure 5] The HPLC radiation detector traces of the sample are shown with and without TEAF spikes. [Figure 6] The HPLC radiation detector traces of the sample in saline and 35% ethanol are shown. [Figure 7] This shows the concentration-dependent formation of free 18F in saline solution in the presence of 20% ethanol [18F]DCFPyL. [Figure 8] HPLC radiation detector traces of T0 and T4 time samples from [18F]DCFPyL in 100 mg / mL ascorbic acid (pH 2) are shown. [Figure 9]HPLC radioactive detector traces of T0 and T4 time samples from [18F]DCFPyL in 50 mg / mL ascorbic acid (pH 5.8) are shown. [Figure 10] This shows the concentration-dependent formation of free 18F in the presence of ascorbic acid, specifically [18F]DCFPyL. [Figure 11] This shows the concentration-dependent formation of free 18F in the presence of sodium ascorbate [18F]DCFPyL. [Figure 12] [18F]DCFPyL drug product generation process is shown. [Figure 13] A list of AIO reagents and a schematic diagram showing the locations of the reagents are provided. [Figure 14] A flowchart illustrating the different stages in which ascorbic acid is introduced is shown. [Figure 15] The radiochromatogram at T=0 time shows the radiolysis of 147 mCi[18F]DCFPyL / mL of 110 mCi[18F]DCFPyL / mL in 50 mg / mL pH 5.8 ascorbic acid. [Figure 16] The RCP vs. time plots for lots 220816PyL, 220817PyL, and 220818PyL are shown. [Figure 17] The plots of 18F formation versus time for lots 220816PyL, 220817PyL, and 220818PyL are shown. [Figure 18] The plots show the formation of peaks with a retention time of 6.0 minutes against time for lots 220816PyL, 220817PyL, and 220818PyL. [Figure 19] The plots show the formation of peaks at a retention time of 9.8 minutes against time for lots 220816PyL, 220817PyL, and 220818PyL. [Figure 20] The plots show the formation of peaks at a retention time of 10.6 minutes against time for lots 220816PyL, 220817PyL, and 220818PyL. [Figure 21]The following plots of RCP against time are shown for lots 220816PyL, 220817PyL, and 220818PyL, calculated to include only 18F degradation products. [Figure 22] A typical radiochemical chromatogram of [18F]DCFPyL formulated in ascorbic acid at a concentration of 5.0 mg / mL in saline, pH 6, is shown. [Figure 23] The radiochemical chromatogram for lot 220908PyL is shown; peak cuts (166 mCi / mL) from semi-preparative HPLC purification, which was delivered to SWFI in the collection vial, then to FPV containing 0.9% saline, and analyzed without further processing. [Figure 24] The radiochemical chromatogram for lot 220909PyL at T=4 hours is shown; 5 mg / mL ascorbic acid at pH 6 in the collected vial and 10 mg / mL ascorbic acid at pH 6 in 0.9% saline in the FPV. [Figure 25] The radiochemical chromatogram for lot 220914PyL at T=4 hours is shown; 5 mg / mL of ascorbic acid in SWFI in the collected vial, pH 2; 5 mg / mL of ascorbic acid in the saline vial, pH 6; and 5 mg / mL of ascorbic acid in 0.9% saline in the FPV, pH 6. [Figure 26] The radiochemical chromatogram for lot 220927PyL at T=4 hours is shown; 5 mg / mL ascorbic acid in SWFI, pH 2, in the collected vial; 10 mg / mL ascorbic acid in 0.9% saline, pH 6, in the FPV vial. [Figure 27] The radiochemical chromatogram for lot 220928PyL at T=4 hours is shown; 5 mg / mL of ascorbic acid in SWFI in the collected vial, pH 2, and 10 mg / mL of ascorbic acid in the saline vial, pH 6. [Figure 28] The radiochemical chromatograms at T=10 hours for [18F]DCFPyL (lot 221025PyL) produced using 10 mg / mL, pH 2 ascorbic acid loaded into the collection vial and 10 mg / mL, pH 5.5 ascorbic acid pre-loaded into the FPV are shown. [Figure 29] The radiochemical chromatograms at T=10 hours for [18F]DCFPyL (lot 221026PyL) produced using 10 mg / mL, pH 2 ascorbic acid loaded into the collection vial and 10 mg / mL, pH 4.5 ascorbic acid pre-loaded into the FPV are shown. [Figure 30] The radiochemical chromatograms for [18F]DCFPyL (lot 230124PyL) produced using 10 mg / mL, pH 2 ascorbic acid loaded into the collection vial and 10 mg / mL, pH 7.0 ascorbic acid pre-loaded into the FPV are shown at T=10 hours. [Figure 31] The radiochemical chromatograms at T=10 hours for [18F]DCFPyL (lot 230130PyL) produced using 10 mg / mL, pH 2 ascorbic acid loaded into the collection vial and 6.6 mg / mL, pH 5.5 ascorbic acid pre-loaded into the FPV are shown. [Figure 32] The radiochemical chromatograms at T=10 hours for [18F]DCFPyL (lot 230131PyL) produced using 10 mg / mL, pH 2 ascorbic acid loaded into the collection vial and 15.6 mg / mL, pH 5.5 ascorbic acid pre-loaded into the FPV are shown. [Figure 33] The radiochemical chromatogram of lot 220908PyL is shown; peak cuts (115 mCi / mL) from semi-preparative HPLC purification, which was delivered to SWFI in the collection vial, then to FPV containing 0.9% saline, and analyzed without further processing. [Figure 34] The UV impurity chromatogram for the development lot at T=6 hours is shown. [Figure 35] The UV impurity chromatogram for the development lot at T=5 days is shown. [Figure 36] This diagram illustrates the time course of the ascorbic acid impurity peak. [Figure 37] The UV chromatograms of ascorbic acid matrix solutions with and without F18 are shown. [Figure 38]Shows the UV-HPLC / MS chromatogram of the development lot. The area highlighted in green in the mask chromatogram represents the background subtraction range. The area highlighted in bright blue in the mask chromatogram represents the retention time range (3.6 - 3.9 minutes) of the unknown impurity. [Figure 39] Shows the UV-HPLC / MS chromatogram of 5 mg / mL ascorbic acid + F18 solution at T = 24 hours. The area highlighted in green in the mask chromatogram represents the background subtraction range. The area highlighted in bright blue in the mask chromatogram represents the retention time range (3.6 - 4.0 minutes) of the unknown impurity. [Figure 40] Shows a flowchart indicating examples of different stages at which ascorbic acid can be introduced into the [18F]-DCFPyL ascorbic acid formulation.

Mode for Carrying Out the Invention

[0020] Detailed Description of the Invention 18 [18F]DCFPyL (shown below) has been found to be a powerful imaging agent for the evaluation of cancers such as prostate cancer. However, generally, at the end of synthesis (EOS), there is an upper limit of a radioactivity concentration of 80 mCi / mL. To improve drug supply and / or enable more doses per lot (the lot size may also be limited by the maximum drug concentration product vial size (e.g., 50 mL)) and / or improve storage, products with higher radioactivity concentrations such as above 80 mCi / mL at EOS can be beneficial. In addition, the main radiolytic product observed is free 18 F, 18 formed by the radiolysis of [18F]DCFPyL. It can also be beneficial to produce [18F]DCFPyL while minimizing radiolysis. 18

Chemical

[0021] ​​It is possible to provide higher radioactivity concentrations and purity with little or no radiolysis. 18 Methods for producing [F]DCFPyL and related compositions are provided herein. These methods and compositions may help provide patients with better access to imaging agents and purer formulations for improved use. The methods and related compositions provided herein involve the use of ascorbic acid, a buffer with a pKa of 4.2. However, the concentration and pH of a solution with ascorbic acid that can yield desired characteristics, such as maintaining purity at a desired level of radioactivity for a particular radiopharmaceutical agent, vary and are specific to that particular radiopharmaceutical agent.

[0022] In any one embodiment of the method or composition provided herein, the desired characteristics may be obtained not only at the end of synthesis (EOS) but also post-synthesis, such as 10 hours after synthesis, resulting in a preparation that maintains high purity at high radioactivity concentrations and may yield other desired characteristics. 18 Compositions and methods comprising the use of ascorbic acid at specific concentrations and pH in the synthesis and / or storage of F]DCFPyL are provided herein. Such features are present in imaging patients. 18 F]DCFPyL may be important for its availability and use.

[0023] Surprisingly, ascorbic acid at a specific concentration within a specific pH range, 18 It has been found to be particularly beneficial for the generation of F]DCFPyL. The present invention is generally [ 18 This disclosure relates to at least a method for preparing or synthesizing a composition containing F]DCFPyL together with ascorbic acid at such a concentration and within such a pH range, as well as related compositions and methods. 18 Ascorbic acid can be used as a stabilizer that can increase the radioactivity concentration and purity of F]DCFPyL. 18This provides an advantageous F]DCFPyL formulation. In addition, in some embodiments, the pH range can enhance the stability and shelf life of the composition and also minimize severe local site reactions at injection. In some embodiments, the beneficial features of formulations prepared using the methods provided herein are [ 18 It was found that [F]DCFPyL can be found at the end of synthesis and post-synthesis, such as 10 hours after synthesis. Therefore, in some embodiments, ascorbic acid at the concentrations and within a specific pH range provided herein is [ 18 F]DCFPyL can serve as a stabilizer with remarkably beneficial results during the preparation, transport, and / or storage of radiopharmaceutical compositions.

[0024] Ascorbic acid is provided herein [ 18 F]DCFPyL is used as a stabilizing component in radiopharmaceutical compositions. Ascorbic acid is known as vitamin C and is used as an antioxidant to prevent the radiolysis of certain radiopharmaceuticals (International Publication No. 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). As used herein, the term "ascorbic acid" includes ascorbic acid itself, as well as analogs and salts of acids known to those skilled in the art. Ascorbic acid is a readily available FDA inactive ingredient and can be used in pharmaceutical compositions and other formulations for biological purposes at concentrations as high as 200 mg / mL in the final formulation. Previous compositions containing ascorbic acid were typically pH values ​​within the biological pH range (e.g., 6-8) throughout all processing steps, as well as 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 in a buffer solution to stabilize radiopharmaceutical solutions can be significantly reduced.

[0025] Ascorbic acid, as described herein, has been found to be a very effective protective agent for PyL. It is important to note that various compounds can be protected in various ways by various protective or stabilizer agents. In addition, for any particular compound, the effective concentration and pH of the possible protective agent can also vary, including combinations with other components of the composition, such as ethanol, whose concentration can also vary. For example, ethanol in FDG can stabilize defluorination at very low concentrations (Dantas et al., 2012; Fawdry, 2007), while ethanol in some other products can be stabilized at 100% EtoH or 50% ethanol (Scott, 2009; AV 19). As another example, ascorbic acid can stabilize FDG from defluorination, but less than 2% can be obtained in 10 hours at 10 mg / mL (Fawdry, 2007). Since ascorbic acid exhibits pH-dependent inhibition of the radiolysis process (Castner et al., U.S. Patent No. 9,687,571), the amount of ascorbic acid required for radiation protection is compound-dependent and pH-dependent, and was not known for PyL until the discoveries described herein were made. Furthermore, the detection of impurities at the levels described herein using HPLC was also not known or recognized.

[0026] Disclosed herein [ 18 Some advantages of using ascorbic acid or its analogues in the F]DCFPyL radiopharmaceutical composition include: (1) the ability to prepare a radiopharmaceutical composition with a radioactivity concentration of at least 80 mCi / mL; (2) the ability to prepare a radiopharmaceutical composition with a radiochemical purity of at least 90% within 10 hours after synthesis; and / or (3) less than 5% free particles. 18The ability to prepare radiopharmaceutical compositions having F. In some aspects of any one of the compositions or methods provided herein, ascorbic acid may be added to the formulation. In some aspects of any one of the compositions or methods provided herein, ascorbic acid may be used in an uncharged form or in a composition in which a higher proportion of ascorbic acid is protonated at a suitable pH. Although not bound by any particular theory, the effectiveness of antioxidants may, in some cases, be directly related to the nonionic nature of the hydrogen-oxygen bond in the antioxidant, and stability is improved at acidity levels in which a substantial portion of the antioxidant is in protonated form.

[0027] In this aspect and embodiment of the present invention, ascorbic acid may exist in an acidic form (e.g., ascorbic acid) and / or a basic form (e.g., ascorbate), depending on the pH. For example, at pH values ​​above about 4.2 (i.e., the pKa of ascorbic acid), the basic form will be dominant over the acidic form. The higher the pH, the greater the proportion present in the basic form. Conversely, at pH values ​​below about 4.2, the acidic form will be dominant over the basic form. The lower the pH, the greater the proportion present in the acidic form. Therefore, when the term ascorbic acid is used herein in relation to a composition, it should be understood that the composition may include the acidic form of ascorbic acid, the basic form of ascorbic acid, or a combination thereof.

[0028] In some embodiments of any one of the methods or compositions provided herein, the basic form (i.e., ascorbate) may associate with a counterion. Those skilled in the art will know of pharmaceutically acceptable salts suitable for association with ascorbate and for use with the compositions described herein. Non-limiting examples of pharmaceutically acceptable salts are given herein. In some cases of any one of the methods or compositions provided herein, the counterion is sodium (for example, so that the composition contains sodium ascorbate).

[0029] In some embodiments of any one 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 one of the methods or compositions provided herein, the radiopharmaceutical compositions provided herein may contain ascorbic acid as a stabilizer, and may also contain ethanol. In some of these embodiments, the ethanol is maintained at one of the specific concentrations provided herein.

[0030] In some aspects of any one 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 aspects of any one of the methods or compositions provided herein, the pH of the composition is about 2.5 to about 8. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 3 to about 8. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.3 to approximately 7.8. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 7. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3 to approximately 7. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 7. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is approximately 4 to approximately 7. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 7.In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 5 to about 7. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 5.5 to about 7. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 2.5 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 3 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 3.5 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 4 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 4.5 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 5 to about 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 5.5 to about 6.5. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 2.5 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 3 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 3.5 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 4 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 4.5 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 5 to about 6. In some embodiments of any one of the methods or compositions provided herein, the pH of the composition is about 5.5 to about 6.In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH is one of the pH values ​​provided herein.

[0031] In some aspects of any one 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 aspects of any one of the methods or compositions provided herein, the pH of the composition is about 2.5 to about 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 3.0 to about 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 3.5 to about 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 4.0 to about 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is about 4.5 to about 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.0 to approximately 7.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.0 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.0 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.0 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.5 to approximately 7.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 6.5.In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.0 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.0 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.0 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.5 to approximately 6.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.0 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.0 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.0 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.5 to approximately 6.0. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 2.5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.0 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 3.5 to approximately 5.5.In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.0 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 4.5 to approximately 5.5. In some aspects of any one of the methods or compositions provided herein, the pH of the composition is approximately 5.0 to approximately 5.5.

[0032] In any one embodiment of the pH described above, pH is the pH of the solution in the collection vial, such as the final collection vial (FCV). In any one embodiment of the composition or method provided herein, the collection vial is semi-prepared (e.g., semi-preparative by HPLC) but before solvent exchange. When used herein, the FCV is prepared or synthesized [ 18 This refers to a vial from which a solution containing [F]DCFPyL is collected, and the solution is considered to be the obtained solution from a preparation or synthesis method, such as the method provided herein. In one embodiment of any of the methods or compositions provided herein, the solution collected in the FCV can be administered to a subject without any further operation other than dilution. In one embodiment of any of the compositions or methods provided herein, the collection vial is the final product vial (FPV). In one embodiment of any of the compositions or methods provided herein, the FPV is after solvent exchange and ready for administration (see, for example, Figure 13).

[0033] In some embodiments of any one of the methods or compositions provided herein, ascorbic acid is present at a concentration 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 aspects of any one 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 aspects of any one 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 aspects of any one 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 aspects of any one 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 aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.3 to approximately 7.8 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 7.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4 to approximately 7.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.0 to approximately 7.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 7.5 mg / mL.In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5 to approximately 7.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.0 to approximately 7.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5 to approximately 7 mg / mL.In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.5 to approximately 7 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.5 to approximately 6.5 mg / mL.In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5 to approximately 6 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.5 to approximately 6 mg / mL.In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 2.5 to approximately 5.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3 to approximately 5.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.0 to approximately 5.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 3.5 to approximately 5.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4 to approximately 5.5 mg / mL. In some aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.0 to approximately 5.5 mg / mL. In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 4.5 to approximately 5.5 mg / mL. In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5 to approximately 5.5 mg / mL. In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration of the composition is approximately 5.0 to approximately 5.5 mg / mL. In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration is one of the concentrations provided herein.

[0034] In one embodiment of the aforementioned ascorbic acid concentration, the ascorbic acid concentration is that of the solution in the collection vial, such as an FCV or FPV.

[0035] In one aspect, the following equation [ 18There is a method for preparing a composition containing F]DCFPyL: [ka] In one embodiment, such a method is [ 18 Add the second solution containing ascorbic acid to the first solution containing F]DCFPyL, 18 The process involves forming a third solution containing F]DCFPyL and ascorbic acid. The concentration and pH of the ascorbic acid in the second solution may be any one of the concentrations and pH provided herein, respectively. Alternatively, the concentration and pH of the ascorbic acid in the second solution may be such that the third solution has any one of the concentrations and pH of the ascorbic acid provided herein, respectively. Alternatively, [ 18 A method for preparing a composition containing F]DCFPyL is, 18 The solution containing [F]DCFPyL may be prepared such that it has one of the ascorbic acid concentrations and pH values ​​provided herein. The solution obtained from one of the aforementioned methods may be collected in or transferred to a collection vial such as an FCV or FPV. The specific ascorbic acid concentrations and pH values ​​provided herein may have one or more or all of the desirable characteristics provided herein. 18 It was found that this resulted in a composition containing F]DCFPyL.

[0036] In some aspects, [ 18 F]DCFPyL is purified by chromatography before adding the first solution to the second solution or before preparing the solution as provided herein (and any one of the methods provided herein may further include such purification). In some embodiments of any one of the methods or compositions provided herein, [ 18 F]DCFPyL is not purified by chromatography before adding the first solution to the second solution, or before preparing the solutions.

[0037] In some embodiments of any one of the methods or compositions provided herein, the solution, such as the first solution, further comprises a solvent, such as an elution from a cartridge, such as an HLB cartridge. 18 F]DCFPyL and / or ascorbic acid may be substantially soluble in the solvent. In some aspects of any one of the methods or compositions provided herein, the composition comprises water. In some aspects of any one of the methods or compositions provided herein, the composition comprises water and at least one additional solvent, the solvent of which may be substantially miscible with water. Non-limiting examples of solvents include, but are not limited to, alcoholic 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, picoline, and pyridine. In some aspects of any one of the methods or compositions provided herein, the composition comprises water and a polar solvent substantially miscible with water.

[0038] In some embodiments of any one of the methods or compositions provided herein, the solvent comprises ethanol. In some embodiments of any one of the methods or compositions provided herein, such as when the solvent is eluted from a cartridge, such as an HLB cartridge, or for elution from a cartridge, the solution comprises at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% ethanol (w / v). In some of the embodiments described above, the solution comprises 100% ethanol (w / v).

[0039] In some embodiments of any one of the methods or compositions provided herein, such as when the solvent is in a collection vial such as an FCV or FPV, the solution contains about 30% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 25% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 20% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 15% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 10% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 5% or less ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution contains about 3% or less ethanol (w / v). In any one of the embodiments described above, the solution contains at least 3% ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution comprises ethanol (w / v) at any one of the values ​​provided herein.

[0040] In some embodiments of any one of the methods or compositions provided herein, the composition comprises acetonitrile. In some embodiments of any one of the methods or compositions provided herein, such as a solution in or transferred to a collection vial such as an FCV or FPV, the acetonitrile is present at a level of about 0.05% (w / v) or less, about 0.04% (w / v) or less, about 0.03% (w / v) or less, about 0.02% (w / v) or less, or about 0.01% (w / v) or less. In some embodiments of any one of the methods or compositions provided herein, the solution comprises acetonitrile (w / v) at any one of the values ​​provided herein.

[0041] In some embodiments, any one of the methods provided herein may further include the steps of applying any one of the solutions provided herein to a solvent exchange cartridge and / or eluting from the solvent exchange cartridge with any one of the solutions provided herein. In one embodiment, any one of the solutions having any one of the ascorbic acid concentrations and pH provided herein is applied to a solvent exchange cartridge such as an HLB cartridge. In another embodiment, [ 18 One of the solutions containing [F]DCFPyL is adjusted to have one of the ascorbic acid concentrations and one of the pH values ​​provided herein, and then applied to the solvent exchange cartridge.

[0042] In any one embodiment of the above-described aspects, the solution applied has or is adjusted to have an ascorbic acid concentration of 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 one of the methods or compositions provided herein, the ascorbic acid concentration is about 3.3 to about 7.8 mg / mL. In any one embodiment of the above-described aspects, the solution applied has or is adjusted to have an ascorbic acid concentration of approximately 5 mg / mL to approximately 50 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 15 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 25 mg / mL to approximately 50 mg / mL, approximately 30 mg / mL to approximately 50 mg / mL, approximately 35 mg / mL to approximately 50 mg / mL, approximately 40 mg / mL to approximately 50 mg / mL, or approximately 55 mg / mL to approximately 50 mg / mL. In any one embodiment of the above-described aspects, the solution applied has or is adjusted to have an ascorbic acid concentration of approximately 5 mg / mL to approximately 45 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 15 mg / mL to approximately 35 mg / mL, or approximately 20 mg / mL to approximately 30 mg / mL. In any one embodiment of the above-described aspects, the solution applied has or is adjusted to have an ascorbic acid concentration of 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 one 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 one of the methods or compositions provided herein, the ascorbic acid concentration is one of the values ​​provided herein.

[0043] In any one aspect of the above-described embodiments, the solution to be applied has or is adjusted to have a pH of about 4 or less, about 3.5 or less, about 3 or less, about 2.5 or less, about 2 or less, about 1.5 or less, or about 1 or less. In any one aspect of the above-described embodiments, the solution to be applied has or is adjusted to have a pH of 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 one aspect of the above-described embodiments, the solution to be applied has or is adjusted to have a pH of 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 one aspect of the above-described embodiments, the solution applied has or is adjusted to have a pH of 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 aspects of any one of the methods or compositions provided herein, is any one of the pH values ​​provided herein.

[0044] In any one embodiment of the above-described aspects, the solution further comprises ethanol. In some embodiments, the solution comprises about 30% or less ethanol (w / v). In some embodiments, the solution comprises about 25% or less ethanol (w / v). In some embodiments, the solution comprises about 20% or less ethanol (w / v). In some embodiments, the solution comprises about 15% or less ethanol (w / v). In some embodiments, the solution comprises about 10% or less ethanol (w / v). In some embodiments, the solution comprises about 5% or less ethanol (w / v). In some embodiments, the solution comprises about 3% or less ethanol (w / v). In any one embodiment of the above-described aspects, the solution comprises at least 3% ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution comprises one of the values ​​provided herein for ethanol (w / v).

[0045] In any one embodiment of the method provided herein, the solvent exchange cartridge is [ 18 The solution containing F]DCFPyL may be applied and then washed. In any one embodiment of the method provided herein, 18 F]DCFPyL is substantially retained on the solvent exchange cartridge during washing. In one embodiment or one of the methods provided herein, the washing solution is one of the solutions provided herein having any one of the concentrations and pH of ascorbic acid provided herein.

[0046] In any embodiment of the method provided herein, the method involves transferring a solvent solution from a solvent exchange cartridge to [ 18The method further comprises eluting F]DCFPyL. In one embodiment or one of the methods provided herein, the solvent solution contains an alcohol. In some embodiments, the solvent solution contains one of the amounts of ethanol provided herein, such as at least 90% ethanol (w / v). In some embodiments, the solvent solution contains 100% ethanol (w / v). In some embodiments, the solvent solution contains about 30% or less ethanol (w / v). In some embodiments, the solvent solution contains about 25% or less ethanol (w / v). In some embodiments, the solvent solution contains about 20% or less ethanol (w / v). In some embodiments, the solvent solution contains about 15% or less ethanol (w / v). In some embodiments, the solvent solution contains about 10% or less ethanol (w / v). In some embodiments, the solvent solution contains about 5% or less ethanol (w / v). In some embodiments, the solvent solution contains about 3% or less ethanol (w / v). In one embodiment of any one of the above, the solvent solution contains at least 3% ethanol (w / v). In some embodiments of any one of the methods or compositions provided herein, the solution comprises ethanol (w / v) at any one of the values ​​provided herein.

[0047] In any one embodiment of the above-described aspects, the solvent solution has an ascorbic acid concentration of 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 one of the methods or compositions provided herein, the ascorbic acid concentration is about 3.3 to about 7.8 mg / mL. In any one embodiment of the above-described aspects, the solvent solution has an ascorbic acid concentration of approximately 5 mg / mL to approximately 50 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 15 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 25 mg / mL to approximately 50 mg / mL, approximately 30 mg / mL to approximately 50 mg / mL, approximately 35 mg / mL to approximately 50 mg / mL, approximately 40 mg / mL to approximately 50 mg / mL, or approximately 55 mg / mL to approximately 50 mg / mL. In any one embodiment of the above-described aspects, the solvent solution has an ascorbic acid concentration of approximately 5 mg / mL to approximately 45 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 15 mg / mL to approximately 35 mg / mL, or approximately 20 mg / mL to approximately 30 mg / mL. In any one embodiment of the above-described aspects, the solvent solution has an ascorbic acid concentration of 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 one 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 one of the methods or compositions provided herein, the ascorbic acid concentration is one of the values ​​provided herein.In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration is one of the values ​​provided herein.

[0048] In any one aspect of the above-described embodiments, the solvent solution has a pH of about 4 or less, about 3.5 or less, about 3 or less, about 2.5 or less, about 2 or less, about 1.5 or less, or about 1 or less. In any one aspect of the above-described embodiments, the solvent solution has a pH of 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 one aspect of the above-described embodiments, the solvent solution has a pH of 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 one aspect of the above-described embodiments, the solvent solution has a pH of 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 one of the methods or compositions provided herein, the pH is one of the pH values ​​provided herein.

[0049] In any embodiment of the method provided herein, the method is [ 18 The method further comprises collecting the eluate containing F]DCFPyL into a collection vial such as an FCV or FPV. In one embodiment of any of the methods provided herein, the method further comprises maintaining or adjusting the ascorbic acid and pH of the collected solution to one of the ascorbic acid concentrations and pH provided herein.

[0050] In some aspects of any one 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 aspects, the pH is maintained or adjusted between about 2.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 3 and about 7.5. In some aspects, the pH is maintained or adjusted between about 3.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 4 and about 7.5. In some aspects, the pH is maintained or adjusted between about 4.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 2.5 and about 7. In some aspects, the pH is maintained or adjusted between about 3 and about 7. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 7. In some embodiments, the pH is maintained or adjusted to approximately 4 to approximately 7. In some embodiments, the pH is maintained or adjusted to approximately 4.5 to approximately 7. In some embodiments, the pH is maintained or adjusted to approximately 5 to approximately 7. In some embodiments, the pH is maintained or adjusted to approximately 5.5 to approximately 7. In some embodiments, the pH is maintained or adjusted to approximately 2.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 3 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 4 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 4.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 5.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 2.5 to approximately 6. In some embodiments, the pH is maintained or adjusted to approximately 3 to approximately 6. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 6. In some embodiments, the pH is maintained or adjusted to approximately 4 to approximately 6. In some embodiments, the pH is maintained or adjusted to approximately 4.5 to approximately 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, the pH is maintained or adjusted to about 5 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 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 one of the methods or compositions provided herein, the pH is one of the pH values ​​provided herein.

[0051] In some aspects of any one 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 aspects, the pH is maintained or adjusted between about 2.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 3.0 and about 7.5. In some aspects, the pH is maintained or adjusted between about 3.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 4.0 and about 7.5. In some aspects, the pH is maintained or adjusted between about 4.5 and about 7.5. In some aspects, the pH is maintained or adjusted between about 5.0 and about 7.5. In some aspects, the pH is maintained or adjusted between about 2.5 and about 7.0. In some embodiments, the pH is maintained or adjusted to approximately 3.0 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 4.0 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 4.5 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 5.0 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 5.5 to approximately 7.0. In some embodiments, the pH is maintained or adjusted to approximately 2.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 3.0 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 4.0 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 4.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 5.0 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 5.5 to approximately 6.5. In some embodiments, the pH is maintained or adjusted to approximately 2.5 to approximately 6.0. In some embodiments, the pH is maintained or adjusted to approximately 3.0 to approximately 6.0. In some embodiments, the pH is maintained or adjusted to approximately 3.5 to approximately 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, the pH is maintained or adjusted to about 5.0 to about 5.5. In some embodiments, the pH is maintained or adjusted to about 5.0 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 one of the methods or compositions provided herein, the pH is one of the pH values ​​provided herein.

[0052] In some embodiments of any one 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 one of the methods provided herein, the 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 one 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 aspects of any one 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 aspects of any one of the methods or compositions provided herein, the ascorbic acid concentration is one of the values ​​provided herein.

[0053] In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.0 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.0 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to 4.5 and approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.0 to approximately 7.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 7 mg / mL.In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.0 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.5 to approximately 7 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.5 to approximately 7.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4 to approximately 6.5 mg / mL.In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.0 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.5 to approximately 6.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 6 mg / mL.In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.0 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.5 to approximately 6 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.5 to approximately 6.0 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 2.5 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.0 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 3.5 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.0 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 4.5 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5 to approximately 5.5 mg / mL. In some aspects of any one of the methods provided herein, the ascorbic acid concentration is maintained or adjusted to approximately 5.0 to approximately 5.5 mg / mL.In some embodiments of any one of the methods or compositions provided herein, the ascorbic acid concentration is one of the values ​​provided herein.

[0054] While we do not wish to be bound by theory, the exemplary methods provided herein are [ 18 To remove impurities from compositions containing F]DCFPyL, and / or [ 18 It may also be useful for replacing the solvent in which F]DCFPyL is present, thus enabling the formation of imaging or diagnostic compositions. For example, the solution is [ 18 [F]DCFPyL may be obtained from purification (e.g., by HPLC or another purification method) and may contain impurities and / or solvents that are unsuitable for administration to the target. Therefore, impurities may be removed and / or the solvent may be replaced using the methods provided herein.

[0055] As a further example, a solution of any one of the methods or compositions provided herein is ascorbic acid, 18 F]DCFPyL, and may contain one or more solvents and / or impurities. In any one embodiment of the method provided herein, the solution may be applied to a solvent exchange cartridge, where [ 18 [F]DCFPyL is substantially retained, and other components (e.g., solvents such as acetonitrile and / or impurities) may be removed by elution (e.g., in a step of washing the resin). In any one embodiment of the method provided herein, 18 F]DCFPyL may be recovered by elution with a solvent solution. In any one embodiment of the method provided herein, then [ 18 The resulting solvent solution containing [F]DCFPyL may be further diluted as needed to form an imaging or diagnostic composition suitable for administration to a subject.

[0056] In another example, a solution of any one of the methods or compositions provided herein may contain acetonitrile (or another solvent unsuitable for administration to a subject, for example). In any one embodiment of the methods provided herein, acetonitrile (and / or impurities) may not adhere to the solvent exchange cartridge and may therefore be eluted or washed away. Thus, in any one embodiment of the methods provided herein, from the resin [ 18 The solution formed by eluting [F]DCFPyL may be substantially free of acetonitrile (or other solvents). In some embodiments of any one of the methods or compositions provided herein, the first solution may be a composition according to any one aspect or embodiment of the present invention as described herein.

[0057] Therefore, in any one embodiment of the methods or compositions provided herein, the solution contains acetonitrile at a level of about 0.05% (w / v) or less, about 0.04% (w / v) or less, about 0.03% (w / v) or less, about 0.02% (w / v) or less, or about 0.01% (w / v) or less. In any one embodiment of the methods or compositions provided herein, the solution contains acetonitrile (w / v) at any one of the values ​​provided herein.

[0058] Any one of the methods or compositions provided herein is an elution solvent, 18 It may be any solvent that enables the elution of [F]DCFPyL. Generally, 18 F]DCFPyL is substantially soluble in the elution solvent. In some embodiment of any one of the methods or compositions provided herein, where the solvent in the elution solution is an alcohol such as ethanol, the alcohol may be an alcohol incorporated in the final imaging composition or diagnostic composition. Such ethanol may be at any of the concentrations provided herein. Suitable cartridges, etc., are known to those skilled in the art and contain HLB and SEP-PAK.

[0059] Radiochemical purity, stability, and radioactivity concentration The compositions described herein and / or compositions prepared according to the methods described herein may have high radiochemical purity and / or maintain high radiochemical purity for a considerable period of time. As used herein, radiochemical purity refers to the ratio of the amount 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 may also be a measure of the degree to which a particular radiopharmaceutical is altered and / or decomposed and / or transformed into other compounds, which may or may not contain the radioisotope. Radiochemical purity may also be the distribution of radioactivity in the parent species relative to other radioactive species.

[0060] In some embodiments of any method or composition provided herein, the composition has at least about 90% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 95% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 96% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 97% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 98% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 98.5% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 98.9% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 99% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has at least about 99.5% radiochemical purity. In some embodiments of any method or composition provided herein, the composition has a radiochemical purity of at least about 99.9%. In some embodiments of any method or composition provided herein, the composition has a radiochemical purity of about 95% to about 98%. In some embodiments of any method or composition provided herein, the composition has a radiochemical purity of about 95% to about 98.5%. In some embodiments of any method or composition provided herein, the composition has a radiochemical purity of about 95% to about 98.9%. In some embodiments of any method or composition provided herein, the composition has a radiochemical purity of about 95% to about 99%.In some embodiments of any one of the methods or compositions provided herein, the composition has a radiochemical purity of about 95% to about 99.5%. In some embodiments of any one of the methods or compositions provided herein, the composition has a radiochemical purity of about 95% to about 99.9%. In some embodiments of any one of the methods or compositions provided herein, the composition has a radiochemical purity of about 95% to about 100%. In some embodiments of any one of the methods or compositions provided herein, the composition has a radiochemical purity of any one of the values ​​provided herein.

[0061] Those skilled in the art will know the techniques and systems for determining the radiochemical purity of a composition. In some cases, radiochemical purity is determined using HPLC associated with a radiation detector. Generally, radiochemical purity is determined under ambient conditions (e.g., ambient temperature, ambient humidity, ambient light, etc.), such as in samples stored under such conditions.

[0062] In some embodiments of any one of the methods or compositions provided herein, the composition maintains high radiochemical purity over a considerable period. While we do not wish to be bound by theory, this may also be due to the selection of appropriate compositional components and conditions that aid in the stability of the imaging agent. For example, the presence of ascorbic acid and / or ethanol, and / or the selection of an appropriate pH for the composition, can significantly affect the radiostability of the imaging agent.

[0063] In some embodiments of any one of the methods or compositions provided herein, the composition has the radiochemical purity provided herein at the end of synthesis (EOS). In some embodiments of any one of the methods or compositions provided herein, the composition has at least about 90% radiochemical purity over a period of at least about 6 hours, at least 8 hours, or at least 10 hours. In some embodiments of any one of the methods or compositions provided herein, the composition has at least about 95% radiochemical purity after about 10 hours. In some embodiments of any one of the methods or compositions provided herein, the composition has at least about 97% radiochemical purity after about 10 hours. In some embodiments of any one of the methods or compositions provided herein, the composition has at least 99% radiochemical purity after at least 10 hours. In such embodiments, the time is measured after synthesis (i.e., time after the end of synthesis (EOS)).

[0064] In any one embodiment of the methods or compositions provided herein, the compositions provided herein exhibit little to no radiolysis after synthesis, such as at least about 6, 7, 8, 9, or 10 hours. In any one embodiment, the compositions provided herein exhibit less than 5% free radiolysis after synthesis, such as at least about 6, 7, 8, 9, or 10 hours. 18 F or less than approximately 4.5% free 18 F or less than 4% free 18 F or less than approximately 3.5% free 18 F or less than 3% free 18 F or less than approximately 2.5% free 18 F or less than 2% free 18 F or less than approximately 1.5% free 18 F or less than 1% free 18 F or less than approximately 0.5% free 18 It has F. In any one of several embodiments of the methods or compositions provided herein, the composition is free provided herein.18 It has one of the F levels.

[0065] In one embodiment of any composition or method provided herein, the incorporation of ascorbate in the collection vial prevents radiolysis during transfer to the solvent exchange cartridge and during addition. This leads to a reduction in impurities in the drug product at T0. In one embodiment of any composition or method provided herein, the presence of ascorbate in the FCV or FPV can stabilize the product during storage for 10 hours.

[0066] In one aspect, free 18 Methods for detecting F are provided herein. In any one such method, TEAF is used at any of the concentrations provided herein, etc. In any one such method, the composition is [ 18 The composition may also contain a radiopharmaceutical such as [F]DCFPyL. Such a method involves adding tetraethylammonium fluoride to the composition to be evaluated; and performing an assay on the sample and determining the free particles on the composition using chromatography such as HPLC. 18 This includes determining the level of F.

[0067] In some embodiments of any one of the methods or compositions provided herein, the radioactivity 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, and at least The radioactivity concentration of the composition is either approximately 130 mCi / mL, at least approximately 135 mCi / mL, at least approximately 140 mCi / mL, at least approximately 145 mCi / mL, at least approximately 150 mCi / mL, at least approximately 155 mCi / mL, at least approximately 160 mCi / mL, at least approximately 165 mCi / mL, at least approximately 166 mCi / mL, at least approximately 167 mCi / mL, at least approximately 168 mCi / mL, at least approximately 169 mCi / mL, or at least approximately 170 mCi / mL. In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is one of the values ​​provided herein.

[0068] In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is approximately 80 mCi / mL to approximately 170 mCi / mL, approximately 80 mCi / mL to approximately 165 mCi / mL, approximately 80 mCi / mL to approximately 160 mCi / mL, approximately 80 mCi / mL to approximately 155 mCi / mL, approximately 80 mCi / mL to approximately 150 mCi / mL, approximately 80 mCi / mL to approximately 145 mCi / mL, approximately 80 mCi / mL to approximately 140 mCi / mL, approximately 80 mCi / mL to approximately 135 mCi / mL, approximately 80 mCi / mL to approximately 130 mCi / mL, approximately 80 mCi / mL to approximately 125 mCi / mL, or approximately 80 mCi / mL to approximately 120 mCi / mL. In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is approximately 85 mCi / mL to approximately 170 mCi / mL, approximately 90 mCi / mL to approximately 170 mCi / mL, approximately 95 mCi / mL to approximately 170 mCi / mL, approximately 100 mCi / mL to approximately 170 mCi / mL, approximately 105 mCi / mL to approximately 170 mCi / mL, approximately 110 mCi / mL to approximately 170 mCi / mL, approximately 115 mCi / mL to approximately 170 mCi / mL, or approximately 120 mCi / mL to approximately The values ​​are either 170 mCi / mL, approximately 125 mCi / mL to approximately 170 mCi / mL, approximately 130 mCi / mL to approximately 170 mCi / mL, approximately 135 mCi / mL to approximately 170 mCi / mL, approximately 140 mCi / mL to approximately 170 mCi / mL, approximately 145 mCi / mL to approximately 170 mCi / mL, approximately 150 mCi / mL to approximately 170 mCi / mL, approximately 155 mCi / mL to approximately 170 mCi / mL, approximately 160 mCi / mL to approximately 170 mCi / mL, or approximately 165 mCi / mL to approximately 170 mCi / mL.In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is approximately 85 mCi / mL to approximately 165 mCi / mL, approximately 90 mCi / mL to approximately 165 mCi / mL, approximately 95 mCi / mL to approximately 165 mCi / mL, approximately 100 mCi / mL to approximately 165 mCi / mL, approximately 105 mCi / mL to approximately 165 mCi / mL, approximately 110 mCi / mL to approximately 165 mCi / mL, approximately 115 mCi / mL to approximately 165 mCi / mL, and approximately The ranges are approximately 120 mCi / mL to 165 mCi / mL, approximately 125 mCi / mL to 165 mCi / mL, approximately 130 mCi / mL to 165 mCi / mL, approximately 135 mCi / mL to 165 mCi / mL, approximately 140 mCi / mL to 165 mCi / mL, approximately 145 mCi / mL to 165 mCi / mL, approximately 150 mCi / mL to 165 mCi / mL, approximately 155 mCi / mL to 165 mCi / mL, or approximately 160 mCi / mL to 165 mCi / mL.

[0069] In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is about 170 mCi / mL or less. In some embodiments of any one of the methods or compositions provided herein, the radioactivity concentration of the composition is about 169 mCi / mL or less, about 168 mCi / mL or less, about 167 mCi / mL or less, about 166 mCi / mL or less, or about 165 mCi / mL or less.

[0070] For example, [ 18 A composition is provided comprising F]DCFPyL and one or more or all of the following characteristics. In one embodiment, the composition comprises 95% or more [ 18The composition has F]DCFPyL (radiochemical purity), a pH of 4.5 to 7.0, and 5 to 15 mg / mL of ascorbic acid. In any one embodiment of the composition described above, the composition has a radioactivity concentration of 1 to 125 mCi / mL at the end of synthesis (EOS) (for example, 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 8 The specific activity (based on EOS) is 5 mCi / mL to 125 mCi / mL, or 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 to 125 mCi / mL, at least 115 mCi / mL to 125 mCi / mL, or at least 120 mCi / mL to 125 mCi / mL) and / or has a specific activity (based on EOS) of 1000 mCi / μmol or more at the expiration date. In any one embodiment of the compositions described above, the composition contains ethanol at 7.89% w / v or less and / or acetonitrile at 0.04% w / v or less. In any one embodiment of the aforementioned compositions, the composition contains a total of 1.5 μg / mL or less of unknown impurities and / or 5.0 μg / mL or less of ascorbic acid-related impurities, such as a relative retention time (RRT) of 0.607. In any one embodiment of the aforementioned compositions, the radioactive identity calculation is within ±10%, and / or the half-life (T 1 / 2 The radionuclide identity obtained by ) is 10⁵–11⁵ minutes. The aforementioned characteristics and the characteristics in the following table can be assayed, measured or evaluated by methods known to those skilled in the art or by methods provided in the following table, respectively. [Table 32-1] [Table 32-2] [Table 32-3]

[0071] Imaging agents and related methods Imaging agents enable the detection, imaging, and / or monitoring of the presence and / or progression of conditions, pathological disorders, and / or diseases. Typically, imaging agents are administered to a subject (e.g., a human) to provide information about at least a portion of that subject. In some cases, imaging agents may be used to highlight specific areas of a subject, making organs, blood vessels, tissues, and / or other parts more detectable and / or more clearly imageable. By improving the detectability and / or image quality of the object being investigated, the presence and extent of disease and / or conditions can be determined.

[0072] The imaging agents provided herein are, 18 It is F]DCFPyL, a radioactive isotope. 18 F is part of imaging, and in one embodiment, in particular, positron emission tomography (PET) imaging. The compositions provided herein may be used in nuclear medicine imaging. In some embodiments, the compositions provided may be pharmaceutically acceptable. The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0073] [ 18F]DCFPyL may also be present in the compositions provided herein as pharmaceutically acceptable salts. A pharmaceutically acceptable salt may be a derivative of the disclosed compound, modified by the parent compound to produce an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. A pharmaceutically acceptable salt may also include, for example, a conventional non-toxic or quaternary ammonium salt of the parent compound formed from a non-toxic inorganic or organic acid. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic 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, pamoic 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 isethionic acid.

[0074] In some aspects, [ 18 F]DCFPyL may be synthesized using an automated synthesis module, which will be known to those skilled in the art. In some cases, the imaging agent may be synthesized according to the teachings of an automated synthesis module described in International Publication No. 2011 / 097649, published on August 11, 2011, the teachings relating to that automated synthesis module are incorporated herein by reference.

[0075] In some embodiments, the imaging or diagnostic compositions described herein may find applications in imaging methods comprising administering the imaging or diagnostic compositions described herein, and imaging methods comprising imaging a region of interest. The region of interest may include, but is not limited to, cancerous tissue, tumors and / or tissues and organs with metastases, the prostate and blood vessels (e.g., arteries, veins). Methods for imaging one or more cells, organs or tissues, comprising contacting or administering an effective amount of the compounds provided herein to the cells, organs or tissues, are also provided herein. In some embodiments, the one or more organs or tissues may include prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue. In several embodiments, the subject is a human subject.

[0076] In some embodiments, the imaging method is suitable for imaging by targeting PSMA. In some embodiments, the imaging method is suitable for imaging cancer, tumors, or neoplasms. In some embodiments, cancer is selected from eye or ocular 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), pharyngeal cancer, cutaneous 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.

[0077] 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 uses include imaging glutamatergic neurotransmission, presynaptic glutamatergic neurotransmission, malignant tumors or cancers expressing PSMA, prostate cancer (including metastatic prostate cancer), and angiogenesis. Solid tumors express PSMA in their neovascular systems. Therefore, the methods and compositions provided herein may be used to image solid tumors including lung, renal, glioblastoma, pancreas, bladder, sarcoma, melanoma, breast, colon, germ cell, pheochromocytoma, esophagus, and stomach. PSMA is frequently expressed in endothelial cells of capillaries in the peritumoral and intratumoral regions of various malignant tumors, so that the methods and compositions provided may be used to image such malignant tumors. Furthermore, certain benign lesions and tissues, including endometrium, Schwann cell tumors, and Barrett's esophagus, can also be imaged according to the provided methods and compositions.

[0078] The methods and compositions provided for imaging angiogenesis are suitable for use in imaging a variety of diseases and disorders in which angiogenesis occurs. Exemplary and non-limiting examples include tumors, collagen vascular diseases, cancer, stroke, vascular malformations, and retinopathy. The methods and compositions provided for imaging angiogenesis are also suitable for use in the diagnosis and observation of normal tissue development.

[0079] In some embodiments, any one of the methods provided herein may include diagnosing or assisting in the diagnosis of a disease or condition, evaluating and / or selecting and / or modifying treatment for a disease or condition, evaluating the effectiveness of treatment for a disease or condition, or imaging in a subject having a known or suspected disease or condition.

[0080] In some embodiments of any one of the methods provided herein, the imaging method comprises (a) administering an imaging composition or diagnostic composition containing an imaging agent to a subject, and (b) obtaining at least one image of at least a portion of the subject. In some embodiments, the acquisition of any one of the methods provided herein employs positron emission tomography (PET) to visualize the distribution of the imaging agent within at least a portion of the subject. As will be understood by those skilled in the art, the imaging may include whole-body imaging of the subject of interest, or imaging of specific body regions or tissues of the subject. For example, if a subject is known or suspected to have cancer, such as prostate cancer, the method may be used to image the organ with the primary tumor, such as the prostate, and / or organs with (or suspected to have) metastases of the subject.

[0081] In one embodiment of any composition or method provided herein, the amount of PyL is 8 to 10 mCi. In one embodiment of any composition or method provided herein, the amount of PyL administered to the patient is 8 to 10 or 8, 9, or 10 mCi from FPV containing ascorbate at one of the concentrations provided herein, such as 80 to 170 mCi / mL, and prepared at one of the concentrations provided herein, such as 5.6 mg / mL ascorbate. In one embodiment of any composition or method provided herein, the amount of PyL administered to the patient is 8-10 or 8, 9, or 10 mCi from an FPV prepared at one of the concentrations provided herein, such as 80-125, 80-130, 80-135, 80-140, 80-145, 80-150, 80-155, 80-160, or 80-165 mCi / mL, containing ascorbate at one of the concentrations provided herein, such as 5.6 mg / mL ascorbate, having a pH at one of the pH provided herein, such as 4.5-7 or 7.0, and having one of the radiochemical purities provided herein, such as at least 90% (up to 10 hours after EOS), and / or having one of the specific activity provided herein, such as at least 1000 mCi / μmol, at the time of administration. In any one of the embodiments described above, the composition contains 78.9 mg or less of ethanol in 0.9% sodium chloride (injection solution (USP)). In any one of the embodiments described above, imaging using a PET camera is performed 1 hour after administration.

[0082] In some embodiments of any one of the methods or compositions provided herein, the radiolabeled compound is detected by positron emission tomography (PET) or situational radiography / computed tomography (PET / CT). The image may be generated by differences in the spatial distribution of the imaging agent accumulating at a site. The spatial distribution may be measured using some means suitable for a particular label, such as a gamma camera, PET device, PET / CT device, etc. The degree of accumulation of the imaging agent may be quantified using known methods for quantifying radioactive emissions.

[0083] In general, a detectable effective amount of the compositions provided herein for imaging may be administered to a subject. According to the present invention, “detectable effective amount” is defined as an amount sufficient to produce an acceptable image using equipment available for clinical use. The detectable effective amount of the compositions provided herein may be administered in one or more injections. The detectable effective amount may vary depending on factors such as the degree of individual sensitivity, individual age, sex and weight, individual idiosyncratic reactions, and dosimetry. The detectable effective amount may also vary depending on equipment and film-related factors. Optimization of such factors is well within the realm 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 treatment the patient is receiving, and the patient's idiosyncratic reactions. Ultimately, the attending physician can determine the amount to administer to each individual patient and the duration of the imaging study.

[0084] In one embodiment of any method or composition provided herein, the subject is human, rat, mouse, cat, dog, horse, sheep, dairy cow, monkey, bird, or amphibian. In another embodiment of any method or composition provided herein, the cells are in vivo or in vitro. Typical subjects to which the compounds of the present invention may be administered are mammals such as primates and humans. For veterinary applications, a wide variety of subjects include, for example, livestock such as cattle, sheep, goats, dairy cows, and pigs; poultry such as chickens, ducks, geese, and turkeys; and domestic animals, particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs such as inbred pigs, are suitable subjects. In addition, for in vitro applications such as in vitro diagnostics and research, any of the above-mentioned bodily fluids and cell samples, such as human blood, urine, or tissue samples, are suitable for use.

[0085] kit Also provided are kits containing one of the compositions, reagents, or combinations of reagents provided herein. In some embodiments, the kit provides a packaged pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of the present invention. In other embodiments, the kit provides compounds and reagents necessary to carry out one of the methods provided herein. Thus, in some embodiments, the kit as provided herein contains a combination of reagents for one of the methods provided herein. In one embodiment of any of the kits provided, the kit further includes markings containing at least one of the following instructions: for carrying out one of the methods provided herein, for preparing one of the compositions provided herein, and / or for using the final composition as provided herein in a method of use such as one of the methods of use provided herein. In one embodiment of any of the kits provided, the kit contains one of the compositions provided herein in combination with a pharmaceutically acceptable carrier. One of the compositions in any of the kits provided may be in solution. In one embodiment of any of the kits provided, the final composition is provided in a syringe or vial, or the kit further includes a syringe or vial, such as one useful for administration, such as an FCV or FPV.

[0086] In one embodiment of any of the kits provided herein, the kit is for synthesizing PyL. In one embodiment of any of the kits provided herein, the kit comprises ascorbic acid, such as one of the concentrations provided herein, or an amount sufficient to prepare ascorbic acid at one of the concentrations provided herein. In the aforementioned embodiment, the kit further comprises a PyL precursor, saline, and / or phosphoric acid. In the aforementioned embodiment, the kit further comprises 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 comprises a cassette for automated synthesis, such as an all-in-one synthesis. In one embodiment of any of the kits provided, the automated synthesis is for synthesizing PyL for PET imaging.

[0087] example Examples are provided below so that the disclosures described herein may be understood more fully. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope.

[0088] Example 1.[ 18 Synthesis of F]DCFPyL 5-(((S)-6-(tert-butoxy)-5-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-6-oxohexyl)carbamoyl)-N,N,N-trimethylpyridine-2-aminium trifluoromethanesulfonate precursor is ((2S)-2-[[(1S)-1-carboxy-5-[(6-fluoroanylpyridine-3-carbonyl)-amino]-pentyl]-carba [Moyl-amino]pentanedioic acid was custom synthesized, similar to the reference standard. The synthesis reagents were from the FDA-approved Trasis kit. Ascorbic acid and citrate were USPs. The synthesis of 2-(3-{1-carboxy-5-[(6-[18F]fluoropyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid was performed on an all-in-one module (Trasis). Cyclotron generated 18 F has been captured.

[0089] All chemicals and components are cyclotron generated. 18 [F] fluoride ions were loaded onto an all-in-one synthesis cassette with the SPE cartridge. The resin cartridge was eluted into the reaction vessel and dried. The reaction vessel was cooled and dried. 18 F] To the reaction vessel containing fluoride [ 18 A solution of the [F]DCFPyL precursor was added, and the solution was heated. After the labeling reaction was complete, phosphoric acid (85%) was added to the reactant to promote the removal of the tert-butoxy protecting group. Then, sodium hydroxide was added to quench the deprotection reaction. 18 [F]DCFPyL was purified from this reaction mixture by semi-preparative HPLC. 18 The [F]DCFPyL product peak was collected based on radiation detection, and the solvent was then replaced by elution from the retention and separation cartridges. The eluate was in ethanol, which was then diluted in saline alone or in saline containing additional radioprotective agents (Figure 1).

[0090] Stability was assessed using reversed-phase HPLC on a C18 column with a phosphate buffer / acetonitrile gradient mobile phase, and elution profiles were monitored using both UV and radiochemical detectors. Samples were analyzed by either direct injection onto the HPLC, dilution and injection, or by adding tetraethylammonium fluoride (TEAF) to the sample before injection.

[0091] The pH of the solution was determined either by spotting on a pH paper strip or by using a pH probe and pH meter. Ascorbic acid concentration was verified by spotting on an ascorbic acid detection paper strip.

[0092] Example 2. Radiolysis Evaluation Method [ 18 F]DCFPyL is generally radiolytically stable, except for the observation of early, consecutive peaks in the analytical method during process validation (PV) lots. These early, consecutive peaks exhibited a broad tail and were free-released. 18 It co-eluted with F. Poor peak shape indicates free elution in the RCP chromatogram. 18 This resulted in insufficient integration of the F peak and the possibility of underestimating impurities (Figure 2).

[0093] Free particles in the analytical sample 18 We improved the HPLC radiation detector quantification of potassium fluoride (15 mg / mL) incorporating F, and free 18 Methods to sharpen the F peak (Journal of Pharmaceutical and Biomedical Analysis 111 2015 209-214) may be used. However, investigation with tetraethylammonium fluoride (TEAF, 44 mg / mL) (Figure 3) demonstrated an improved peak shape. Potassium fluoride is [ 18 F]DCFPyL resulted in a deterioration of the peak shape, so TEAF was selected.

[0094] Known amounts of free TEAF, either alone or spiked.18 F was injected onto the analytical column, and the eluate from the column was collected during the chromatogram process and assayed for radioactivity using Capintec. The results showed recoveries of 90.9% and 101.3% for free 18 F alone and free 18 F spiked with TEAF, respectively. This demonstrates an improvement in free 18 F recovery when the sample was spiked with TEAF, in addition to the improvement in the peak shape described above. The addition of TEAF to the analytical sample was incorporated into subsequent investigations to overcome some of the limitations of free 18 F quantification in order to 18 examine the potential radiolysis of

[0095] Example 3. Ethanol as a Radioprotectant As in Example 1 18 a 18 F]DCFPyL sample was synthesized. The final product was at 325 mCi / mL at the end of synthesis and was maintained in 100% ethanol. As in Example 1, the sample was taken every hour for 10 hours, and the radiochemical and chemical purity were determined by HPLC-radiometric detection or UV detection, respectively. The time-dependent formation of free

Table 1

[0096] Free 18 F estimation was limited by the poor peak shape of 18 F coming out of the HPLC column. This peak shape was improved by the addition of TEAF. This demonstrates the possibility of underestimating free 18 F (). Table 2).

Table 2

[0097] Example 4. Formation of Radioactive Impurities in the Presence of Ethanol and Water As in Example 1 18 An F]DCFPyL sample was synthesized. The final product was at 146.76 mCi / mL at the end of synthesis and was maintained in 36% ethanol in saline. As in Example 1, samples were taken every 30 minutes over 4 hours and the radiochemical and chemical purity were determined by HPLC-radiodetection or UV detection, respectively. The time-dependent formation of free 18 F with some additional unidentified radioactive impurities was evident (Table 3). [Table 3]

[0098] Example 5. Formation of Impurity-Related Radioactivity Concentrations in the Presence of Ethanol and Water As in Example 1 18 An F]DCFPyL sample was synthesized. The final product radioactivity concentration was in the range of 52 - 85 mCi / mL at the end of synthesis and was maintained in 20% ethanol in saline. As in Example 1, samples were taken every 30 minutes over 4 hours and the radiochemical and chemical purity were determined by HPLC-radiodetection or UV detection, respectively. The time- and concentration-dependent formation of free 18 F with some additional unidentified radioactive impurities was evident (Table 4). [Table 4]

[0099] Example 6. Formation of Radioactive Impurities in Ethanol and 100 mg / mL Ascorbic Acid As in Example 1, a [18F]DCFPyL sample was synthesized. However, the peaks collected from HPLC were added to ascorbic acid at pH 2.0 to obtain a final concentration of 100 mg / mL. At 100 mg / mL, ascorbic acid was added to the washing solution to perform solvent exchange, and the final ethanol eluate was diluted to a final ascorbic acid concentration of 100 mg / mL. The final product radioactivity concentration was 256 mCi / mL at the end of synthesis and was maintained in ethanol. As in Example 1, samples were taken every 30 minutes over 4 hours, and radiochemical and chemical purity were determined by HPLC radiation detection or UV detection, respectively. The formation of free 18F was significantly suppressed, with only 0.08% accumulating over 4 hours (Table 5). However, radioactive impurities at retention times (RT) 12 and 12.2 minutes accumulated over time in the presence of ascorbic acid (Figure 8). Table 5 This shows the free 18F over 4 hours. 18 Unlike samples collected in ethanol alone or in ethanol in saline, where high levels of F formation were observed, radioactive impurities at retention times (RT) 12 and 12.2 minutes accumulated over time in the presence of ascorbic acid (Figure 8). [Table 5]

[0100] Example 7. Formation of radioactive impurities in ethanol and 50 mg / mL ascorbic acid As in Example 1, [ 18 A sample of [F]DCFPyL was synthesized. However, the final ethanol eluate was diluted to a final ascorbic acid concentration of 50 mg / mL at pH 5.8. The final product radioactivity concentration was 111 mCi / mL at the end of synthesis and was maintained in 20% ethanol. As in Example 1, samples were taken every 30 minutes over 4 hours, and radiochemical and chemical purity were determined by HPLC radiation detection or UV detection, respectively. Free 18 The formation of F was significantly suppressed, with only 0.26% accumulating over 4 hours (Table 6). This represents the amount of free F accumulated over 4 hours. 18This differs from samples collected in ethanol alone or in ethanol in saline solution, where high levels of F formation were observed. Furthermore, impurities at RT12 and RT12.2 were not apparent, and impurities at RT5 and RT5.9 were also minimal (Table 6). [Table 6]

[0101] Example 8. Formation of radioactive impurities in ethanol and range of ascorbic acid concentrations. As in Example 1, [ 18 F]DCFPyL samples were synthesized. However, the final ethanol eluate was diluted to a final ascorbic acid concentration of 0.5–50 mg / mL at pH 5.8. The final product radioactivity concentration was 99–139 mCi / mL at the end of synthesis and was maintained in 20% ethanol. As in Example 1, samples were taken at times 0, 2, 4, 6, and 10, and their radiochemical and chemical purity was determined by HPLC radiation detection or UV detection, respectively. Free 18 The formation of F was inhibited in a concentration-dependent manner, but was significantly suppressed at all ascorbic acid concentrations tested over 10 hours (Table 7 and Figure 10). This was compared to the free formation over 4 hours. 18 This differs from samples collected in ethanol alone or in ethanol in saline, where high levels of F formation were observed. Furthermore, impurities in RT12, 12.2, and 5.9 were not apparent, and the impurity in RT5 was also minimal. [Table 7-1] [Table 7-2]

[0102] Example 9. Formation of radioactive impurities in the presence of ethanol and within the range of sodium ascorbate concentrations. As outlined in Example 1, [ 18F]DCFPyL samples were synthesized. However, the final ethanol eluate was diluted to a final sodium ascorbate concentration of 1, 2.5, or 5 mg / mL. The radioactivity concentration of the final product at the end of synthesis was measured and maintained in 20% ethanol. As described in Example 1, samples were taken at times 0, 2, 4, 6, and 10, and their radiochemical and chemical purity was determined by HPLC radiation detection or UV detection, respectively. Free 18 The formation of F was inhibited in a concentration-dependent manner and was suppressed at all ascorbic acid concentrations tested over 10 hours. This was followed by a 4-hour period of free fluorine formation. 18 This differs from samples collected in ethanol alone or in ethanol in saline solution, which showed high levels of F formation.

[0103] The comparison between sodium ascorbate and ascorbic acid is that ascorbic acid is 18 This indicates that the defluorination of F-DCFPyL was more effectively inhibited. Furthermore, the impurities RT12, 12.2, 5.9, and 5.0 were not identified (Table 8). [Table 8-1] [Table 8-2]

[0104] Example 10. Formation of radioactive impurities in the presence of ethanol and sodium citrate. As outlined in Example 1, [ 18 A sample of [F]DCFPyL was synthesized. However, the final ethanol eluate was diluted to a final sodium citrate concentration of 20 mg / mL. The final product radioactivity concentration was 104.8 mCi / mL at the end of synthesis and was maintained in 20% ethanol. As described in Example 1, samples were taken at times 0, 2, and 4, and their radiochemical and chemical purity was determined by HPLC radiation detection or UV detection, respectively. Free 18The formation of F occurred rapidly, increasing from 10.22% at time 0 to 20.65% at 4 hours (Table 9). This represents the release over 4 hours. 18 The high formation of F was similar to that observed in samples collected in ethanol alone or in ethanol in saline solution. Most of the formed radioactive impurities were free. 18 It was F. [Table 9]

[0105] Example 11. pH of ascorbic acid and sodium ascorbate as a function of concentration Solutions of Ascor USP ascorbic acid in SWFI at concentrations ranging from 50 mg / mL to 0.5 mg / mL and sodium ascorbate from Spectrum in saline at concentrations ranging from 50 mg / mL to 0.5 mg / mL were prepared. pH was measured using a Corning pH meter calibrated with 4.0 and 7.0 pH buffers and Macherey-Nagel pH paper ranging from 2.0 to 9.0. Since the pH range of the Ascor USP ascorbic acid solutions used was 5.6 to 6.6, aliquots of sodium ascorbate at concentrations of 50 mg / mL, 5 mg / mL, 2.5 mg / mL, and 1 mg / mL from Spectrum in saline were pH-adjusted with concentrated hydrochloric acid to achieve a pH close to the range (Table 10). On a different day, another set of 2.5 mg / mL sodium ascorbate in saline, both stock and pH-adjusted with concentrated hydrochloric acid, was also prepared. The pH of this set was measured using a Corning pH meter calibrated with 4.0 and 7.0 pH buffers, Macherey-Nagel pH paper ranging from 2.0 to 9.0, and EMD pH paper ranging from 2.0 to 9.0 (Table 11). [Table 10] [Table 11]

[0106] Example 12.[ 18 F]DCFPyL formulation [ 18 Desired formulations of F]DCFPyL are provided in (Table 12). The formulation is 0.9% sodium chloride (USP) with up to 7.89% ethanol w / v, such as 3% ethanol. A schematic diagram of the Trasis all-in-one (AIO) synthesis module with reagents and reagent positions is provided in Figure 13. Generally, the upper limit of the radioactivity concentration at end of synthesis (EOS) may be 80 mCi / mL. To improve drug delivery and / or allow for higher doses per lot (lot size may be limited by the maximum drug concentration product vial size (e.g., 50 mL)), products with higher radioactivity concentrations, such as over 120 mCi / mL at EOS, may be beneficial. In addition, the main radiolysis products observed are free 18 F is... 18 It is formed by the radiolysis of [F]DCFPyL. Minimizing radiolysis can be beneficial. [Table 12]

[0107] [ 18 Investigations were conducted to examine the success of adding radioprotective agents to formulations of [F]DCFPyL and minimizing drug substance radiolysis. Ascorbic acid has been demonstrated to quench high-radioactivity-induced radiolysis of certain PET products (e.g., U.S. Patent Application Publication No. 20200222562), but with specific desired characteristics [ 18 The effectiveness of preparing [F]DCFPyL has not been previously evaluated. Ascorbic acid is used at higher radioactivity concentrations (e.g., above 120 mCi / mL) 18 A comprehensive analysis was conducted on the ability to stabilize F]DCFPyL and its impact on such desirable characteristics of the formulation.

[0108] A flowchart illustrating where ascorbic acid is introduced in the production process is shown in Figure 14. In one embodiment, ascorbic acid may be delivered to the final product vial (FPV) as part of product delivery from the HLB solvent exchange cartridge (ascorbic acid added to the delivery solution vial; position F on AIO, Figure 13), and / or by direct introduction into the FPV. In another embodiment, the addition of ascorbic acid to the collection vial used to receive peak cuts from the semi-prepared purification also provides a pathway to stabilize the product before the solvent exchange step. In yet another embodiment, ascorbic acid can be used to pre-prepare cartridges, such as the HLB cartridge used to perform the solvent exchange.

[0109] HPLC radiochemical and chemical impurity assays Analytical HPLC methods were used. For chemical impurities, UV detection at 264 nm was employed, and an Eckert & Ziegler Model B-FC-1000 gamma detector was used for radiochemical assays.

[0110] [ 18 F]DCFPyL specifications desirable[ 18 The specifications for the [F]DCFPyL product are provided in Table 15. A general test plan is also provided (Table 16), although in some cases the test timings have been modified as indicated. [Table 15] [Table 16-1] [Table 16-2]

[0111] The procedure was carried out with an initial radioactivity of approximately 2 CI at 18F. 18 F]DCFPYL Survey Using 1) a collection vial used to receive the product peak cut from the semi-preparative purification process, 2) a pre-adjusted HLB cartridge used to perform solvent exchange, and 3) ascorbic acid to be added to the final product vial, 18 The feasibility of stabilizing [F]DCFPYL was evaluated. To achieve a radioactivity concentration of approximately 120 mCi / mL, the labeled product was eluted from an HLB cartridge used for solvent exchange and delivered using nitrogen push 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 assayed by Capintec and diluted to achieve the desired radioactivity concentration. This resulted in a product with a higher ethanol level (approximately 20%) than typically used clinically (for example, around 3%). While ethanol is known to provide some protection against radiolysis, it provided an initial assessment of the effect of ascorbic acid on stabilization compared to an ethanol control.

[0112] The control lot was produced without incorporating ascorbic acid and had a final radiochemical concentration of 147 mCi / mL and an ethanol level of 29.8%. The product was sampled every 30 minutes and assayed with an extended gradient to allow detection of hydrophobic impurities. The product was delivered from the HLB into 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 radioactivity concentration. The initial radiochemical purity (RCP) was 94%, and the T=4 hour RCP was 89%, far below the desired RCP product specification of 95% or higher. 18 In addition to F, in the initial chromatogram, [ 18 There were two additional radioactive impurities that eluted before the [F]DCFPYL peak but did not appear to grow over time. These may be process impurities, as opposed to ongoing radiolysis. 18There are two additional peaks below the reportable limit of 0.3% w / w eluting after the [F]DCFPYL product peak. Data are provided in Table 17. The T=0 time chromatogram is provided in Figure 15.

[0113] Lots were generated by pre-loading 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution into collection vials. The HLB cartridge was also rinsed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. 18 F]DCFPYL was delivered from HLB into a vial containing 1.3 mL of 0.9% sodium chloride (USP). The product was assayed and diluted to the desired radioactivity concentration using 0.9% sodium chloride (USP). Samples were taken and assayed every 30 minutes. For radiochemical purity HPLC analysis, the sample was removed to reduce column retention and release. 18 To enhance the F peak and enable better quantification, 44 mg / mL of tetraethylammonium fluoride was added. The product had a radiochemical concentration of 256 mCi / mL. The initial RCP was 99.7%, free 18 The F impurity was 0.29%. 18 Only one of the two impurities observed in the control lot that eluted before the [F]DCFPYL peak was present sporadically in the range of <LLQ to 0.35%, but was not consistently observed at reportable levels (≥0.3%). At T=4 hours, RCP was 98.0%. Data for this lot are provided in Table 18. This clearly demonstrates that radiolysis was significantly reduced when ascorbic acid was added to the collection vial.

[0114] A lot was generated by pre-loading 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution into collection vials. The HLB cartridge was also rinsed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. Finally, in a vial pre-loaded with 50 mg / mL, pH 5.8 ascorbic acid solution, [ 18F]DCFPYL was collected, assayed by Capintec, and diluted to the desired concentration using a 50 mg / mL pH 5.8 ascorbic acid solution. The product was sampled and assayed every 30 minutes. For radiochemical purity HPLC analysis, the sample was removed to reduce column retention and free the sample. 18 To enhance the F peak and enable better quantification, 44 mg / mL of tetraethylammonium fluoride was added. The product had a radiochemical concentration of 110 mCi / mL and an ethanol level of 24% (w / w). The initial RCP was 99.7%. 18 The F impurity level was below LLQ. 18 Two impurities, observed in the control lot eluting before the [F]DCFPYL peak, were present at levels ranging from less than LLQ to 0.37%, but were not consistently present at reportable levels (greater than 0.3%). The RCP remained above 99% at T=4 hours. Data for this lot are provided in Table 19. This clearly demonstrates that radiolysis was significantly reduced by using ascorbic acid in the collection container, washing solution, and FPV. However, [ 18 The contribution of ethanol to the stabilization of [F]DCFPYL is unknown. [Table 17] [Table 18] [Table 19]

[0115] [The experiment was conducted at 18F with starting radioactivity (over 10 Ci). 18 F]DCFPyL Survey At a radioactivity exceeding the current product limit of 80 mCi / mL, [ 18The stability of the F]DCFPYL injection solution was investigated. As indicated in Table 20, ascorbic acid was added to the FPV and / or the "delivery solution vial" (position F, Figure 13) as a radioprotective agent, or was not incorporated into lot production. A list of solution compositions for these investigations is provided in Table 21. The starting radioactivity for the labeling reaction was targeted at 15 Ci, aiming to produce the product at a radioactivity concentration greater than 120 mCi / mL.

[0116] Three lots were produced, each containing ascorbic acid at pH 6.0 incorporated into a final product vial (FPV). The lots were prepared using 18F starting radioactivities of 17.6 Ci, 13.5 Ci, and 13.4 Ci, yielding final radioactivity concentrations of 166 mCi / mL, 120 mCi / mL, and 127 mCi / mL, respectively. Samples were assayed using radiochemical HPLC assays at 0, 2, 4, 6, and 10 hours after end of synthesis (EOS). Results for T=0, T=4, and T=10 hours for lots 220816PyL, 220817PyL, and 220818PyL are provided in Table 22. RCP, 18 Plots of the peak retention time (RT) results for F, 6.0 minutes, 9.8 minutes, and 10.6 minutes are provided in Figures 16 to 20, respectively, and include additional time point data not listed in Table 22.

[0117] The data and plots of total RCP as a function of time show that when the ascorbic acid level is 5.6 mg / mL, [ 18F]DCFPYL indicated greater stability at lower radioactivity concentrations (95.5% and 96.9% T=10 hour RCP at 166 and 120 mCi / mL, respectively), while reducing the ascorbic acid concentration to 2.8 mg / mL for formulations with approximately the same radiochemical concentration (120-127 mCi / mL) resulted in lower RCP (96.9% vs. 96.1% RCP), Figure 16. Lots formulated at 127 mCi / mL with 2.8 mg / mL, pH 6.0 ascorbic acid exhibited slightly better stability (approximately 0.5% RCP difference) compared to lots formulated at 5.6 mg / mL, pH 6.0 ascorbic acid (165 mCi / mL), consistent with greater radiolysis at higher radioactivity concentrations, Figure 16. The same lot was formulated with ascorbic acid at 5.6 mg / mL, pH 6.0, but exhibited slightly inferior stability (a difference of approximately 0.5%) compared to a lot with a similar radioactivity concentration (120 mCi / mL). This is consistent with lower ascorbic acid concentrations in formulations that provide less radioprotection, and is also evident from the plot of 18F formation in the lot, Figure 17.

[0118] Plots for the peaks at retention times 6.0, 9.8, and 10.6 minutes show a range of 0.4–0.6% at T=0 minutes, indicating small changes (less than 0.2%) from their initial levels over the course of 10 hours of the study. Representative chromatograms are provided in Figure 22. The lack of significant change from T=0 to T=10 hours may indicate that these three peaks are process impurities. Overall, the three lots did not achieve the desired RCP (over 99%) at T=0 hours, and the lower RCP results were potentially caused by the presence of process impurities. However, the addition of both 2.8 and 5.6 mg / mL ascorbic acid to the FPV was effective even at high concentrations of 165 mCi / mL. 18 We have demonstrated that it stabilizes the degradation of [F]DCFPYL. [Table 20] [Table 21] [Table 22]

[0119] In addition to adding ascorbic acid (5 mg / mL) to 20 mL of saline solution pre-filled into the final product vial (FPV), the addition of ascorbic acid (5 mg / mL) to the saline vial (position F, Figure 13) used to deliver the product from the HLB cartridge to the FPV is highly effective. 18 The product was examined using [F]DCFPyL. Lot 220819PyL was produced with an initial radioactivity of 13.7 Ci, and the radioactivity concentration of the product was 134 mCi / mL at EOS. The RCP and free 18F results for lot 220819PyL (5 mg / mL ascorbic acid in both FPV and delivery solution) and lot 220817PyL (10 mg / mL ascorbic acid only in FPV diluted to 5 mg / mL by the addition of delivery solution) were similar, at 97.9% vs. 97.8% and 0.52% vs. 0.6%, respectively, indicating that delivery of the product from HLB using pH 6.0 ascorbic acid (5 mg / mL) does not result in additional stabilization, Table 22.

[0120] Lot 220908PyL(HCl) was produced, and it was determined whether approximate RT impurities of 6.0, 9.8, and 10.6% were present in the peak cuts from semi-preparative HPLC purification. The peak cuts were delivered into 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 the contents were immediately analyzed without further processing. This provided an assessment of whether the observed impurities were process impurities. The RT peaks of 6.0, 9.8, and 10.6% were present at 2.13, 1.42, and 0.72% RC impurities, respectively, which were consistent with the levels observed in lots produced using ascorbic acid in the FPV, Table 22. This further supports the conclusion that the 6.0, 9.8, and 10.6 peaks of RT are process impurities. Radiochemical chromatograms are provided in Figure 23.

[0121] Addition of ascorbic acid to the collection vial (position I, Figure 13) [ 18 Further investigations were devised to determine whether the initial RCP of [F]DCFPyL could be increased by stabilizing the purified product prior to the solvent exchange step with the HLB cartridge. As indicated in Table 23, ascorbic acid was added to the collection vial (position I, Figure 13) and / or the "delivery solution vial" (position F, Figure 13). A list of solution compositions for these investigations is provided in Table 24.

[0122] Lot 220909Pyl(HCl) was produced using pH 6.0 ascorbic acid loaded into the collection vial and FPV, respectively. The concentration of ascorbic acid in the FPV after delivery of the product from the HLB cartridge was 5.6 mg / mL. The pH of the product in the collection vial after delivery of the peak cut was 4.7. The radiochemical concentration in the FPV was 89 mCi / mL, which was significantly lower than the expected over 120 mCi / mL. The initial RCP was 99% and remained over 97% at 4 hours, Table 25. This study is [ 18While the good stability of [F]DCFPyL was demonstrated, the radioactivity concentration was not high enough to support the stability assessment at high radioactivity concentrations. Process impurities were below reportable levels (<0.3%) at T=4 hours, Figure 24. Results from this investigation, together with results from peak cut analysis analyzed without further processing (lot 220908PyL), indicate that the impurities are decomposition products and not process impurities, as they can be reduced by stabilizing the product with ascorbate before solvent exchange. High levels of radioactivity were detected by the AIO waste line radiation detector during solvent exchange, indicating that the product was not adequately retained on the HLB cartridge. 18 F]DCFPyL retention decreases as pH increases, and when pH increases [ 18 This can be hypothesized to coincide with the increased ionization of [F]DCFPyL.

[0123] Lot 220914PyL(HCl) was produced using 5.0 mg / mL, pH 6 ascorbic acid in the delivery solution vial and FPV. The collection vial was prepared by loading the sample onto the HLB cartridge, and the pH of the sample was [ 18 To test whether it would affect the retention of [F]DCFPyL, 5.0 mg / mL of ascorbic acid at pH 2 was included. The radioactivity concentration of the product was 159 mCi / mL, and the RCP was 99.0% and 97.6% at T=0 and T=4 hours, respectively. No radiochemical impurities were at reportable levels, Table 25. The T=4 hour radiochromatogram is provided in Figure 25. The RCP results are similar to those of the product produced without adding ascorbic acid to the saline vial (Lot 220909PyL; 99.6% and 98.8% at T=0 and T=4 hours, respectively, Table 25). When the pH of the collection vial was reduced to 2, the product was retained and [ 18 [F]DCFPyL was virtually unobserved (based on low radioactivity being detected by AIO waste line radiation detectors).

[0124] Lot 220927 (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 the lot was 127 mCi, and the RCP was 99.0% and 98.1% at T=0 and T=10 hours, respectively, Table 25. Radiochemical impurities were close to the limit (0.3%) but not at reportable levels; radiochromatograms are provided in Figure 26. The results for this lot are similar to those for lot 220914 PyL (99.0% and 98.6% at T=0 and T=4 hours [no ascorbic acid in delivery vial], Table 26), indicating that the presence of ascorbic acid in a saline vial does not improve stability compared to simply adding it to the collection vial.

[0125] Lot 220928PyL(HCl) was prepared with 10 mg / mL ascorbic acid in a delivery vial, pH 6.0, 5 mg / mL ascorbic acid in a SWFI in a collection vial, pH 2.0, and saline in FPV. The radiochemical concentration was 138 mCi / mL, and the RCPs were 99.7%, 98.3%, and 97.8% at T=0, T=4, and T=10 hours, reproducing the results of Lot 220927Pyl, which were 99.0%, 98.0%, and 98.0% at T=0, T=4, and T=10 hours, Table 25. No reportable radiochemical impurities were present; radiochemical chromatograms are provided in Figure 27. Adding ascorbic acid to a saline vial does not offer any advantages over adding ascorbic acid to a saline vial. [Table 23] [Table 24] [Table 25] [Table 26-1] [Table 26-2]

[0126] Effects of FPV pH and ascorbic acid concentration on the stability of the formulation Based on a study showing a pH drift to approximately pH 6.8 at T=10 hours, a pH target of 5.5 was selected for the ascorbic acid formulation. The production involved loading 10 mg / mL of pH 2 ascorbic acid in 35 mL of 0.9% sodium chloride (USP) into a collection vial, and pre-loading 10 mg / mL of pH 5.5 ascorbic acid in 20 mL of 0.9% sodium chloride (USP) into the FPV. The resulting ascorbic acid concentration was 5.6 mg / mL after delivery of the purified product from the HLB solvent exchange cartridge to the FPV.

[0127] [ 18 The effect of FPV pH on the stability of [F]DCFPyL was investigated at the target pH and the pH limits of 4.5 and 7.0. Lots were prepared at pH 4.5, 5.5, and 7.0, and samples were analyzed for RCP and pH at 0, 2, 4, 6, and 10 hours. Table 27 provides an overview of the composition of the delivery solution vial, collection vial, and FPV.

[0128] Lot 221025Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 10.0 mg / mL of ascorbic acid at pH 5.5 in an FPV. The radiochemical concentration of the product was 133 mCi / mL. RCP was 98.9% at 0 hours and 97.4% at 10 hours, Table 28. One radiochemical impurity was present at approximately 0.5% throughout 4 hours and was not present at 4 hours. No other impurities were present at reportable levels; the T=10 hour chromatogram is provided in Figure 28.

[0129] Lot 221026Pyl was prepared using ascorbic acid at 10 mg / mL, pH 2.0 in the collection vial and ascorbic acid at 10.0 mg / mL, pH 4.5 in 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. There were no reportable radiochemical impurities throughout the investigation. The T = 10 hour chromatogram is provided in Figure 29.

[0130] Lot 230124Pyl was prepared using ascorbic acid at 10 mg / mL, pH 2.0 in the collection vial and ascorbic acid at 10.0 mg / mL, pH 7.5 in 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. There were no reportable radiochemical impurities throughout the investigation. The T = 10 hour chromatogram is provided in Figure 30.

Table 27

Table 28

[0131] Produced at the extreme pH specifications (4.5 and 7.0) for radiochemical concentrations up to 165 mCi / mL 18 F]DCFPyL is predicted to meet the RCP and chemical impurity product specifications for related substances over 10 hours post - EOS. The lowest actual RCP value was 97.4%, which was also at the highest pH (7.5) and the highest radioactivity concentration (162 mCi / mL). This investigation supports the use of the 5.5 mg / mL, pH 5.5 ascorbic acid formulation in one aspect, providing confirmation that products with pH specification tolerance limits of 4.0 - 7.0 or near thereto will meet the RCP specification of 96% or greater at concentrations up to 165 mCi / mL.

[0132] 18 ​The effect of ascorbic acid on the stability of F]DCFPyL was investigated at the target ascorbic acid level and at the specification limits of 3.0 and 7.0 mg / mL. Lots were prepared and samples were analyzed for RCP and pH at 0, 2, 4, 6, and 10 hours. Table 29 provides an overview of the composition of the delivery solution vial, collection vial, and FPV.

[0133] Lot 230130PyL was prepared using ascorbic acid at 10 mg / mL, pH 2.0 in the collection vial and ascorbic acid at 3.3 mg / mL, pH 5.5 in the 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 present at reportable levels; the T = 10 hour chromatogram is provided in Figure 31.

[0134] Lot 221026PyL was prepared using ascorbic acid at 10 mg / mL, pH 2.0 in the collection vial and ascorbic acid at 10.0 mg / mL, pH 5.5 in 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 present throughout the investigation. The T = 10 hour chromatogram is provided in Figure 29.

[0135] Lot 230131PyL was prepared using ascorbic acid at 10 mg / mL, pH 2.0 in the collection vial and ascorbic acid at 14.0 mg / mL, pH 5.5 in 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 present throughout the investigation. The T = 10 hour chromatogram is provided in Figure 32.

Table 29

Table 30

[0136] For radiochemical concentrations up to 165 mCi / mL, the target and specification levels of ascorbic acid (3.0, 5.0, and 7.0 mg / mL) were used. 18 F]DCFPyL is predicted to meet RCP and chemical impurity product specifications for the relevant substances for 10 hours after EOS. The lowest actual RCP value was 96.7% for a lot with an ascorbic acid concentration of 3.0 mg / mL and a radioactivity concentration of 150 mCi / mL. This study supports a 5.5 mg / mL, pH 5.5 ascorbic acid formulation in one embodiment and provides confirmation that products at or near the ascorbic acid specification tolerance limit of 3.0–7.0 mg / mL will meet RCP specifications of 95% or more at concentrations up to 165 mCi / mL.

[0137] [ on HLB cartridge 18 Effect of pH on [F]DCFPyL retention The purpose of this study is to investigate the [ 18 The objective was to clarify the characteristics of the effect of pH on the retention of F]DCFPyL. Three separate 10 mg / mL ascorbic acid solutions were prepared. By adding 1N HCl, the pH of one solution was adjusted to 2, and the pH of the second solution to 4. The third solution was used without adjusting its original pH as in 7.2. Using a BD syringe, each 10 mL solution was adjusted by adding 0.5 mL of 100 μg / mL stock solution. 19F]DCFPyL (50 μg) was spiked. Each spiked solution was loaded onto an HLB cartridge at a rate of approximately 2 mL / min. The eluate from each HLB cartridge was collected individually and identified as the "loading solution". Each HLB cartridge was then rinsed with 10 mL of water at a rate of approximately 2 mL / min. The eluate from each HLB cartridge was collected individually and identified as the "washing solution". Each HLB cartridge was then eluted individually with 1 mL of ethanol, and the samples were collected and identified as the "product samples". The loading solution and washing solution samples were analyzed using a drug product chemical impurity assay after dilution from 1 to 10 mL with saline, while the ethanol product samples were analyzed after dilution from 0.5 to 10 mL with saline.

[0138] Loaded sample and recovered sample [ 19 The concentration of [F]DCFPyL varied as a function of pH. At pH 7.2, 19 F-DCFPYL was not retained by the HLB cartridge and was recovered in the loaded sample. A small amount of [ 19 F]DCFPyL was recovered in the washing sample (3.8 μg / mL), but not in the product sample. In the pH 4 sample, [ 19 A portion of [F]DCFPyL was recovered in the loaded sample (approximately 31%, less than 1 μg), and a larger amount was recovered in the product sample (approximately 68% of the total amount recovered from all samples). At pH 2, in the loaded sample or washing sample, [ 19 F]DCFPyL was not detected. In the product solution, [ 19 F]DCFPyL was recovered. The HLB cartridge at pH 2 was eluted with a second volume of ethanol with a recovery rate of 98%. 19 Additional recovery of [F]DCFPyL was observed (approximately 25% of the amount recovered in the initial elution).

[0139] Recovery was based on the concentration in the sample and the volume of the applied solution. Volume loss in dead space or adsorption of [19F]DCFPyL on the surface may account for overall recovery of less than 100%. Nevertheless, it is clear that retention is optimized at lower pH levels (e.g., pH 2). These investigations indicate that the pH of the collection vial solution (solution loaded onto the HLB solvent exchange cartridge) can, in one embodiment, be set to pH 2. [Table 31]

[0140] Example 13.[ 18 F]DCFPyL formulation The composition of PYLARIFY is provided in Table 33. The formulation is 0.9% sodium chloride (USP) with up to 7.89% ethanol (w / v) (a typical lot contains approximately 3% ethanol). The process is provided in Figure 13. A schematic diagram of the Trasis all-in-one (AIO) synthesis module with indicated reagents and reagent positions is provided in Figure 14. The product has an upper limit of 80 mCi / mL of radioactivity concentration at end of synthesis (EOS). The main radiolysis product observed is liberated 18 F is 18 It is formed by the radiolysis of F-DCFPyL. The rapid commercial adoption of PYLARIFY has led to the need for multiple lots to be produced daily by several commercial PMFs.

[0141] To ensure that drug supply limitations do not occur, products with higher radioactivity concentrations (above 120 mCi / mL) at EOS are desirable as they provide more dose per lot. To achieve higher radioactivity concentrations, an investigation was conducted to examine the addition of radioprotective agents to the drug product to minimize potential drug substance radiolysis. The ability of ascorbic acid to stabilize PYLARIFY at radioactivity concentrations above 120 mCi / mL was investigated. The flow diagrams indicate the different locations where ascorbic acid was introduced in the production process to protect the product at the high radioactivity stage. Ascorbic acid can be delivered as part of the product delivery from the HLB solvent exchange cartridge (ascorbic acid added to the delivery solution vial; position F on the AIO, Figure 14), and / or directly into the final product vial (FPV) by introduction into the FPV. In any one of the methods provided herein, ascorbic acid is introduced at any one of the concentrations provided herein in such a process. The addition of ascorbic acid to the collection vial used to receive the peak cut from semi-preparative purification also provides a potential route to stabilize the product prior to the solvent exchange step. In any one of the methods provided herein, ascorbic acid is introduced at any one of the concentrations provided herein in such a process.

Table 33-1

Table 33-2

[0142] Exemplary PYLARIFY product specifications are provided in Table 34. A general test plan is provided in Table 35 as an example. In multiple aspects, the test time points can be changed.

Table 34

Table 35

[0143] Preliminary survey conducted at an initial radioactivity of approximately 2 CI for 18F The feasibility of stabilizing PYLARIFY was investigated using ascorbic acid to be added to the final product vial, 1) a collection vial used to receive the product peak cut from the semi-preparative purification process, 2) a pre-preparation process for the HLB cartridge used to perform solvent exchange, and / or 3) an ascorbic acid to be added to the final product vial. In any one of the methods provided herein, ascorbic acid is introduced in such a process at any one of the concentrations provided herein.

[0144] The first experiment was conducted to understand the stability of the product in ethanol as a baseline from which improvements could be measured. It also provided information on radiochemical impurities, which can form at very high radioactivity concentrations before the product is exposed to an aqueous medium. The product was collected in a stoppered and crimped 10 mL GRACE headspace vial. The final product volume was 1.41 mL, the final product radioactivity at the end of synthesis was 514 mCi, and the final radioactivity concentration (RAC) for the generated lot was 364.5 mCi / mL. To analyze the product at each time point, the stopper was uncrimped, aliquots were pipetted and diluted with saline (at this point, the product was no longer under a nitrogen atmosphere and was exposed to air). The results of the tests are given in Table 36. [Table 36]

[0145] The data shows that the only radioactive impurity formed in ethanol was 18 We have shown that it is F. 18Fluorine is substituted over time, with levels initially increasing and then plateauing over time. Although ethanol is a radical scavenger, this study demonstrated that fluorine is substituted primarily within 4 hours after EOS, occurring in the presence of ethanol radical scavengers. Halogen substitution from the pyridine ring is known to occur under harsh basic conditions, such as sodium methoxide or ethoxide solutions. These can only exist in aqueous media. If the HLB cartridge is eluted during processing, any water remaining in the HLB may be incorporated into the elution band.

[0146] When examining the chromatogram, 18 Integrating the F peak is difficult, 18 It was confirmed that the plateau during the formation of F can be caused by challenges related to its integration. When TEAF (tetraethylammonium fluoride) was added to the product at 10 hours, the peak became sharper and easier to integrate. At this point, the level of radiolysis impurities was 7.35% compared to 4.55% when TEAF was not added to the sample. The ethanol eluting HLB was 2-3 Ci when it came out of the HLB cartridge. 18 It is noteworthy that the presence of F-DCFPyL suggests that the possibility of radiolysis in ethanol alone is much higher than in the bulk product solution. Chromatograms of the injection product at 10 hours, with and without TEAF, are given in Figure 5.

[0147] Subsequent pilot studies aimed to minimize radiation exposure to the greatest extent possible. 18This was performed when the handling of F was limited to approximately 2 Ci. To achieve a radioactivity concentration of approximately 120 mCi / mL, the labeled product was eluted from an HLB cartridge used for solvent exchange and delivered using nitrogen push 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 assayed using a Capintec dose calibrator and diluted to achieve the desired radioactivity concentration. This results in a product with a higher ethanol level (approximately 20%). Although ethanol is known to provide some protection against radiolysis, investigations at high ethanol levels nevertheless provide a method for initial assessment of stabilization using ascorbic acid.

[0148] The control lot was produced without incorporating ascorbic acid and had a final radiochemical concentration of 147 mCi / mL and an ethanol level of 29.8%. The product was sampled every 30 minutes and assayed with an extended gradient to allow detection of hydrophobic impurities. The product was delivered from the HLB into 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 radioactivity concentration. The initial radiochemical purity (RCP) was 94%, and the T=4 hour RCP was 89%, far below the RCP product specification of 95% or higher. 18 In addition to F, the initial chromatogram 18 There were two additional radioactive impurities that eluted before the F-DCFPyL peak but did not appear to grow over time. These may be process impurities, as opposed to ongoing radiolysis. 18 There are two additional peaks below the reportable limit of 0.3% w / w eluting after the F-DCFPyL product peak. Data are provided in Table 37. The T=0 time chromatogram is provided in Figure 6.

[0149] A lot was generated by pre-loading a collection vial with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. The HLB cartridge was also rinsed 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 was captured on the HLB, this ascorbic acid solution was used to wash the HLB and perform solvent exchange instead of SWFI. Then, 18 F-DCFPyL was delivered from HLB into an empty product vial in 100% ethanol. The product was assayed. To analyze the sample, 12.5 μL of the product in the required 100% ethanol was diluted with 237.5 μL of saline. Samples were taken and assayed every 30 minutes. Column retention was reduced. 18 To sharpen the F peak and achieve better quantification, 44 mg / mL of tetraethylammonium fluoride was added to the sample for radiochemical purity HPLC analysis. The product had a radiochemical concentration of 256 mCi / mL. The initial RCP was 99.7%. 18 The F impurity level was 0.29%. 18 Only one of the two impurities eluting before the F-DCFPyL peak, as seen in the control lot, was present sporadically in the range of <LLQ to 0.35%, but was not consistently observed at reportable levels (≥0.3%). At T=4 hours, RCP was 98.0%. Data for this lot are provided in Table 38. This clearly demonstrates that radiolysis was significantly reduced when ascorbic acid was added to the collection vial. Chromatograms at T=0 and T=4 hours are shown superimposed in Figure 8.

[0150] A lot was generated by pre-loading a collection vial with 35 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. The HLB cartridge was also rinsed with 5 mL of 100 mg / mL, pH 2.0 ascorbic acid solution. Finally, in the final product vial pre-loaded with 50 mg / mL, pH 5.8 ascorbic acid solution... 18F-DCFPyL was collected, assayed by Capintec, and diluted to the desired concentration with a 50 mg / mL pH 5.8 ascorbic acid solution. The product was sampled and assayed every 30 minutes, and 44 mg / mL of tetraethylammonium fluoride was added. The product had a radiochemical concentration of 110 mCi / mL and an ethanol level of 24% (w / w). The initial RCP was 99.7%. 18 The F impurity level was below LLQ. 18 Two impurities, observed in the control lot eluting before the F-DCFPyL peak, were present at levels ranging from less than LLQ to 0.37%, but were consistently absent at reportable levels (greater than 0.3%). RCP remained above 99% at T=4 hours. Data for this lot are provided in Table 39. Chromatograms at T=0 and T=4 hours are superimposed in Figure 9. This clearly demonstrates that radiolysis was significantly reduced by using ascorbic acid in the collection container, washing solution, and FPV. However, 18 The contribution of ethanol to the stabilization of F-DCFPyL was unclear. [Table 37] [Table 38] [Table 39]

[0151] Initial batch of PYLARIFY formulations to investigate the addition of ascorbic acid. At a radioactivity exceeding the currently approved product limit of 80 mCi / mL 18The stability of F-DCFPyL injection was investigated. Ascorbic acid was added to the FPV as a radioprotective agent to demonstrate the feasibility of product stabilization, and then also to the delivery solution vial. It was determined whether additional stabilization was achievable by adding ascorbate to the saline solution (position F, Figure 13) used to deliver the product from the HPB cartridge to the FPV, as indicated in Table 40. The final lot in this series was examined for the stability of peak cut (not delivered to the FPV containing ascorbic acid) in the collection vial. A list of solution compositions for these investigations is provided in Table 41. The starting radioactivity for the labeling reaction was targeted at 15 Ci, aiming to produce the product at a radioactivity concentration greater than 120 mCi / mL.

[0152] Three lots were produced, each containing ascorbic acid at pH 6.0 incorporated into a final product vial (FPV). The lots were prepared using 18F starting radioactivities of 17.6 Ci, 13.5 Ci, and 13.4 Ci, yielding final radioactivity concentrations of 166 mCi / mL, 120 mCi / mL, and 127 mCi / mL, respectively. Samples were assayed using radiochemical HPLC assays at 0, 2, 4, 6, and 10 hours after end of synthesis (EOS). Results for T=0, T=4, and T=10 hours for lots 220816PyL, 220817PyL, and 220818PyL are provided in Table 42. RCP, 18 Plots of the peak retention time (RT) results for F, 6.0 minutes, 9.8 minutes, and 10.6 minutes are provided in Figures 16 to 20, respectively, and include additional time point data not listed in Table 42.

[0153] The data and plots of total RCP as a function of time are shown when the ascorbic acid level is 5.6 mg / mL. 18F-DCFPyL indicated greater stability at lower radioactivity concentrations (95.5% and 96.9% T=10 hour RCP at 166 and 120 mCi / mL, respectively), while reducing the ascorbic acid concentration to 2.8 mg / mL in formulations with nearly the same radiochemical concentration (120-127 mCi / mL) resulted in lower RCP (96.9% vs. 96.1% RCP). Lots formulated with 127 mCi / mL ascorbic acid at 2.8 mg / mL, pH 6.0 showed slightly better stability (approximately 0.5% RCP difference) compared to lots formulated with 5.6 mg / mL, pH 6.0 ascorbic acid (165 mCi / mL), consistent with greater radiolysis at higher radioactivity concentrations. The same lot was formulated with ascorbic acid at 5.6 mg / mL, pH 6.0, but exhibited slightly inferior stability (a difference of approximately 0.5%) compared to a lot with a similar radioactivity concentration (120 mCi / mL). This is consistent with the lower concentration of ascorbic acid in the formulation, which provides less radioprotection. 18 This is also evident from the plot of F formation.

[0154] Plots for the peaks at retention times 6.0, 9.8, and 10.6 minutes show a range of 0.4–0.6% at T=0 minutes, indicating small changes (less than 0.2%) from their initial levels over the course of 10 hours of the study. Representative chromatograms are provided in Figure 20. The lack of significant change from T=0 to T=10 hours may indicate that these three peaks are process impurities or were formed before transfer to the FPV. Overall, the three lots did not achieve the desired RCP (over 99%) at T=0 hours, and the lower RCP results were potentially caused by the presence of process impurities. However, the lots showed that the addition of both 2.8 and 5.6 mg / mL of ascorbic acid to the FPV was effective even at high concentrations of 165 mCi / mL. 18 We have demonstrated that it stabilizes the decomposition of F-DCFPyL.

[0155] In addition to adding ascorbic acid (5 mg / mL) to 20 mL of saline solution pre-filled into the final product vial (FPV), the addition of ascorbic acid (5 mg / mL) to the saline vial (position F, Figure 13) used to deliver the product from the HLB cartridge to the FPV was investigated at high 18F-DCFPyL concentrations. Lot 220819PyL was produced with an initial radioactivity of 13.7 Ci, and the radioactivity concentration of the product was 134 mCi / mL at EOS. RCP and 18 The results for F were similar, at 97.9% vs. 97.8% and 0.52% vs. 0.6%, respectively, indicating that delivery of the product from HLB using pH 6.0 ascorbic acid (5 mg / mL) does not result in additional stabilization, Table 42.

[0156] Lot 220908PyL(HCl) was produced, and it was determined whether impurities at approximately 6.0, 9.8, and 10.6 percent RT were present in the peak cuts from semi-preparative HPLC purification. The peak cuts were delivered into 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 the contents were immediately analyzed without further processing. This provided an assessment of whether the observed impurities were process impurities or degradation impurities. The RT peaks at 6.0, 9.8, and 10.6 percent were present at 2.13, 1.42, and 0.72%, respectively, which were consistent with the levels observed in lots produced using ascorbic acid in the FPV, Table 42. Radiochemical chromatograms are provided in Figure 22. [Table 40] [Table 41] [Table 42]

[0157] Addition of ascorbic acid to the collection vial (position I, Figure 13) Further investigations were devised to determine whether the initial RCP of PYLARIFY could be increased by stabilizing the purified product before the solvent exchange step to the HLB cartridge. Based on previously completed investigations, this seemed like a way to stabilize the product before loading it onto the HLB. As indicated in Table 43, ascorbic acid was added to the collection vial (position I, Figure 13) and / or to the delivery solution vial (position F, Figure 13) in addition to the FPV. The final lot in this series investigated adding the ascorbate to the formulation only via the delivery solution vial, thus eliminating the pre-loading of ascorbic acid into the FPV. A list of solution compositions for these investigations is provided in Table 44.

[0158] Lot 220909Pyl(HCl) was produced using pH 6.0 ascorbic acid loaded into both the collection vial and the FPV. The concentration of ascorbic acid in the FPV after product delivery from the HLB cartridge was 5.6 mg / mL. The pH of the product in the collection vial after peak cut delivery was 4.7. The radiochemical concentration in the FPV was 89 mCi / mL, which was significantly lower than the expected over 120 mCi / mL. The initial RCP was 99%, and over 97% at 4 hours, Table 45. This study was 18The good stability of F-DCFPyL was demonstrated, but the radioactivity concentration was not high enough to support the stability assessment at high radioactivity concentrations. Impurities were below reportable levels (less than 0.3%) at T=4 hours, Figure 24. Results from this study indicate that impurities can be reduced by stabilizing the product with ascorbate before solvent exchange. During the formation of lot 220909Pyl(HCl), high levels of radioactivity were detected by the AIO waste line radiation detector during solvent exchange, indicating that the product was not adequately retained on the HLB cartridge. 18 F-DCFPyL retention decreases as pH increases, and when pH increases... 18 This can be hypothesized to coincide with an increase in the ionization of F-DCFPyL.

[0159] Lot 220914PyL(HCl) was produced using 5.0 mg / mL, pH 6 ascorbic acid in the delivery solution vial and FPV. The collection vial was prepared using the pH of the sample loaded onto the HLB cartridge. 18 To test whether it would affect the retention of F-DCFPyL, 5.0 mg / mL of ascorbic acid at pH 2 was included. The radioactivity concentration of the product was 159 mCi / mL, and the RCP was 99.0% and 97.6% at T=0 and T=4 hours, respectively. No radiochemical impurities were at reportable levels, Table 45. The T=4 hour radiochromatogram is provided in Figure 25. The RCP results are similar to those of the product produced without adding ascorbic acid to the delivery solution vial (Lot 220909PyL; 99.6% and 98.8% at T=0 and T=4 hours, respectively, Table 45). When the pH of the collection vial was reduced to 2, the product was retained and in HLB cartridge washing. 18 F-DCFPyL was virtually not observed (based on low levels of radioactivity detected by AIO waste line radiation detectors).

[0160] Lot 220927PyL(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 the lot was 127 mCi, and the RCP was 99.0% and 98.1% at T=0 and T=10 hours, respectively, Table 45. Radiochemical impurities were close to the limit (0.3%) but not at reportable levels; radiochromatograms are provided in Figure 26. The results for this lot are similar to those for lot 220914PyL (99.0% and 98.6% at T=0 and T=4 hours [no ascorbic acid in 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.

[0161] Lot 220928 PyL (HCl) was prepared using 10 mg / mL ascorbic acid, pH 6.0 in the delivery solvent vial, 5 mg / mL ascorbic acid, pH 2.0 in the SWFI in the collection vial, and saline in the FPV. The radiochemical concentration was 138 mCi / mL, and the RCPs were 99.7%, 98.3%, and 97.8% at T=0, T=4, and T=10 hours, reproducing the results of Lot 220927 Pyl, 99.0%, 98.0%, and 98.0% at T=0, T=4, and T=10 hours, Table 45. No reportable radiochemical impurities were present; radiochemical chromatograms are provided in Figure 27. Adding ascorbic acid to the delivery vial does not offer any advantages over adding ascorbic acid to the FPV (final product vial) vial. [Table 43] [Table 44] [Table 45]

[0162] Effects of FPVpH and ascorbic acid concentration on the stability of the target formulation Based on the above investigation showing a pH drift from the initial target pH 6.0 at EOS to approximately pH 6.8 at T=10 hours, the pH target of the formulation was lowered to 5.5 for the ascorbic acid formulation. Production can involve loading 10 mg / mL of pH 2 ascorbic acid in 35 mL of 0.9% sodium chloride (USP) into a collection vial, and pre-loading 10 mg / mL of pH 5.5 ascorbic acid in 20 mL of 0.9% sodium chloride (USP) into the FPV. The ascorbic acid concentration in the product may be 5.6 mg / mL after delivery of the purified product from the HLB solvent exchange cartridge to the FPV.

[0163] 18 The effect of FPV pH on the stability of F-DCFPyL was investigated at the target pH and the pH specification limits of 4.5 and 7.0. Lots were prepared at pH 4.5, 5.5, and 7.0, and samples were analyzed for RCP at 0, 2, 4, 6, and 10 hours, and for pH at 0 and 10 hours. See Table 46 for an overview of the composition of the delivery solution vial, collection vial, and FPV.

[0164] Lot 221025Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 10.0 mg / mL of ascorbic acid at pH 5.5 in an FPV. The radiochemical concentration of the product was 133 mCi / mL. RCP was 98.9% at 0 hours and 97.4% at 10 hours, Table 47. One radiochemical impurity was present at approximately 0.5% throughout 4 hours and was not present at 4 hours. No other impurities were present at reportable levels; the T=10 hour chromatogram is provided in Figure 28.

[0165] Lot 221026Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 10.0 mg / mL of ascorbic acid at pH 4.5 in a 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 present throughout the study. The T=10 hour chromatogram is provided in Figure 29.

[0166] Lot 230124Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 10.0 mg / mL of ascorbic acid at pH 7.5 in a FPV. The radiochemical concentration of the product was 162 mCi / mL. RCP was 99.2% at 0 hours and 97.4% at 10 hours, Table 47. No reportable radiochemical impurities were present throughout the study. The T=10 hour chromatogram is provided in Figure 30. [Table 46] [Table 47]

[0167] Considerations for pH analysis Radiochemical concentrations up to 165 mCi / mL were generated at the extreme ends of the pH specification (4.5 and 7.0). 18 F-DCFPyL is expected to meet the RCP and chemical impurity product specifications for the relevant substances for 10 hours after EOS. The lowest actual RCP value was 97.4%, which was also present at the highest pH (7.5) and highest radioactivity concentration (162 mCi / mL). This study supports the exemplary target of 5.5 mg / mL, pH 5.5 ascorbic acid formulation and provides confirmation that products at or near the pH specification tolerance limit of 4.0–7.0 will meet the RCP specification of 95% or more at concentrations up to 165 mCi / mL.

[0168] Ascorbic acid concentration survey 18 The effect of ascorbic acid on the stability of F-DCFPyL was investigated at exemplary target ascorbic acid levels and at limits of 3.0 and 7.0 mg / mL. Lots were prepared, and samples were analyzed for RCP at 0, 2, 4, 6, and 10 hours, and for pH at 0 and 10 hours. See Table 48 for a summary of the composition of the delivery solution vial, collection vial, and FPV.

[0169] Lot 230130Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 3.3 mg / mL of ascorbic acid at pH 5.5 in an FPV. The radiochemical concentration of the product was 150 mCi / mL. RCP was 99.0% at 0 hours and 96.7% at 10 hours, Table 49. No other radiochemical impurities were present at reportable levels; the T=10 hour chromatogram is provided in Figure 31.

[0170] Lot 221026Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 10.0 mg / mL of ascorbic acid at pH 5.5 in a 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 entire study.

[0171] Lot 230131Pyl was prepared using 10 mg / mL of ascorbic acid at pH 2.0 in a collection vial and 14.0 mg / mL of ascorbic acid at pH 5.5 in a 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 present throughout the study. The T=10 hour chromatogram is provided in Figure 32. [Table 48] [Table 49]

[0172] Radiochemical concentrations up to 165 mCi / mL were generated at the exemplary target and specification levels (3.3, 5.5, and 7.8 mg / mL) for ascorbic acid. 18 F-DCFPyL is expected to meet RCP and chemical impurity product specifications for the relevant substances for 10 hours after EOS. The lowest actual RCP value was 96.7% for a lot with an ascorbic acid concentration of 3.3 mg / mL and a radioactivity concentration of 150 mCi / mL. This study supports an exemplary target ascorbic acid formulation of 5.6 mg / mL, pH 5.5, and provides confirmation that products at or near the ascorbic acid specification tolerance limit of 3.3–7.8 mg / mL will meet RCP specifications at 95% or higher at concentrations up to 165 mCi / mL.

[0173] On HLB cartridge 18 Investigation of the effect of pH on F-DCFPyL retention The purpose of this study is to examine the HLB solvent exchange cartridge. 18 The objective was to clarify the characteristics of the effect of pH on the retention of F-DCFPyL. Three separate 10 mg / mL ascorbic acid solutions were prepared. By adding 1N HCl, the pH of one solution was adjusted to 2, and the pH of the second solution to 4. The third solution was used without adjusting its original pH from 7.2. At this pH, the solution would be mainly sodium ascorbate. Using a BD syringe, each 10 mL solution was adjusted by adding 0.5 mL of 100 μg / mL stock solution. 19F-DCFPyL (50 μg) was spiked. Each spiked solution was loaded onto an HLB cartridge at a rate of approximately 2 mL / min, and the solution collected after the HLB column was identified as the loading solution. Next, each HLB cartridge was rinsed with 10 mL of water at a rate of approximately 2 mL / min, and the solution collected after the HLB column was identified as the washing solution. Then, each HLB cartridge was individually eluted with 1 mL of ethanol, and the solution collected after the HLB column was identified as the product sample. The loading solution and washing solution samples were analyzed using a drug product chemical impurity assay after dilution from 1 to 10 mL with saline, and the ethanol product sample was analyzed after dilution from 0.5 to 10 mL with saline.

[0174] Loaded sample and recovered sample 19 The F-DCFPyL concentration varied as a function of pH. At pH 7.2, 19 F-DCFPYL was not meaningfully retained by the HLB cartridge and was recovered in the loaded sample (collected after column). 19 F-DCFPyL was recovered in the washing sample (3.8 μg / mL), but not in the product sample. At pH 4, 19 A portion of F-DCFPyL was recovered in the loaded sample (approximately 31%; less than 1 μg), and a larger amount was recovered in the product sample (approximately 68% of the total amount recovered from all samples). At pH 2, in the loaded sample or washing sample... 19 F-DCFPYL was not detected in the product solution. 19 F-DCFPYL was recovered. A second ethanol elution volume was used because the overall recovery rate (concentration) was significantly lower than the amount applied to the HLB column. 19 Additional recovery of F-DCFPyL was observed (approximately 25% of the amount recovered in the initial elution). The results are summarized in Table 50.

[0175] To enable the calculation of mass recovery rates, different solution volumes were determined. The results showed that at pH 4 or higher, the solution was recovered on the HLB cartridge. 19This clearly indicates that F-DCFPyL is only partially retained. Retention on the HLB column was evident at lower pH levels (e.g., pH 2). These investigations suggest that the pH of the collection vial solution (the solution loaded onto the HLB solvent exchange cartridge) can be set to pH 2. [Table 50]

[0176] Investigation of oxidative impurities in ascorbin Prepared at 163.0 mCi / mL [ 18 In the development lot of [F]-DCFPyL, a chemical impurity was observed at 0.9 μg / mL with a retention time of approximately 4.6 minutes on UV trace, Figure 34. Since the peak had not been previously observed in preparations in the absence of ascorbic acid, it was considered potentially related to ascorbic acid and was further investigated. Further analysis of disintegration samples from the generated lot confirmed the presence of the peak, Figure 35. To eliminate impurities involved in plylarification and demonstrate formation from ascorbic acid, free 18 F (129 mCi / mL) was incubated in a 5 mg / mL, pH 6 ascorbic acid solution for various periods. When held upside down under ambient conditions, the samples were assayed for chemical impurities at T=0, 4, 10, and 24 hours. The 4.6-minute RT peak, as assessed by HPLC UV detection, was absent at T=0 and increased in a time-dependent manner over 24 hours at a concentration of approximately 1.75 μg / mL at T=24 hours. 19 A relative response coefficient of 1 is assumed for the F]-DCFPyL standard (see Figure 36). Impurities were formed only upon radioactive exposure, but not when stored in light or darkness under ambient conditions (see Figure 37). The ascorbic acid-related UV impurity peak was, 18 Since it can be formed in the absence of PYLARIFY through incubation with F, does not coincide with a radioactive peak, and is not formed by exposure to light or darkness, it can be concluded that it is formed from ascorbic acid by radiolysis.

[0177] The degradation of ascorbic acid has been investigated (Analytical Biochemistry, 265, 238-245 (1998), Journal of Chromatography A, 881 299-307 (2000)). Oxidation of ascorbic acid to dehydroascorbic acid (DHA) is an important species in ascorbate degradation. Dehydroascorbic acid was obtained from Apollo Scientific (catalog number BIB6039) and analyzed using HPLC UV chemical impurity methods. DHA did not elute simultaneously with impurities.

[0178] HPLC / MS analysis was performed on the disintegrated development sample. For mass spectrometry suitability, 0.1% formic acid was used as a modifier instead of 0.1% TFA. With the modified mobile phase, the disintegrated sample was analyzed for approximately 7.5 minutes [ 19 In addition to the [F]-DCFPyL peak, a UV peak with a retention time of approximately 3.8 minutes was observed at 264 nm. The mass spectrometry chromatogram at the corresponding retention time showed a peak at m / z 346.9, Figure 38. HPLC / MS analysis also revealed that approximately 120 mCi / mL of F was added to a 5 mg / mL, pH 6 ascorbic acid solution at T=24 hours. 18 This procedure was also performed on spiked samples (see Figure 39).

[0179] 5 mg / mL ascorbic acid + F 18 The solution sample showed a UV peak with a retention time of approximately 3.8 minutes at 264 nm. Mass spectrometry chromatograms at the corresponding retention time showed a peak with m / z 347.1, confirming that the mass of the impurity peak formed from ascorbic acid was the same as that found in the development lot. DHA with m / z 175 was not detected in this sample. An m / z of approximately 347 was observed in two separate samples, one a decayed PYLARIFY sample and the other a sample containing ascorbic acid and F. 18 This was confirmed in samples produced by incubation.

[0180] Unknown impurity peaks from the decayed PYLARIFY sample were fragmented using LC / MS / MS across a range of collision energies in both positive and negative modes. Literature suggests that a common degrading agent of ascorbic acid is dehydroascorbic acid monomer (DHA), which may also have the potential to bind with other DHA molecules or alternative forms of ascorbic acid. The mass of the fragments observed from the 347 m / z impurity was [ 19 It did not match any of the major fragments of the [F]-DCFPyL standard, and therefore it was further confirmed that the impurity was related to ascorbic acid and not to PYLARIFY.

[0181] Composition of the final process formulation using ascorbic acid The data generated during these investigations led to the selection of an exemplary formulation for PYLARIFY having 5.6 mg / mL ascorbic acid at pH 5.5. It also led to the use of a 10 mg / mL ascorbic acid solution at pH 2 in the collection vial (position I, Figure 13). The final formulation can be obtained by delivering 1.3 mL of ethanol, followed by 15 mL of saline, into the FPV. The FPV can be pre-loaded with 20 mL of a 10 mg / mL ascorbic acid solution at pH 5.5. The final product volume may be 36 mL, thus having a 5.6 mg / mL ascorbic acid concentration. This formulation demonstrated stability at RAC (radioactivity concentration) below 165 mCi / mL. To protect the product at high radioactivity levels, ascorbic acid is [ 18 Figure 40 shows a flowchart indicating where the F]-DCFPyL is pre-loaded before the start of generation. In any embodiment of the methods or compositions provided herein, one or more or all of the aforementioned steps and / or features may be included as part of the method or composition, respectively.

[0182] Investigations were conducted to develop a PYLARIFY formulation with a higher radioactivity concentration. 18 The first-order decomposition of F]-DCFPyL is, 18This is radiolysis that releases F. Incorporation of 5 mg / mL, pH 6 ascorbate as ascorbic acid in the final product provided 96% RCP at 10 hours. In addition to loading 5 mg / mL pH 6 ascorbic acid into the final product vial, adding 10 mg / mL pH 6 ascorbate as ascorbic acid to the collection vial receiving peak cuts from the semi-preparative HPLC purification step provided a product with 99% RCP at 4 hours, although a significant portion of the product (approximately 40%) was not retained on the 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 provided additional stabilization, resulting in 98% RCP at 10 hours with over 98% of the product retained on the SepPak. In any embodiment of the methods or compositions provided herein, one or more or all of the aforementioned steps and / or features may be included as part of the method or composition, respectively.

[0183] The selection of pH2 for collection vials is based on 98% vs. 81% of HLB cartridges at pH2 and 4. 18 This was driven by improved retention of [F]-DCFPyL. The optimal pH for the product to bind to HLB is pH 2, and therefore, an ascorbic acid solution at pH 2 was selected for pre-filling the collection vials. While 5 or 10 mg / mL of ascorbic acid is sufficient to achieve stabilization, a 10 mg / mL stock ascorbic acid solution was selected for ease of preparation, which can then be used after pH adjustment to pre-fill the FPV vials or collection vials. Supply of kits containing the ascorbic acid solution would be feasible using 5 mg / mL ascorbic acid. In any embodiment of the methods or compositions provided herein, one or more or all of the aforementioned steps and / or features may be included as part of the method or composition, respectively.

[0184] Finally, using 5 mg / mL ascorbate at pH 6 as a pre-filling for 20 mL of FPV, and using 6 mg / mL ascorbate at pH 6 (16 mL) as the formulation delivery solution for HLB instead of saline, did not provide the additional 98% RCP stabilization at 4 hours compared to using saline for formulation delivery from HLB. A slight increase in pH was observed over 10 hours during stability determination, indicating that the product produced at pH 6 or 7 may be close to the specification upper limit of 7. Based on the pH changes observed during stability investigation, the target pH was changed from 6 to 5.5 to ensure that the product was well within the specification upper limit of 7 at 10 hours. These investigations established exemplary target solutions of 16 mL of 5.6 mg / mL ascorbate at pH 5.5 in 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, one or more or all of the aforementioned steps and / or features may be included as part of the method or composition, respectively.

[0185] Next, investigations were conducted in the FPV at three ascorbic acid levels while maintaining 10 mg / mL pH2 ascorbic acid in the collection vial. The results for 3.3, 5.6, and 7.8 mg / mL ascorbic acid were 97, 98, and 97% RCP at 10 hours. To confirm that the product meets the product specifications across the pH specification range, investigations were also conducted at the extreme ends of the pH specification and the target pH. The results were 98, 97, and 97% RCP at pH 4.5, 5.5, and 7.0 at 10 hours. These investigations confirmed that the exemplary proposed product preparation solution meets the specifications at the extreme ends of the ascorbate concentration and pH. 18The production of [F]-DCFPyL was established. The data generated during these investigations led to the selection of an exemplary final formulation for PYLARIFY having 5.6 mg / mL ascorbic acid at pH 5.5. This formulation demonstrated stability at RAC (radioactivity concentration) of 160 mCi / mL or less. In any embodiment of the method or composition provided herein, one or more or all of the aforementioned steps and / or features may be included as part of the method or composition, respectively.

[0186] Equivalents and range Unless otherwise indicated or otherwise evident from the context, articles such as “a,” “an,” and “the” in a claim may mean one or more. Unless otherwise indicated or otherwise evident from the context, a claim or description containing “or” among one or more members of a group is considered satisfied if one member, more than one member, or all members of that group are present in, adopted into, or otherwise related to a given product or process. This disclosure contains embodiments in which exactly one member of that group is present in, adopted into, or otherwise related to a given product or process. This disclosure contains embodiments in which more than one or all members of that group are present in, adopted into, or otherwise related to a given product or process.

[0187] Furthermore, this disclosure covers all variations, combinations, and rearrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more enumerated 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. Where elements are presented, for example, as enumerated in Markush group form, each subgroup of the element is also disclosed, and any element(s) may be removed from the group. In general, where this disclosure or aspects described herein are referred to as including certain elements and / or features, the particular aspects described herein or herein should be understood to consist of, or essentially consist of, such elements and / or features. For the sake of brevity, those aspects are not specifically revealed herein in haec verba. The terms “comprising” and “containing” are intended to be open and should also be noted to allow for the inclusion of additional elements or processes. Where a range is given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and the understanding of those skilled in the art, a value expressed as a range may be assumed to be any specific value or a subrange of the range described in the various embodiments described herein, up to one-tenth of the lower limit of the range, unless the context explicitly indicates otherwise.

[0188] This application references various issued 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 of the incorporated references and this specification, this specification shall prevail. In addition, any particular aspect of this disclosure contained in the prior art may be expressly excluded from one or more of the claims. Such aspects may be excluded even if the exclusion is not expressly stated herein, as they would be considered publicly known to those skilled in the art. Any particular aspect described herein may be excluded from any of the claims for any reason, whether or not it relates to the existence of prior art.

[0189] Those skilled in the art will be able to verify many equivalents to the specific embodiments described herein using only recognizable or routine experiments. The scope of the embodiments described herein is not intended to be limited to the foregoing, but rather as described in the appended claims. Those skilled in the art will understand that various changes and modifications may be made to this description without departing from the spirit or scope of the disclosure as defined in the following claims.

Claims

1. In the solution, optionally, in the ethanol solution, the formula, 【Chemistry 1】 of[ 18 A composition comprising F]DCFPyL, wherein the solution further contains ascorbic acid at a concentration of 3–15 mg / mL, 3–8 mg / mL, or 5–15 mg / mL, wherein the pH of the solution is in the range of 4–7.

5.

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

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

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

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

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

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

13. The composition according to claim 12, wherein the solution has a radioactivity concentration of 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 at EOS.

14. The composition according to claim 12 or 13, wherein the solution has a radioactivity concentration of 155 mCi / mL or less, 160 mCi / mL or less, 161 mCi / mL or less, 162 mCi / mL or less, 163 mCi / mL or less, 164 mCi / mL or less, 165 mCi / mL or less, 166 mCi / mL or less, 167 mCi / mL or less, 168 mCi / mL or less, 169 mCi / mL or less, or 170 mCi / mL or less, as measured by EOS.

15. The solution contains less than 5% free 18 A composition according to any one of claims 1 to 14, comprising F.

16. The solution contains less 4.5% free 18 The composition according to claim 15, comprising F.

17. The solution contains less than 4% free 18 The composition according to claim 16, having F.

18. The solution contains less than 3.5% free 18 The composition according to claim 17, having F.

19. The solution contains less than 3% free 18 The composition according to claim 18, having F.

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

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

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

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

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

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

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

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

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

29. The composition according to claim 28, wherein the unknown impurity is undetectable by HPLC at RT6.0, RT9.8, or RT10.

6.

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

31. The composition according to claim 30, wherein ascorbic acid-related impurities are located at RRT 0.607 by HPLC UV detection.

32. The composition according to any one of claims 1 to 31, wherein the solution contains acetonitrile at a concentration of 0.04% w / v or less.

33. The composition according to any one of claims 1 to 32, wherein the solution has an ascorbic acid concentration of 5.5 mg / mL or 5.6 mg / mL.

34. The composition according to any one of claims 1 to 33, wherein the pH of the solution is 5.

5.

35. formula: 【Chemistry 2】 of 18 F] DCFPyL, comprising a method of preparing a composition, the method comprising: 18 adding a second solution containing ascorbic acid to a first solution containing 18 F] DCFPyL to form a third solution containing 18 F] DCFPyL and ascorbic acid, wherein the third solution has an ascorbic acid concentration as defined in any one of claims 1-34 or as otherwise defined herein, and a pH as defined in any one of claims 1-34 or as otherwise defined herein, and wherein the third solution is collected or transferred into a collection vial such as a final collection vial (FCV) or a final product vial (FPV).

36. formula: 【Transformation 3】 of[ 18 A method for preparing a composition containing F]DCFPyL, wherein the method is [ 18 A method comprising adjusting a solution containing F]DCFPyL to have an ascorbic acid concentration as defined in any one of claims 1 to 35 or as otherwise defined herein, and a pH as defined in any one of claims 1 to 35 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 final product vial (FPV).

37. The method according to claim 35 or 36, wherein the third solution or prepared solution further comprises ethanol.

38. The method according to claim 37, wherein the % ethanol w / v is as defined in any one of claims 1 to 37, or as otherwise defined herein.

39. The method according to any one of claims 35 to 38, wherein the third solution or prepared solution has radiochemical purity (RCP) as defined in any one of claims 1 to 38 or as otherwise defined herein.

40. The method according to any one of claims 35 to 39, wherein the third solution or prepared solution has a radioactivity concentration as defined in any one of claims 1 to 39, or as otherwise defined herein.

41. The third solution or the prepared solution is % free as defined in any one of claims 1 to 40, or as otherwise defined herein. 18 The method according to any one of claims 35 to 40, wherein F is present.

42. The method according to any one of claims 35 to 41, wherein the third solution or prepared solution contains a total amount of unknown impurities as defined in any one of claims 1 to 41 or as otherwise defined herein.

43. The method according to any one of claims 35 to 42, wherein the third solution or prepared solution contains ascorbic acid-related impurities as defined in any one of claims 1 to 42, or as otherwise defined herein.

44. The method according to any one of claims 35 to 43, wherein the third solution or prepared solution comprises % w / v acetonitrile as defined in any one of claims 1 to 43, or as otherwise defined herein.

45. formula: 【Chemistry 4】 of[ 18 A method for preparing a composition containing F]DCFPyL, wherein the method is [ 18 To the first solution containing F]DCFPyL, add the second solution containing ascorbic acid at a concentration of 3-50 mg / mL and a pH of 4 or less, and [ 18 A method comprising forming a third solution containing F]DCFPyL and ascorbic acid.

46. formula: 【Transformation 5】 of[ 18 A method for preparing a composition containing F]DCFPyL, wherein the method is [ 18 A method comprising adjusting a solution containing F]DCFPyL to have an ascorbic acid concentration of 3 to 50 mg / mL and a pH of 4 or less.

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

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

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

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

53. The method according to claim 52, wherein the pH of the third solution or the prepared solution is 2 or less.

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

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

5.

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

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

58. [ 18 The method according to any one of claims 45 to 57, wherein the solution containing F]DCFPyL is purified by chromatography before the addition of the second solution or preparation of the solution.

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

60. The method involves loading the third solution or prepared solution onto the solvent exchange cartridge, 18 The method according to any one of claims 45 to 59, further comprising eluting F]DCFPyL using a solvent solution.

61. The method according to claim 60, wherein the solvent exchange cartridge is an HLB solvent exchange cartridge.

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

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

64. The method according to any one of claims 1 to 63, wherein the solvent solution comprises ascorbic acid.

65. The method according to claim 64, wherein the concentration of ascorbic acid is one of the concentrations defined in any one of claims 1 to 64 or as otherwise defined herein.

66. The method according to any one of claims 1 to 65, wherein the pH of the solvent solution is as defined in any one of claims 1 to 65, or as otherwise defined herein.

67. The method according to any one of claims 1 to 66, further comprising collecting an eluate and maintaining or adjusting the ascorbic acid concentration to one as defined in any one of claims 1 to 66, or to one as defined in any other form herein, along with a pH as defined in any one of claims 1 to 66, or as defined in any other form herein.

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

69. formula: 【Transformation 6】 of[ 18 A method for preparing a composition containing F]DCFPyL, wherein the method is [ 18 F] Load the solution containing DCFPyL onto the solvent exchange cartridge, [ 18 A method comprising eluting F]DCFPyL using a solvent solution, wherein the solvent solution has an ascorbic acid concentration of 3 to 50 mg / mL and a pH of 4 or less.

70. The method according to claim 69, wherein the solvent exchange cartridge is an HLB solvent exchange cartridge.

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

72. The method according to claim 71, wherein the solvent solution comprises % ethanol w / v as defined in any one of claims 1 to 71, or as otherwise defined herein.

73. The method according to any one of claims 69 to 72, wherein the solvent solution comprises ascorbic acid in a concentration as defined in any one of claims 1 to 72, or as otherwise defined herein.

74. The method according to any one of claims 69 to 73, wherein the pH of the solvent solution is as defined in any one of claims 1 to 73, or as otherwise defined herein.

75. The method according to any one of claims 69 to 74, further comprising collecting an eluate and maintaining or adjusting the ascorbic acid concentration to one as defined in any one of claims 1 to 74, or to one as defined in any other form herein, along with a pH as defined in any one of claims 1 to 74, or as defined in any other form herein.

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

77. The method is [ 18 The method according to any one of claims 1 to 76, further comprising sterile filtration before or as part of the collection of a solution containing F]DCFPyL and ascorbic acid.

78. The method according to any one of claims 1 to 77, wherein the collected solution has a radiochemical purity (RCP) as defined in any one of claims 1 to 77, or as otherwise defined herein.

79. The method according to any one of claims 1 to 78, wherein the collected solution has a radioactivity concentration as defined in any one of claims 1 to 78, or as otherwise defined herein.

80. The collected solution is as defined in any one of claims 1 to 79, or as otherwise defined herein, with a % free content. 18 The method according to any one of claims 1 to 79, wherein F is present.

81. The method according to any one of claims 1 to 80, wherein the collected solution contains a total of unknown impurities as defined in any one of claims 1 to 80 or as otherwise defined herein.

82. The method according to any one of claims 1 to 81, wherein the collected solution contains ascorbic acid-related impurities as defined in any one of claims 1 to 81, or as otherwise defined herein.

83. The method according to any one of claims 1 to 82, wherein the collected solution contains % w / v acetonitrile as defined in any one of claims 1 to 82, or as otherwise defined herein.

84. The method according to any one of claims 1 to 83, wherein the collected solution comprises % w / v ethanol as defined in any one of claims 1 to 83, or as otherwise defined herein.

85. The method according to any one of claims 1 to 84, wherein the solution is collected in a collection vial such as an FCV or FPV.

86. A composition comprising [18F]DCFPyL and ascorbic acid, produced by the method described in any one of claims 1 to 85.

87. A method for administering the composition according to any one of claims 1 to 86 to a subject.

88. The method according to claim 87, wherein the method is for imaging.

89. The method according to claim 88, wherein the imaging is for cancer.

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

91. The method according to any one of claims 1 to 90, wherein the method is an automated synthesis method such as an all-in-one synthesis method.

92. The composition according to any one of claims 1 to 91, wherein the composition is intended for use in an automated synthesis method such as an all-in-one synthesis method.

93. The method or composition according to any one of claims 1 to 92, wherein the automated synthesis method is for us in an automated PET synthesis apparatus.

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

95. A method comprising any one of the methods provided herein.

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

97. The kit according to claim 96, wherein the kit includes a cassette for automated synthesis, such as all-in-one synthesis.

98. The kit according to claim 96 or 97, comprising ascorbic acid, such as one of the concentrations provided herein, or an ascorbate salt in an amount sufficient to prepare ascorbic acid at one of the concentrations provided herein.

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

100. The kit according to any one of claims 96 to 99, further comprising phosphoric acid such as one of the concentrations provided herein, or an amount sufficient to prepare a composition comprising phosphoric acid at one of the concentrations 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 according to claim 102, wherein one or more collection vials are FCVs or FPVs.

104. The kit according to claim 102, wherein one or more collection vials are for collecting the solution immediately after semi-preparation (e.g., semi-preparative separation by HPLC).

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

106. A 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 in any concentration provided herein.

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

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

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

111. A 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 ascorbic acid or ascorbate is present in the collection vial.

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

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

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

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

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

119. The method according to claim 118, wherein the composition is the composition described in claim 116 or 117.

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

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

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

123. The method according to any one of claims 118 to 122, wherein the composition further comprises ascorbic acid or an ascorbate salt in any one of the same concentrations as provided herein.

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

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

126. The method according to any one of claims 118 to 125, wherein imaging using a PET camera is performed one hour after administration.

127. In a radiopharmaceutical composition 18 A method for detecting F, wherein the method is (a) Formula: 【Transformation 7】 optionally, generated according to any one of the methods provided herein [ 18 To prepare or obtain any one of the compositions provided herein, such as a composition containing F]DCFPyL or a salt thereof; (b) Adding tetraethylammonium fluoride to the composition; and (c) Chromatography such as HPLC, etc. 18 A method comprising performing an assay to determine the level of F.

128. The method according to claim 127, wherein HPLC is analytical HPLC.

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

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

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