Fully automated manufacturing and purification of CU-61 and uses thereof

Abstract

Aspects of the present disclosure include a methods for purifying a metal radionuclide and radiolabeling a precursor compound with a radionuclide to produce a radiopharmaceutical composition. Aspects of the present disclosure include a cassette device and system for performing the methods as described herein.

Description

Attorney Ref: NCL-008WO FULLY AUTOMATED MANUFACTURING AND PURIFICATION OF CU-61 AND USES THEREOF 1. BACKGROUND

[0001] The efficient purification of radioisotopes and subsequent manufacturing of radiopharmaceuticals with high radiochemical and isotopic purity is a non-trivial task. Separating desired radionuclides from other transmuted by-products is difficult and should be performed in an automated manner to avoid radiation poisoning of the operator. The subsequent manufacturing of the radiopharmaceutical is often conducted manually, thus exposing the operator to high radiation doses. On an industrial scale, this hurdle has been solved in the past for non-metal radionuclides such as18F, however for radio-metals this is not yet the case. 2. BRIEF DESCRIPTION OF THE DRAWINGS

[0002] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0003] FIG. 1 illustrates with increasing magnification homogenous nickel coating having durable adhesion to a niobium coin upon completion of electroplating, as evaluated using a DINOLite digital microscope. Panel A, 20x magnification; panel B, 50x magnification; panel C, 250x magnification.

[0004] FIG.2 shows samples of the coin provided according to the present disclosure with nickel deposited in the center of a niobium backing.

[0005] FIG.3 displays the analysis of61Cu purity of [61Cu]CuCl2 solution obtained by irradiation ofnatNi on Nb backing with deuteron beam at 8.4 MeV for 3 h at 50 µA. The curved line corresponds to reduction in % purity of61Cu over time and the bars correspond to radiocobalt activity over time.

[0006] FIG.4 displays an analysis of61Cu purity of [61Cu]CuCl2solution obtained by irradiation of60Ni on Nb backing with a deuteron beam at 8.4 MeV for 3 h at 50 µA. The curved line corresponds to the reduction in % purity of61Cu over time, and the bars correspond to radiocobalt activity over time.

[0007] FIG.5 presents the activity concentration of detected impurities in [61Cu]CuCl2solutions produced according to various methods. The ext. coin (Ag, natNi) data was generated by 1 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO irradiation of a commercially availablenatNi target on Ag backing. The (Nb, natNi) and (Nb, Ni- 61) data were generated based on irradiation of Ni targets (natural and isotopically enriched in61Ni, respectively) electroplated according to the present disclosure on high-purity Nb backing. The activity concentration was assessed by gamma spectrometry and reported in Bq / g. The data shows that silver and cobalt isotopes are significantly reduced in the [61Cu]CuCl2 solution produced by irradiation of Ni targets electroplated according to the present disclosure on high- purity Nb backing.

[0008] FIG.6 shows the significant reduction in the sum of radionuclidic impurities present in a [61Cu]CuCl2solutions produced according to various methods. The ext. coin (Ag, natNi) data was generated based on irradiation of a commercially availablenatNi target on Ag backing. The (Nb, natNi) and (Nb, Ni-61) data were generated based on irradiation of Ni targets (natural and isotopically enriched in61Ni, respectively), electroplated according to the present disclosure on high-purity Nb backing. The radionuclidic impurities were determined by gamma spectrometry and reported in Bq / g (summed radionuclidic impurities). The presented data highlight in particular the reduction of overall impurities in the [61Cu]CuCl2 solution when produced in accordance with the present disclosure.

[0009] FIG. 7 illustrates the sustained high radionuclidic purity of a [61Cu]CuCl2solution produced according to the present disclosure compared to a commercially availablenatNi target on a Ag backing (ext. coin (Ag,natNi)). The (Nb,natNi) and (Nb, Ni-61) coins were prepared by electrodeposition according to the present disclosure on high-purity Nb backing. The data was generated using gamma spectrometry and reported in Bq / g providing the summed radionuclidic purities at t = 0h and at t = 12h. The presented data highlight the superior quality of the [61Cu]CuCl2solution when produced by irradiation of Ni targets electroplated according to the present disclosure on high purity Nb backing, where the purity after 12 hours is still well above the purity limits set by pharmacopeia for similar radionuclides for medical use.

[0010] FIG.8 displays chemical impurities, as measured by ICP-MS, of the [61Cu]CuCl2solution when produced by bombardment ofnatNi vs.61Ni when produced by irradiation of Ni targets electroplated according to the present disclosure on high-purity Nb backing.

[0011] FIGs. 9A-B illustrate embodiments of valves that may be used in cassettes described herein. 2 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0012] FIG.10 illustrates an embodiment of a cassette for purifying a metal radionuclide;

[0013] FIG. 11 illustrates a system for purifying a metal radionuclide and forming a pharmaceutical composition with a metal radionuclide;

[0014] FIG.12 provides a non-limiting example of a cassette and workflow stream of the present disclosure for purifying a metal radionuclide.

[0015] FIG.13 provides a non-limiting example of a cassette and workflow stream of the present disclosure for radiolabeling a precursor compound with the purified radionuclide such as61Cu, on a single cassette.

[0016] FIG.14 provides a non-limiting example of a cassette and detailed workflow stream of the present disclosure for purifying a radionuclide and for radiolabeling a precursor compound with the purified radionuclide such as61Cu, on a single cassette. 3. DETAILED DESCRIPTION 3.1. Definitions

[0017] When describing the embodiments of the present disclosure, the following terms, if present, have the following meanings, unless otherwise indicated. If not otherwise defined, terms have their customary meaning in the relevant art.

[0018] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite 3 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0019] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group 4 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0020] As used herein, “absorbed dose” refers to the amount of radiation absorbed by an object (e.g., an organ or tissue) or a person. The gray (Gy) is the SI unit of absorbed dose and is defined as the absorption of one joule of energy, in the form of ionizing radiation, per kilogram of matter, i.e., one gray = 1 J / kg2.

[0021] As used herein, “activity” or “radioactivity” refers to a physical quantity defined as the number of radioactive transformations per second that occur in a particular compound or composition that contains one or more radioactive substances. The unit of activity used herein is the becquerel (Bq), which is defined equivalent to reciprocal seconds (1 / seconds or s-1).

[0022] As used herein, “activity concentration” refers to the total amount of radioactivity per unit volume. In certain embodiments, activity concentration is expressed in Bq / L or magnitudes thereof (e.g., MBq / mL).

[0023] As used herein, “radiocobalt activity content” refers to the ratio, expressed as a percentage, of the radioactivity of radiocobalt species in a composition to the total radioactivity of the composition.

[0024] As used herein, “end of synthesis” (EoS) refers to the completion of radiolabeling of a precursor (e.g., NODAGA-PSMA I&T) with a radionuclide (e.g., [61Cu]CuCl2) and subsequent preparation of the pharmaceutical composition, e.g., dilution with saline solution.

[0025] As used herein, “effective amount,” “pharmaceutically effective amount,” or “therapeutically effective amount” mean a sufficient amount of the pharmaceutical composition to provide the desired utility when administered to a subject. In certain embodiments, an effective amount includes an amount of pharmaceutical composition sufficient to generate an image of subject. In certain embodiments, an effective amount includes an amount of pharmaceutical composition sufficient to diagnose a disease in a subject. It is understood that for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using routine experimentation. For example, when administered in clinic, such pharmaceutical compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., imaging cancerous tissue). 5 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0026] As used herein, “effective dose” refers to the internationally accepted central radiological risk metric quantity. The calculation of effective dose can be seen as a three-step process. First, the mean absorbed doses to organs and tissues are determined in gray (Gy; J kg−1). Second, the absorbed doses are converted to equivalent doses in sievert (Sv) using tissue / organ radiation weighting factors (wR). The weighting factors were computed from radiation epidemiological data, and take into consideration that some organs (e.g., breasts, stomach, and, lungs) are more radiosensitive than others (e.g., brain and skin). The summing of organ / tissue equivalent doses, each weighted by the appropriate tissue weighting factor (wT), gives the effective dose, in Sv or Sv / MBq (i.e., the effective dose received per unit of activity administered) The effective dose is therefore a risk metric, and not a dosimetric quantity per se.

[0027] As used herein, “molar activity” refers to the amount of radioactivity (e.g., number of nuclear disintegrations per second) per unit mole of the radiolabeled compound. In certain embodiments, apparent molar activity is expressed in Bq / mol, e.g., MBq / nmol and is used where the molecular weight of the labelled material is known. The “apparent molar activity” (apparent Am) takes into account the amounts of the radiolabelled (compound A*) and non-radiolabelled radiotracer (compound A), radiolabelled impurities (compound B*) and non-radiolabelled impurities (compound B) and remaining precursor (compound C) present expressed in mol (or µmol). See, e.g., Luurtsema, G., et al. “EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality.” EJNMMI radiopharm. chem.6, 34 (2021).

[0028] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, 6 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0029] As used herein, “pharmaceutical composition” refers to a composition suitable for administration to a subject that comprises [61Cu]Cu-NODAGA-PSMA I&T or a salt thereof and one or more pharmaceutically acceptable excipients. A “pharmaceutically acceptable excipient”, as used herein refers to for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for intravenous administration that do not deleteriously react with the [61Cu]Cu-NODAGA-PSMA I&T or salt thereof. Exemplary pharmaceutical excipients are known to those of skill in the art.

[0030] As used herein, “positive predictive value” or PPV refers to a given method’s precision in identifying cancerous lesions / tumors. A method that has a high PPV is more desirable. Mathematically, PPV is the number of true positives (TP) divided by the sum of TP and false positives (FP). In other words, PPV is TP / (TP + FP).

[0031] As used herein, “peptide receptor radionuclide therapy” (PRRT) refers to the use of one or more radiotherapeutic agents for the delivery of targeting radiation, usually by a chelated radionuclide, to a specific tissue or receptor associated with cancer. The targeting and selection of certain tissues over another is accomplished by specific peptide hormone receptors expressed or overexpressed on the surface of cancerous biomass. 7 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0032] As used herein, “radiochemical purity” refers to the ratio, given as a percent, of radioactivity from the radionuclide in the pharmaceutical composition (e.g., the desired radionuclide that is chelated in a radiotracer as described herein) to the total radioactivity of the composition that comprises the radiotracer. The majority of the radioactive isotope is attached to the tracer construct and is not free or attached to another chemical entity as these forms may have a different biodistribution. Radiochemical purity (RCP) measurements establish the content of impurities labelled with the same radionuclide used to prepare a radiopharmaceutical, but with a different chemical form.

[0033] Radiochemical purity is determined according to methods well known to those of skill in the art, e.g., radio-HPLC, iTLC. As is understood in the art, determination of radiochemical purity is not strictly quantitative, and it is calculated as the ratio between the peak area of the desired radiotracer and the overall area of all the detected peaks in the radiochromatogram (corrected for decay). The instrument used to determine radiochemical purity with HPLC (radio- HPLC) is a radiometric detector (radiodetector), which has an in-line detector connected in series with a UV or other physicochemical detector. The radiometric detector can be a Geiger-Müller probe, a scintillation detector, or a PIN diode. As compared with radio-HPLC it has the big advantage that all applied radioactivity is detected and there are no concerns with recovery. The radiochemical purity is reported at a particular time point, e.g., a certain time after end of synthesis (EoS, described herein). In certain embodiments, a radiotracer radiochemical purity is measured at 3 hours after end of synthesis of the radiotracer, at 6 hours after end of synthesis of the radiotracer, at 9 hours after end of synthesis of the radiotracer, or at 12 hours after end of synthesis of the radiotracer.

[0034] As used herein, “radionuclidic purity” refers to the ratio, expressed as a percentage, of the radioactivity of a particular radionuclide to the total radioactivity of the sample, e.g., the starting material used to prepare a radiotracer. In certain embodiments, radionuclidic purity can be determined by high resolution gamma spectroscopy (e.g., high-purity germanium (HPGe) detector) on a sample after expiration, e.g. >8 hours or >3 weeks) and is then extrapolated (e.g., using the TENDL-2019 database according to procedures well known in the art), and reported herein as the value at the end of synthesis (e.g., EoB+2hours) of the radionuclide. 8 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0035] As used herein, “radionuclidic impurities” refer to all non-61Cu radionuclides in a composition.

[0036] As used herein, “radiotracer” refers to a compound of the present disclosure comprising a radionuclide or radioisotope. It is understood herein that when a compound, e.g., a radiotracer, is described as comprising a particular radioisotope or radionuclide (e.g.,61Cu) that the compound is isotopically enriched in that isotope at the indicated position.

[0037] As used herein, “sensitivity” refers to the ability of a given method to accurately identify cancerous lesions / tumors. A method that has high sensitivity is more desirable. Mathematically, sensitivity is the number of true positives (TP) divided by the sum of the number of TPs and false positives (FP). In other word, sensitivity (Se) = TP / (TP + FN).

[0038] As used herein, “specific activity” refers to the activity of a radionuclide per unit mass or per unit volume. In certain embodiments, specific activity refers to the activity of a radionuclide per unit mass of the radiotracer. In certain embodiments, specific activity refers to the activity of a radionuclide per unit mass of the [61Cu]CuCl2 solution used to radiolabel the NODAGA-PSMA I&T. In certain embodiments, specific activity refers to the activity of a radionuclide per unit volume of the [61Cu]CuCl2solution used to radiolabel the NODAGA-PSMA I&T. In certain embodiments, specific activity is measured at EoS.

[0039] As used herein, “subject” refers to the person or organism to which the composition is, or is intended to be, administered. As such, subjects of the present disclosure may include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees and other ape and monkey species. In preferred embodiments the subject are humans. The term subject includes a person or organism of any age, weight, or other physical characteristic, including an adult, an adolescent, a child, an infant or a newborn.

[0040] As used herein, “valve” refers to a mechanical device capable of alternating a flow of fluid in one or more directions.

[0041] As used herein, “port” or “valve port” refers to a fluidic outlet of a valve through which a fluid is capable of flowing.

[0042] As used herein, “manifold” refers to a structure having one or more tubes. 9 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0043] As used herein, “fluidically coupled” refers to an arrangement of two or more objects in which a fluidic channel is formed between the two or more objects.

[0044] As used herein, “pressure source” refers to an device capable of increasing or decreasing a fluid pressure relative to an atmospheric pressure.

[0045] As used herein, “dissolution vessel” refers to a fluid housing in which dissolution is capable of occurring.

[0046] As used herein, “ion exchanger system” refers to a device or arrangement of devices capable of transferring ions of a same charge between an insoluble bound solid phase and a mobile phase solution in contact with the insoluble bound solid phase.

[0047] As used herein, “vessel” refers to a device having an interior capable of holding one or more liquids and / or solids.

[0048] As used herein, “fluid pathway” refers to a channel in which fluid flows.

[0049] As used herein, “pathway segment” refers to a sub portion of a fluid pathway.

[0050] As used herein, “fluidic inlet” refers to an end of a device designed for receiving a fluid.

[0051] As used herein, “fluidic outlet” refers to an end of a device designed for providing a fluid.

[0052] As used herein, “spigot” refers to a device capable of controlling a flow of fluid.

[0053] As used herein, “fluid orientation” refers to an arrangement of one or more ports of a valve. 3.2. Cassette

[0054] Aspects of the present disclosure provide for cassettes for purifying one or more metal radionuclides and optionally preparing pharmaceutical compositions comprising the one or more metal radionuclides, and methods of purifying one or more metal radionuclides and preparing pharmaceutical compositions, e.g., by using the cassettes. In particular, cassettes described herein may allow for both purification of a metal radionuclide and forming a pharmaceutical composition of a purified metal radionuclide in a single device.

[0055] Modern production of purified radio-metals and radiolabeling using those radio-metals is difficult to combine on one cassette due to the fact that the dissolution of the metal matrix and the subsequent purification requires more consumables and materials than non-metal 10 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO radionuclides. Modern cassettes may spread purification consumables across the entire cassette, which may increase risk of contaminating a final product. Cassettes described herein may have a layout that allows for reduced risk of contamination of a final product. In some embodiments, cassettes described herein may provide for increased efficiency and reduced total production time compared to conventional cassettes, which may improve the longevity of the radionuclide product as less radioactive decay will have occurred in the shorter production time. For instance, radionuclides may have a relatively short half-life, such as about 200 minutes. By providing a faster process of producing metal radionuclides using cassettes described herein, conservation of metal radionuclides respective to their half lives may be achieved, resulting in higher radioactivity that may be used in radiopharmaceutical compositions.

[0056] Referring now to FIG.9A, a valve 900A is shown. In some embodiments, valve 900A may be circular, square, triangular, or other shapes. Valve 900A may have a hollow interior. A hollow interior of valve 900A may allow for fluid to flow in one or more directions through valve 900A. In some embodiments, valve 900A may be a three-way valve. For instance and without limitation, valve 900A may be a T-pattern or L-pattern valve. In other embodiments, valve 900A may include four or more ports and may be a four-way valve or greater.

[0057] Valve 900A may include first port 908. First port 908 may be an extension from a central body of valve 900A. For instance, first port 908 may extend outwards from a central portion of first port 908. First port 908 may form a fluidic pathway between an interior of valve 900A and itself. A fluidic pathway between an interior of valve 900A and first port 908 may allow for a flow of fluid in a direction from first port 908 towards valve 900A or in a direction from valve 900A towards an end of first port 908. First port 908 may be circular, ovular, square, triangular, or other shapes. In some embodiments, first port 908 may have a diameter less than that of an interior of valve 900A. For instance, valve 900A may have an internal diameter of about 0.1 mm to about 2 mm First port 908 may have an internal diameter of about 0.1 mm to about 2 mm. In some embodiments, first port 908 may be funneled towards valve 900A. A funneling of first port 908 towards an interior of valve 900A may include a decreasing radius of first port 908 in a direction from a distal end of first port 908 most distal to valve 900A towards valve 900A. In some embodiments, first port 908 may include one or more threads which may be configured to mate with one or more screws of a tube, port, vessel, or other device. For instance, first port 908 may be rotatable, such as in a clock-wise or counter-clockwise direction. In embodiments where 11 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO first port 908 has threads, first port 908 mate with screws and / or threads of another device, which may mechanically connect first port 908 with another device.

[0058] Valve 900A may include second port 912. In some embodiments, second port 912 may be structurally the same as first port 908. In other embodiments, second port 912 may have differing dimensions and / or geometry than that of first port 908. Second port 912 may be positioned perpendicularly to first port 908. For instance, second port 912 may be positioned along a vertical axis of valve 900A. Second port 912 may be positioned to receive or provide a flow of fluid in a vertical direction towards valve 900A or away from valve 900A. Valve 900A may include third port 916. Third port 916 may be structurally the same as first port 908 and / or second port 912. In other embodiments, third port 916 may have differing dimensions and / or geometry than either or both of first port 908 and second port 912. Third port 916 may be positioned perpendicular to second port 912. In some embodiments, third port 916 may be positioned to mirror first port 908 on an opposite side of valve 900A with respect to first port 908. First port 908 may be positioned about 90 degrees away from second port 912 with respect to a horizontal axis of valve 900A. Second port 912 may be positioned about 90 degrees away from third port 916 with respect to a horizontal axis of valve 900A. First port 908 may be positioned about 180 degrees away from third port 916 with respect to a horizontal axis of valve 900A. In some embodiments, an angle between any two valves of valve 900A may be about, but is not limited to, about 5 degrees to about 10 degrees, about 10 degrees to about 15 degrees, about 15 degrees to about 20 degrees, about 20 degrees to about 30 degrees, about 30 degrees to about 40 degrees, about 40 degrees to about 50 degrees, about 50 degrees to about 60 degrees, about 60 degrees to about 70 degrees, about 70 degrees to about 80 degrees, about 80 degrees to about 90 degrees, about 90 degrees to about 100 degrees, about 100 degrees to about 120 degrees, about 120 degrees to about 140 degrees, about 140 degrees to about 160 degrees, or about 160 degrees to about 180 degrees. Variations of degrees between any of valves 904, 908, and 912 may be selected to accommodated fluid pathways, vessels, or other devices.

[0059] Referring still to FIG.9A, valve 900A may include rotatable spigot 904. Rotatable spigot 904 may be any type of plug or faucet. In some embodiments, rotatable spigot 904 may be positioned on top a central portion of valve 900A. Rotatable spigot 904 may be connected to one or more valve doors. Valve doors may be surfaces inside of an interior of valve 900A that may block off or open one or more of ports 904, 912, and 916. For instance, a valve door connected to 12 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO rotatable spigot 904 may be in the form of a “T”, which may allow an opening of three ports at a time. In some embodiments, a valve door connected to rotatable spigot 904 may be in the form of an “L” which may allow an opening of two ports at a time. Rotatable spigot 904 may rotate in a clockwise or counterclockwise direction, which may open and / or close one or more of ports 908, 912, and 916. In some embodiments, a rotation of rotatable spigot 904 may cause a change in a flow direction of a fluid within valve 900A.

[0060] In some embodiments, valve 900A may be configured to allow a flow of fluid in direction D1 from an interior of valve 900A to a distal end of first port 908. In some embodiments, valve 900A may be configured to allow a flow of fluid in direction D2, from an interior of valve 900A to a distal end of third port 916. In some embodiments, valve 900A may be configured to allow a flow of fluid in direction D3, from an interior of valve 900A to a distal end of second port 912. In some embodiments, valve 900A may be configured to allow a flow of fluid opposite any of directions D1-D3. Rotatable spigot 904 may open or close one or more of first port 908, second port 912, and / or third port 916, which may allow or prevent a flow of fluid in any direction described herein. For instance, rotatable spigot 904 may be rotated into a first position, which may cause valve 900A to be arranged in a first flow orientation. A first flow orientation may be an arrangement in which third port 916 is closed and first port 908 and second port 912 are open and in fluid communication, allowing for a flow of fluid through both first port 908 and second port 912 in direction D3 (and opposite direction D1) or in direction D1 (and opposite direction D3). Rotatable spigot 904 may be rotated into a second position, which may cause valve 900A to be arranged in a second flow orientation. A second flow orientation may be an arrangement in which second port 912 is closed and first port 908 and third port 916 are open and in fluid communication , allowing for a flow of fluid in direction opposite D1 through first port 908 and in direction D2 through third port 916, or a flow of fluid opposite direction D2 through third port 916 and in direction D1 through first port 908. Rotatable spigot 904 may be rotated into a third position, which may cause valve 900A to be arranged in a third flow orientation. A third flow orientation may be an arrangement in which first port 908 is closed while third port 916 and second port 912 are open and in fluid communication, which may allow for a flow of fluid in second port 912 in direction opposite D3 and into third port 916 in direction D2 or a flow of fluid opposite direction D2 through third port 916 and in direction D3 through second port 912. Rotatable spigot 904 may be rotated into a fourth position, which may cause 13 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO valve 900A to be arranged in a fourth flow orientation. A fourth flow orientation may be an arrangement of valve 900A in which all ports 908, 912, and 916 are open and in fluid communication, allowing for a flow of fluid in first port 908 in or opposite to direction D1, a flow of fluid in second port 912 in or opposite to D3, and / or a flow of fluid in third port 916 in or opposite to direction D2.

[0061] In some embodiments, rotatable spigot 904 may be controllable by a computing device. For instance, an actuator or other device may be mechanically connected to rotatable spigot 904 and may be in electrical connection with a computing device. A computing device may be configured to rotate rotatable spigot 904 in any direction and may cause valve 900A to enter into any orientation described herein. In some embodiments, one or more robotic arms of a synthesizer or other device may interact with rotatable spigot 904, which may cause rotatable spigot 904 to enter any position, causing valve 900A to enter any flow orientation as described herein. In some embodiments, valve 900A may be pre-set in a flow orientation based on a positioning of valve 900A within a cassette system. In other embodiments, valve 900A may be transitioned from any flow orientation to any other flow orientation described herein in real-time during a process carried out by a cassette.

[0062] Referring now to FIG.9B, a plurality of valves fluidically connected to a manifold 920 is presented. A plurality of valves may include valves 900A, 900B, and / or 900C or additional similar valves not depicted. While valves 900A, 900B, and 900C are illustrated in a linear arrangement in FIG.9B, this is for illustrative purposes only, and the valves can be arranged in any configuration. Valves 900B and 900C may be structurally the same as valve 900A as described above with reference to FIG.9A. In some embodiments, valves 900B and / or 900C may differ from valve 900A in, but not limited to, size, geometry, number of ports, type of valve, or other attributes. Valves 900A-C may be fluidically coupled to manifold 920. Manifold 920 may have inlet 934 and outlet 938, with an interior volume providing for a flow of fluid therebetween. Manifold 920 may have a diameter of about 0.1 mm to about 2 mm. In some embodiments, one or more ports of valves 900A-C may have a diameter greater than that of a diameter of manifold 920, which may allow for a portion of a tube of manifold 920 to be inserted into any port of valves 900A-C, e.g., to establish fluid connectivity. In some embodiments, valves 900A-C may make up manifold 920. For instance, connections between two or more ports of valves 900A-C may create manifold 920. In some embodiments, manifold 920 may be broken 14 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO up into pathway segments 930A and 930B. Pathway segments 930 may be portions of manifold 920 positioned between two adjacent valves. In some embodiments, a flow of fluid in one fluid pathway 930 may differ from a flow of fluid in another fluid pathway 930. For instance, and without limitation, a flow of fluid in pathway segment 930A between valves 900A and 900B may occur in a first direction, while a flow of fluid in pathway segment 930B between valves 900B and 900C may occur in a second direction that may be opposite or perpendicular to the first direction. In some embodiments, fluid may be prevented from flowing in pathway segment 930A and / or 930B based on a positioning of ports of valves 900A-C. 3.3. Purification Using a Cassette

[0063] Referring now to FIG.10, a cassette 1000 for purification of a metal radionuclide is presented. Cassette 1000 may have valves 900A-C, which may be as described above with reference to FIGs.9A-B. In some embodiments, cassette 1000 may have valve 900D, which may be structurally the same as valve 900A as described above with reference to FIG.9A. In some embodiments, valve 900D may differ from any of valves 900A-C, such as, but not limited to, in size, geometry, number of ports, type of valve, or other attributes. Valves 900A-D may be fluidically coupled to manifold 920. For instance, one or more ports of valves 900A-D may be fluidically coupled to manifold 920. In some embodiments, valves 900A-D may make up manifold 920. For instance, ports of valves 900A-D may fluidically connect to each other, forming a fluid pathway therein.

[0064] In some embodiments, cassette 1000 includes fluidic inlet 1008. Fluidic inlet 1008 may be a tube or other cylindrical object that may be designed to carry a flow of fluid. For instance, fluidic inlet 1008 may provide a flow of fluid 1016 to valve 900A. Fluidic inlet 1008 may be fluidically coupled to a port of valve 900A. In some embodiments, fluidic inlet 1008 may be fluidically coupled to a port of valve 900A that may be perpendicular to manifold 920. Fluidic inlet 1008 may be held in place by one or more holders of cassette 1000. A holder of cassette 1000 may hold fluidic inlet 1008 in a vertical position such as about 90 degrees rotated from a longitudinal axis of manifold 920. In some embodiments, fluidic inlet 1008 may be fluidically coupled to valves 900B, 900C, or 900D. Fluidic inlet 1008 may be configured to deliver an amount of fluid 1016 to valve 900A. Fluid 1016 may be a chemical solution, such as, but not limited to, a dissolution fluid. In some embodiments, fluid 1016 may be a crude solution of a metal, including a radio-metal, such as, but not limited to, copper (e.g.,57Cu,59Cu,58Cu,60Cu, 15 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO61Cu,62Cu,64Cu, and67Cu, such as one or more of61Cu,64Cu, and67Cu, preferably61Cu), gallium (e.g.,68Ga), actinium, lutecium, iron, lead, technetium, indium, zirconium, lithium, or other metals. A crude solution of a metal may include one or more dissolution reagents, such as, but not limited to, one or more acids, bases, oxidizing agents, fusion salts, or other reagents. In some embodiments, fluid 1016 may be a crude solution of a metal. Fluid 1016 may be a crude solution of a metal radionuclide.

[0065] In some embodiments, fluid 1016 may be created from dissolution vessel 1012. Dissolution vessel 1012 may be fluidically connected to fluidic inlet 1008 and may provide fluid 1016 to fluidic inlet 1008. Dissolution vessel 1012 may be a container having an interior designed for dissolution of one or more compounds or metals. In some embodiments, dissolution vessel 1012 may dissolve, at least partially, a capsule and / or metallic coin through a dissolution process. A dissolution process may include dissolution of a crude starting material from a substrate into fluid 1016. For instance, a crude starting material within dissolution vessel 1012 may be a metallic coin partially covered with a target metal (e.g., nickel, such asnatNi,60Ni,61Ni, or62Ni). In some embodiments, a target metal adhered to the surface of the metallic coin within dissolution vessel 1012 may have been bombarded with one or more subatomic particles (e.g., protons, deuterons, etc.), which may have caused the target metal to be converted to a desired crude metal radionuclide product (e.g., radio-copper, such as61Cu or64Cu) that is adhered to the surface of the metal coin. Dissolution vessel 1012 may be heated. For instance, a heating element, such as but not limited to a resistive heating element, may be placed underneath dissolution vessel 1012, which may increase a speed at which dissolution within dissolution vessel 1012 occurs. For instance, dissolution of a plating of a capsule and / or coin may occur in less than about 10 minutes. Temperatures provided by a heating element may be about, but are not limited to, about 60 C to about 70 C, about 70 C to about 80 C, about 80 C to about 90 C, or about 90 C to about 100 C. Dissolution vessel 1012 may dissolve a crude metal radionuclide product adhered to an irradiated metallic coin into a dissolution solution, which may be fluid 1016. In some embodiments, fluid 1016 may be radioactive. Fluid 1016 may be provided to a port of valve 900A at a rate of about 0.1 mL / min to about 5 mL / min.

[0066] Valve 900A may be arranged in a fluid orientation that allows for three or more ports of valve 900A to be open. For instance, a first port of valve 900A may be fluidically coupled to pressure source 1004. Pressure source 1004 may be an air pump, vacuum, or other device. In 16 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO some embodiments, pressure source 1004 may be configured to provide a fluid pressure to manifold 920 through one or more valves of valves 900A-D and / or inlet 934. A fluid pressure provided by pressure source 1004 may be a liquid or gas. In some embodiments, a fluid pressure provided by pressure source 1004 may be inert. For instance, pressure source 1004 may be configured to provide a fluid pressure of inert gas. Inert gas may include, but is not limited to, nitrogen, carbon dioxide, helium, neon, argon, krypton, xenon, radon, or other inert gases. An inert gas may be provided by pressure source 1004 to drive a flow of fluid within manifold 920 while avoiding undesired chemical reactions between different components of cassette 1000. In some embodiments, a pressure provided by pressure source 1004 may be about 1 millibar to about 1 bar, 1 bar to about 5 bar, about 5 bar to about 10 bar, or greater than about 10 bar.

[0067] Valve 900A may be fluidically coupled to pressure source 1004 at a first valve, fluidically coupled to fluidic inlet 1008 at a second valve, and / or fluidically coupled to manifold 920 at a third valve. In some embodiments, valve 900A may start in a position in which three or more ports of valve 900A are open. In other embodiments, valve 900A may transition form a first flow orientation in which one or more ports are closed into a second flow orientation in which three or more ports of valve 900A are open. Pressure source 1004 may cause a movement of fluid in direction D1 through manifold 920. For instance, fluid 1016 may travel through a first port of valve 900A and may be directed into a third port of valve 900A facing direction D1 due to a fluid pressure provided by pressure source 1004. Fluid 1016 may travel between valve 900A and valve 900B in direction D1. Pathway segment 930A may be open and may allow for a flow of fluid 1016 in direction D1 from valve 900A to valve 900B. Fluid may flow in pathway segment 930A at a rate of about 0.5 mL / min to about 120 mL / min.

[0068] With continued reference to FIG.10, valve 900B may start in a first flow orientation in which three or more ports of valve 900B are open and may transition into a second flow orientation in which one or more ports of valve 900B are closed. Valve 900B may be arranged in a flow orientation in which a first port facing valve 900A is open, a second port fluidically coupled to ion exchanger system 1020 is open, and a third port facing valve 900C is closed. Ion exchanger system 1020 may be fluidically coupled to a port of valve 900B and / or a port of valve 900C. Ion exchanger system 1020 may include one or more ion exchangers. For instance, ion exchanger system 1020 may include a sole ion exchanger. A sole ion exchanger may include an ion exchanger column. An ion exchanger column may include one or more chemicals and / or 17 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO compounds that may chemically purify fluid 1016. For instance, and without limitation, an ion exchanger column may have a resin, such as a phosphate-functionalized resin. A sole ion exchanger may include a phosphate-functionalized resin (e.g., TBP, LN, TK100, TK101, LN2, LN3) or an amine functionalized resin, such as a tertiary amine functionalized resin (e.g., TK201). In particular embodiments, a sole ion exchanger may include a TBP ion exchanger. Interaction with a phosphate-functionalized resin may remove one or more impurities from fluid 1016. In some embodiments, one or more valves may be positioned between valve 900A and valve 900B. One or more valves positioned between valve 900A and valve 900B may be fluidically coupled to one or more vials that may house various chemicals and / or chemical compounds that may assist in purification of fluid 1016. For instance, there may be a first valve fluidically coupled to a vial housing an aqueous NaCl solution, a second valve fluidically coupled to a vial housing an aqueous HCl solution, an / or a third valve fluidically coupled to a waterbag. An aqueous NaCl solution, an aqueous HCl solution, and / or water may travel within a respective port of a valve and may flow into fluid pathway 1020. In some embodiments, a valve coupled to a vial may be arranged in a flow orientation in which three or more ports are open. For instance, a first port of a valve may be fluidically coupled to a vial, and a second and third port of a valve may be fluidically coupled to manifold 920. Fluids from one or more vials fluidically coupled to one or more valves may flow in direction D1 along with fluid 1016. In some embodiments, a valve fluidically coupled to a vial may be adjusted to increase or decrease an amount of fluid flowing into manifold 920. In embodiments where a plurality of valves coupled to vials are implemented, each valve may be operated sequentially. For instance and without limitation, a first valve fluidically coupled to a vial housing an aqueous NaCl solution may be opened first, a second valve fluidically coupled to a vial housing an aqueous HCl solution may be opened subsequently to the first valve, and a third valve fluidically coupled to a waterbag may be opened subsequently to both the first and second valves. Any combination of opening and / or closing of valves may be implemented, without limitation.

[0069] In some embodiments, ion exchanger system 1020 may include two or more ion exchangers. Ion exchangers of ion exchanger system 1020 may include, but are not limited to, TK201, TBP, Zr, TK200, TK211, TK212, TK213, LN, Pb, or other ion exchanger columns. In some embodiments, the ion exchanger system is suitable for purifying one or more radionuclides, such as Cu radionuclides (e.g.,61Cu), Ga radionuclides, Lu radionuclides, Pb 18 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO radionuclides, and Zr radionuclides. One or more prominent nuclides that may be separated by one or more ion exchangers of the ion exchanger system may include, but are not limited to, Lu, Pb, Ga, Zr, Cu (e.g.,61Cu), or other nuclides. Separation of nuclides using one or more ion exchangers of ion exchanger system 1020 may occur at a rate of about, but not limited to, about 0.5 mol / L to about 1 mol / L, about 1 mol / L to about 1.5 mol / L, about 1,5 mol / L to about 2 mol / L, about 2 mol / L to about 2.5 mol / L, about 2.5 mol / L to about 3 mol / L, about 3 mol / L to about 3.5 mol / L, about 3.5 mol / L to about 4 mol / L, about 4.5 mol / L to about 5 mol / L, or greater than about 5 mol / L. For instance, a first ion exchanger may include a phosphate-functionalized resin (e.g., TBP, LN, TK100, TK101, LN2, LN3), and a second ion exchanger may include an amine functionalized resin, such as a tertiary amine functionalized resin (e.g., TK201). In some embodiments, a first ion exchanger may be a TBP ion exchanger and a second ion exchanger may be a TK201 ion exchanger. In embodiments where ion exchanger system 1020 has two ion exchangers, each ion exchanger may be fluidically coupled to a respective valve. For instance, a first ion exchanger may be fluidically coupled to valve 900B and a second ion exchanger may be fluidically coupled to a valve positioned between valve 900B and valve 900C. Interaction of fluid 1016 with ion exchanger system 1020 may create purified solution 1028. Purified solution 1028 may include a purified metal radionuclide as described herein. For instance, purified solution 1028 may include a purified metal radionuclide having a chemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5%.

[0070] In some embodiments, dissolution within dissolution vessel 1012 may occur at a same time as purification of fluid 1016 within ion exchanger system 1020. Dissolution within dissolution vessel 1012 may occur simultaneously as a conditioning of ion exchanger system 1020. By performing dissolution within dissolution vessel 1012 at a same time as conditioning of ion exchanger system 1020, an overall time to produce a metal radionuclide using cassette 1000 may be reduced. For instance, formulating a metal radionuclide using cassette 1000 may take about, but not limited to, about or less than 30 minutes, about or less than 20 minutes, or about or less than 10 minutes. Dissolution within dissolution vessel 1012 may occur within about 1 minutes to about 10 minutes or greater. Conditioning ion exchanger system 1020 may include flowing one or more chemicals and / or chemical compounds into ion exchanger system 1020. For instance, one or more valves may be fluidically coupled to one or more vials that may house 19 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO conditioning chemicals, such as, but not limited to, aqueous NaCl, aqueous HCl, and / or water. Valves may be operated to flow aqueous NaCl, aqueous HCl, water, and / or other conditioning chemicals into ion exchanger system 1020 while dissolution occurs within dissolution vessel 1012.

[0071] Referring still to FIG.10, fluid 1016 may travel into ion exchanger system 1020 through a port of valve 900B perpendicular to manifold 920. Ion exchanger system 1020 may be fluidically coupled to valve 900C at a port perpendicular to manifold 920. Valve 900C may be arranged in a flow orientation in which one or more ports of valve 900C are closed. In some embodiments, valve 900C may be operated to transition from a first flow orientation in which all ports are open to a second flow orientation in which one or more ports are closed. For instance, valve 900C may have a first port facing valve 900B that may be closed, which may prevent a flow of fluid in pathway segment 930B. A second port of valve 900B may be fluidically coupled to manifold 920 opposite a side of valve 900C facing valve 900B. For instance, a second port of valve 900B may face valve 900D along manifold 920. A third port of valve 900B may be fluidically coupled to ion exchanger system 1020, which may allow for purified solution 1028 to flow into manifold 920. Purified solution 1028 may flow in direction D1 towards valve 900D. Pathway segment 930C may be open, and may allow for a flow of fluid, such as but not limited to purified solution 1028, to flow from valve 900C to valve 900D. Valve 900D may be arranged in a flow orientation in which one or more ports are closed. In some embodiments, valve 900D may start in a flow orientation in which one or more ports are closed. In other embodiments, valve 900D may transition from a first flow orientation in which all ports are open to a second flow orientation in which at least one port is closed. For instance, valve 900D may have a first port fluidically coupled to manifold 920 and facing valve 900C, a second port fluidically coupled to vessel 1024, perpendicular to the first port, and a third port that may be fluidically coupled to manifold 920 on a side of valve 900D opposite the first port. A third port of manifold 920 may be closed, which may prevent a flow of fluid past valve 900D in direction D1. Purified solution 1028 may flow through valve 900C via a first port of 900C and into manifold 920 via a second port of valve 900C. Purified solution 1028 may flow into a first port of valve 900D in direction D1 and may be directed into vessel 1024 via a second port of valve 900D, preventing purified solution 1028 from entering outlet 938. Vessel 1024 may be fluidically coupled to valve 900D at a port of valve 900D. Vessel 1024 may be a container or housing that may be designed to hold 20 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO purified solution 1028. In some embodiments, vessel 1024 may hold up to or greater than about 1 mL to about 2 mL, about 2 mL to about 3 mL, about 3 mL to about 4 mL, or greater than about 4 mL of purified solution 1028. In some embodiments, vessel 1024 may hold up to between about 20 mL to about 200 mL of purified solution 1028. 3.4. Computing Device Embodiments for Purification

[0072] In some embodiments, a computing device may be in electrical communication with an actuator of any or all of valves 900A-D. Operation of cassette 1000 may be automatic through a computing device, in some embodiments. A computing device may be configured to control a flow orientation of any or all of valves 900A-D. For instance, a computing device may operate an actuator of any or all of valves 900A-D. An actuator may be in mechanical communication with a respective valve of valves 900A-D. In some embodiments, an actuator may be in mechanical communication with a rotatable spigot of any of valves 900A-D. An actuator may be, but is not limited to, a servo motor, electrical driving motor, linear actuator, or other form of actuator. In some embodiments, a computing device may be in electrical communication with an actuator for each of valve 900A, 900B, 900C, and / or 900D. A computing device may be configured to operate one or more of valves 900A, 900B, 900C, and / or 900D through actuation of an actuator. For instance, a computing device may be configured to transition valve 900A from a first flow orientation to a second flow orientation or more flow orientations. A computing device may be configured to open one or more ports of valves 900A-D. In some embodiments, a computing device may be configured to operate valves 900A-D in a sequential pattern. A sequential pattern may include a timed arrangement of operation of one or more valves 900A-D. For instance, a computing device may first operate valve 900A to open a fluid pathway between fluidic inlet 1008 and pathway segment 930A, may secondly close off a port of valve 900B while keeping open a port to manifold 920 and a port to ion exchanger system 1020, may thirdly open a port of valve 900C to ion exchanger system 1020 and open a port fluidically coupled to pathway segment 930C while keeping closed a port fluidically coupled to pathway segment 930B, and may fourthly close a port of valve 900D fluidically coupled to an end of manifold 920 while opening a port of valve 900D fluidically coupled to pathway segment 930C and open a port fluidically coupled to vessel 1024.

[0073] In some embodiments, a sequence of opening and / or closing one or more ports of one or more valves 900A-D may be timed. For instance, a time between operating a first valve from a 21 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO second valve may be about, but is not limited to, about 1 second to about 5 seconds, about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, or greater than about 30 seconds. In some embodiments, a sequence of rotation of one or more of valves 900A-D may occur in periods of time between about 1 minute to about 10 minutes. In some embodiments, two or more valves 900A-D may be rotated and / or positioned simultaneously. In some embodiments, two adjacent valves 900 may be rotated simultaneously. In some embodiments, two non-adjacent valves may be rotated simultaneously. For instance, and without limitation, valves 900A and 900B may be rotated while valves 900C and 900D remain stationary or vice versa. Valves 900A and 900C may be rotated while valves 900B and 900D remain stationary and vice versa. Any sequence of operations of any ports of valves 900A-D may be implemented, without limitation. In some embodiments, pathway segment 930B may be open while ports of valves 900B and 900C to ion exchanger system 1020 may be closed, which may allow for a flow of fluid throughout an entirety of manifold 920.

[0074] A sequence may be a timed actuation process. A timed actuation process may include opening and / or closing one or more ports of any of valves 900A-900D in timed increments. Timed increments may include periods of time from about 1 ms to about 30 seconds or greater. For instance, a computing device may be configured to perform a sequence of purification, washing, and / or radiolabeling processes, each of which may include a time actuation process. A computing device may perform a purification process. A purification process may include directing fluid 1016 from fluidic inlet 1008 into valve 900A through operation of one or more ports of valve 900A. Fluid 1008 may flow into ion exchanger system 1020 through operation of one or more ports of valve 900B. In some embodiments, a computing device may allow for fluid pressure generated by fluid pressure source 1004 to flow in direction D1 through one or more ports of valves 900A, 900B, 900C, and / or 900D. A fluid pressure may be an inert gas. A flow of a fluid pressure in direction D1 may cause a drying of ion exchanger system 1020. For instance, about 100 millibar to about 200 millibar, about 200 millibar to about 300 millibar, about 300 millibar to about 400 millibar, about 400 millibar to about 500 millibar, about 500 millibar to about 600 millibar, about 600 millibar to about 700 millibar, about 700 millibar to about 800 millibar, about 800 millibar to about 900 millibar, or about 900 millibar to about 1 bar of fluid pressure may be applied throughout manifold 920 via fluid pressure source 1004. Ion exchanger 22 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO system 1020 may be exposed to a fluid from fluid pressure source 1004 for a period of time, such as, but not limited to, about 1 second to about 5 seconds, about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, or greater than about 30 seconds. In some embodiments, a period of time may be between about 1 minute to about 10 minutes or greater. One or more resins of ion exchanger system 1020 may be dried due to a flow of fluid form fluid pressure source 1004. In some embodiments, a computing device may be configured to perform a washing process. A washing process may occur after one or more steps within a purification process. A washing process may include rinsing a fluid through manifold 1020. For instance, there may be a valve between any of valves 900A-D that may be fluidically coupled to a water bag, which may be referred to as a washing valve. A washing valve may have a first and second port fluidically coupled to manifold 920 with a third port fluidically coupled to a water bag. A washing valve may be operated by a computing device to open and / or close one or more ports to allow a flow of water within manifold 920. In some embodiments, a flow of water may occur through all of valves 900A-D and throughout an entirety of manifold 920. In other embodiments, a washing valve may be placed between any of valves 900A-D and may be operated to wash one or more of pathway segments 930A-C.

[0075] In some embodiments, a computing device may operate cassette 1000 to perform a conditioning process. A conditioning process may include operating one or more valves fluidically coupled to manifold 920 and a conditioning solution. Valves fluidically coupled to a conditioning solution may be referred to as “conditioning valves”. In some embodiments, one or more conditioning valves may be placed between valve 900A and valve 900B. One or more conditioning valves may be operated to allow a flow of conditioning solution into manifold 920 and through valve 900B into ion exchanger system 1020. A computing device may close off one or more ports of valves 900A, 900E, 900F, and / or 900G, while opening a port three or more ports of a washing valve to allow a conditioning solution to flow through valve 900B into ion exchanger system 1020. Conditioning solutions may include, but are not limited to, NaCl, HCl, water, or other solutions. In some embodiments, a computing device may operate one or more valves to dry ion exchanger system 1004 after a conditioning process is performed. For instance, a flow of fluid generated by fluid pressure source 1004 may flow into ion exchanger system 1020 through one or more valves, which may dry out ion exchanger system 1020. A flow of fluid from 23 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO pressure source 1004 into ion exchanger system 1020 may occur for about, but not limited to, about 1 second to about 5 seconds, about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, or greater than about 30 seconds. In some embodiments, a cleaning process may be performed after a drying of ion exchanger system 1020.

[0076] Manifold 920 may be connected to an impurity collection vial through a fifth valve. A fifth valve may be positioned between valve 900C and valve 900D and may be fluidically coupled to pathway segment 930C through one or more ports. Impurities may flow through a fifth valve into an impurity collection vial through one or more ports of the fifth valve. Impurities may include metal impurities, in some embodiments, such as Al, Cd, Co, Fe, Fe, Pt, Ni, Zn, Cr, Mn, Y, Ag, and Sn, particularly Ni, such asnatNi,60Ni,61Ni, and62Ni. Impurities may flow in direction D1 into a first port of a fifth valve and may be redirected to flow in a direction perpendicular to D1 through a second port of a fifth valve. In some embodiments, a plurality of impurity vials and / or waste chambers, each connected to a respective valve, may be operated. One or more impurities, e.g., nickel, or other forms of waste may be recyclable for one or more subsequent processes. 3.5. Purification of A Metal Radionuclide and Formation of a Pharmaceutical Composition thereof using a Cassette

[0077] Referring now to FIG.11, a system for purification of a metal radionuclide and formation of a pharmaceutical composition of a metal radionuclide is presented. System 1000 may be structurally the same as described above with reference to FIG.10 with the addition of valves 900E-G, second pressure source 1032, and second vessel 1056.

[0078] As described above with reference to FIG.10, purified solution 1028 may flow in direction D1 through valve 900D and into vessel 1024. Vessel 1024 may be fluidically coupled to a port of valve 900F. A port of valve 900F fluidically coupled to vessel 1024 may be perpendicular to manifold 920. In some embodiments, a flow of purified solution 1028 into vessel 1024 and / or into valve 900F may be perpendicular to a flow of fluid in a first direction, such as D1. Purified solution 1028 may flow into valve 900F at a port of valve 900F perpendicular to manifold 920. Pressure source 1004 may be shut off, which may stop a flow of fluid in direction D1 through manifold 920. In some embodiments, valve 900E may be fluidically coupled to second pressure source 1032. A port of valve 900E may be closed off from 24 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO manifold 920, such as from pathway segment 930B. Second pressure source 1032 may provide a fluid pressure that may enable a flow of fluid in direction D2 towards an inlet of manifold 920, opposite direction D1. Second pressure source 1032 may be a syringe or other device that may provide a fluidic pressure to purified solution 1028 within pathway segments 930F and / or 930A.

[0079] In some embodiments, second pressure source 1032 may be a liquid pressure source. For instance, a liquid may be pumped into valve 900E via second pressure source 1032. A liquid may include, but is not limited to, aqueous solutions of NaCl or HCl and / or dissolution reagents. Purified solution 1028 may flow through a port of valve 900F to a port of valve 900G through pathway segment 930F. A first port of valve 900G may be fluidically coupled to pressure source 1004 but may be closed. A second port of valve 900G may be fluidically coupled to manifold 920 and may allow for a flow of fluid in direction D2 into valve 900G. A third port of valve 900G may be open and may be perpendicular to manifold 920. A third port of valve 900G may be fluidically coupled to a second vessel. In some embodiments, a second vessel may include a precursor compound, e.g., an organic compound that is a radiotracer with the metal radionuclide not yet chelated therein. Purified solution 1028 may flow into second vessel 1056 through valve 900G, which may prepare a radiopharmaceutical composition including a purified metal radionuclide chelated by an organic compound (i.e., collectively, a radiopharmaceutical or a radiotracer). In some embodiments, a total time to form a radiopharmaceutical composition using manifold 920 may be about, but not limited to, about 10 minutes or less, about 9 minutes or less, about 8 minutes or less, about 7 minutes or less, about 6 minutes or less, or about 5 minutes or less. In some embodiments, second vessel 1056 may be designed to hold up to, but not limited to, about 1 mL to about 2 mL of fluid, about 2 mL to about 3 mL of fluid, about 3 mL to about 4 mL of fluid, about 4 mL to about 5 mL of fluid, or greater than about 5 mL of fluid. Second vessel 1056 may be chemically isolated from vessel 1024. For instance, second vessel 1056 may be physically separate from vessel 1024, which may reduce or prevent possible cross- contamination of one or more chemicals and / or chemical compounds between vessel 1024 and second vessel 1056.

[0080] In some embodiments, fluid 1016 may have a starting radioactivity. For instance, fluid 1016 may have a radioactivity before it enters manifold 920. A starting radioactivity of fluid 1016 may be about, but is not limited to, about 1 GBq to about 1.5 GBq, about 1.5 GBq to about 2 GBq, about 2GBq to about 2.5 GBq, about 2.5 GBq to about 3 GBq, about 3 GBq to about 3.5 25 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO GBq, about 3.5 GBq to about 4 GBq, about 4 GBq to about 4.5 GBq, about 4.5 GBq to about 5 GBq, about 5 GBq to about 5.5 GBq, about 5.5 GBq to about 6 GBq, about 6 GBq to about 6.5 GBq, about 6.5 GBq to about 7 GBq, about 7 GBq to about 7.5 GBq, about 7.5 GBq to about 8 GBq, about 8 GBq to about 8.5 GBq, about 8.5 GBq to about 9 GBq, about 9 GBq to about 9.5 GBq, about 9.5 GBq to about 10 GBq, about 10 GBq to about 10.5 GBq, about 10.5 GBq to about 11 GBq, about 11 GBq to about 11.5 GBq, about 11.5 GBq to about 12 GBq, about 12 GBq to about 12.5 GBq, about 12.5 GBq to about 13 GBq, about 13 GBq to about 13.5 GBq, about 13.5 GBq to about 14 GBq, about 14 GBq to about 14.5 GBq, about 14.5 GBq to about 15 GBq, or greater than about 15 GBq.

[0081] In some embodiments, fluid 1016 may have a starting radioactivity of about 45 GBq to about 50 GBq, about 50 GBq to about 55 GBq, about 55 GBq to about 60 GBq, about 60 GBq to about 65 GBq, about 65 GBq to about 70 GBq, about 70 GBq to about 75 GBq, about 75 GBq to about 80 GBq, about 80 GBq to about 85 GBq, about 85 GBq to about 90 GBq, about 90 GBq to about 95 GBq, about 95 GBq to about 100 GBq, or greater than 100 GBq. For instance, a starting radioactivity of fluid 1016 may be between about 100 GBq to about 200 GBq or greater.

[0082] In some embodiments, purified solution 1028 may have a radioactivity of about, but not limited to, about 1 GBq to about 10 GBq, about 10 GBq to about 20 GBq, about 20 GBq to about 30 GBq, about 30 GBq to about 40 GBq, about 40 GBq to about 50 GBq, about 50 GBq to about 60 GBq, about 60 GBq to about 70 GBq, about 70 GBq to about 80 GBq, about 80 GBq to about 90 GBq, about 90 GBq to about 100 GBq, or greater than about 100 GBq.

[0083] Purification of fluid 1016 using cassettes and methods described herein may allow for a conservation of radioactivity of purified solution 1028 relative to fluid 1016. For instance, purified solution 1028 may conserve about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 80% to about 90%, or greater than about 90% a starting radioactivity of fluid 1016. Manifold 920 may allow for a purification of fluid 1016 into purified solution 1028 in about less than, but not limited to, about 60 minutes to about 50 minutes, about 50 minutes to about 40 minutes, about 40 minutes to about 30 minutes, about 30 minutes to about 20 minutes, about 20 minutes to about 10 minutes, or less than about 10 minutes. 26 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0084] In some embodiments, cassette 1000 may have a cassette layout. A cassette layout may be an arrangement of one or more elements of cassette 1000 in which a purification process occurs on a first side of cassette 1000 and a radiolabeling process occurs on a second side of cassette 1000, opposite the first side. A first side of cassette 1000 may be a right side of cassette 1000 relative to a positioning of first valve while a second side of cassette 1000 may be a left side of cassette 1000 closest to pressure source 10004. A cassette layout may reduce a risk of contamination of a final product produced by cassette 1000 through segmenting one or more fluid pathways and / or valves of cassette 1000. 3.6. Cassette Examples

[0085] Non-limiting examples of the cassette are provided in FIGs.12-14. As a non-limiting example, the cassette of the present disclosure may be configured to perform at least two main functions: purifying a metal radionuclide (see e.g., FIG.12), and radiolabeling a precursor compound with the metal radionuclide (see e.g., FIG.13), all in a single cassette (see e.g., FIG. 14). A detailed workflow of the cassette for purifying a radionuclide and radiolabeling a precursor compound with the radionuclide to produce a radiopharmaceutical composition is provided in FIG.14.

[0086] As shown in FIG.14, the layout of the cassette may include two main sections on the backbone (e.g., manifold). The right side of the cassette (see FIG.14 red rectangle) may be reserved for the purification of the radioisotope in the present example61Cu. The left side of the cassette (see FIG.14 valve 10 onward) may be reserved for the radiolabeling of the desired tracer (e.g., precursor compound) with the purified61Cu. In some embodiments, the layout shown in FIG.14 fits all required consumables for purification and radiolabeling on the cassette. In some embodiments, there is no contamination of the radiolabeling side of the cassette with the by-products of the radionuclide purification since they are separated and the purified radionuclide (e.g.,61Cu in this example) may be stored externally in a reaction vial (second vessel) and may enter the cassette through a pristine inlet at valve 10.

[0087] In some embodiments, the metal radionuclide that is received by the cassette is a crude solution. The crude solution may be prepared by irradiative bombardment of a target metal adhered to a niobium backing, where such irradiative bombardment may produce an irradiative bombardment product metal. The irradiative bombardment product metal may be dissolved in 27 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO solution to produce a crude solution comprising a mixture of metals containing a target radionuclide and one or more metal impurities. Dissolving of an irradiative bombardment product metal may occur in the first vessel, also referred to as a “Dissolution Vessel.”

[0088] FIGs.12-14 provide a schematic of cassette for purifying a radionuclide and radiolabeling the precursor compound to the radionuclide to produce a pharmaceutical composition. The cassette may include fluid pathways, vessels, valves, and ports for receiving reagent vials, buffers, cannulas, metal solutions, syringes, plungers, pumps, or nitrogen gas, as well as any solid-phase extraction cartridges (e.g., ion exchangers) used for purification of the radionuclide(s).

[0089] In some embodiments, the cassette as shown in FIGs.12-14 include a manifold comprising 25, 3 way / 3 position stopcocks valves 1-25, respectively. Manifold valves 1-25 are also referred to as their manifold positions 1-25, respectively.

[0090] In some embodiments, one or more valves within the manifold of the cassette have female luer connectors projecting up therefrom. In some embodiments, one or more valves have an elongate open vial housing upstanding therefrom and support an upstanding cannula therein for piercing a reagent vial inserted in the respective vial housing. Movement of the reagent vial to be pierced by the respective cannula may be performed under actuation by a synthesizer device, such as, but not limited to a FASTlab device. In some embodiments, one or more valves support an elongate open syringe barrel upstanding therefrom.

[0091] In some embodiments, valves 1-25 include three open ports opening to adjacent manifold valves and to their respective luer connectors, cannulas, and syringe barrels. Each valve may include a rotatable stopcock which may put any two of the three associated ports in fluid communication with each other while fluidically isolating the third port. In some embodiments, the cassette comprising the manifold further includes, at opposing ends thereof, first and second socket connectors, each defining ports at either end of the manifold, respectively. In some embodiments, the manifold and stopcocks of valves 1-25 are desirably formed from a polymeric material, e.g. PP, PE, Polysulfone, Ultem, or Peek.

[0092] The cassette of the present disclosure may be designed to be adaptable for synthesizing radiopharmaceuticals with minimal customer installation and connections. In some embodiments, the cassette of the present disclosure comprises one or more: vessels, reagent 28 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO vials, cartridges, filters, syringes, tubings, and connectors, for purifying a radionuclide and preparing a radiopharmaceutical composition comprising a radionuclide chelated to a precursor compound according to the present disclosure. Connections may be automatically made to the reagent vials by driving the septa thereof onto penetrating spikes to allow the synthesizer access to use the reagents.

[0093] FIG.14 depicts a non-limiting example of a cassette of the present disclosure for the purification of a radionuclide and / or production of a radiopharmaceutical composition. The cassette may include a polymeric housing having a planar major front surface and defining a housing cavity in which the manifold comprising a plurality of valves may be supported. In some embodiments, the manifold valve 11 of the cassette supports a barrel wall for a syringe pump. The syringe pump can include fluids flowing into and out of the pump, such as HCl (e.g., 6 M of HCl), NaCl, and / or dissolution reagents. In some embodiments, manifold valve 24 supports the elongate barrel of a syringe pump. In some embodiments, the cassette is connected to a syringe pump that includes an elongate syringe rod which is reciprocally moveable by the synthesis device to draw and pump fluid through manifold and the attached components.

[0094] In a non-limiting example, when the cassette of FIG.14 is in use, a crude solution (e.g., dissolved bulk matrix) comprising a mixture of metals including at least one metal radionuclide and one or more metal impurities may be introduced from a first vessel and into the cassette manifold at valve 17. In some embodiments, a Solid Target Valve Box (STVB) may be implemented. For instance, a vial may be connected to a STVB which may be united with mechanical pivot points. In this example, the vial may be connected to STVB4 as shown in FIG. 14. In some embodiments, the STVB can include different concentrations of HCl and H2O2that can be added to the bulk matrix, the cassette, and / or a FASTlab synthetic device. The STVB box is configured to hold additional space for reagents, chemicals etc. and is driven by the FASTlab module. As can be seen in FIG.14, the STVB box may also include STVB3 which holds a molar amount of HCl, STVB2 which holds a molar amount of H2O2, and STVB1 which holds a molar amount of HCl. In some embodiments, the solutions in STVB1, STVB2, STVB3 can be used to dissolve the crude radionuclides outputted from a cyclotron and into a solution to produce a dissolved bulk matrix or crude solution. In some embodiments, the first vessel is connected to the STVB (e.g., STVB4 of FIG.14). In some embodiments, a vial connected to the SVTB may be additionally connected to an acid trap of STVB. A vial connected to the SVTB 29 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO may be designed as a storage for one or more chemicals used in dissolution of a target material. In some embodiments, a vial connected to the SVTB may be designed as a reservoir to hold dissolution fluid, such as a dissolved bulk matrix. In some embodiments, once dissolution is complete, dissolution fluid may travel from SVTB into a valve, such as valve 17. Purification

[0095] The crude solution moves from the first vessel into a first ion exchanger at valve 19 for a first purification step, followed by movement of the solution containing the metal radionuclide and one or more metal impurities into a second ion exchanger at valve 21. The pH of the crude solution may be adjusted by flowing one or more ion exchanger columns from valves 13, 14, 15, and / or 16 through the first and second ion exchangers.

[0096] A first ion exchanger (e.g., TBP) may be positioned at manifold position 19 while a second ion exchanger (e.g., TK201) may be positioned at manifold position 21. In some embodiments, the first ion exchanger is used for primary purification of the metal radionuclide.

[0097] In some embodiments, valves 13, 14, 15, and 16 contain reagents that may be required for purification of the metal radionuclide. In some embodiments, valve 13 is configured to hold a vial containing an aqueous NaCl solution. In some embodiments, valve 14 is configured to hold a vial containing HCl. In some embodiments, valve 16 is configured to a vial containing HCl. In some embodiments, a water vial connected at the spike of manifold position 15, and a product collection vessel connected at manifold position 5. In some embodiments, the vial housing at manifold valve 15 receives an elongate hollow spike extension which is positioned over the cannula at manifold valve 15 and provides an elongate water bag spike a at the free end thereof. The spike may pierce a cap of a water bottle containing water for both diluting and rinsing the fluid flowpaths of the cassette.

[0098] In some embodiments, one or more of the plurality of valves comprises aqueous ethanol (e.g., the valve housed within a valve). In some embodiments, aqueous ethanol is used for the elution of the radionuclide from the first or second ion exchanger.

[0099] In some embodiments, the second ion exchanger is used for secondary purification. In some embodiments, a flow rate of about 1 mL / min, about 1.2 mL / min, about 1.4 mL / min, about 1.5 mL / min, about 1.6 mL / minute, about 1.7 mL / minute, at about 1.8 mL / minute, about 1.9 30 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO mL / min, or about 2 mL / min is used to flow an amount (e.g., 1.5-5 mL) of HCl (e.g., 0.05 M) through the TBP ion exchanger and / or the TK201 ion exchanger to purify and elute the metal radionuclide (e.g.,61Cu). FIG.14 provides a workflow of the fluid streams that go into the TBP ion exchanger and the TK201 ion exchanger for purification of the metal radionuclide. For example, in some embodiments, an amount of HCl moves from valve 14 or 16 through valve 18 where it is then moved into the first ion exchanger (TBP). An amount of HCl may also move from valve 14 or 16 through valve 20 and into a second ion exchanger (TK201). In some embodiments, dissolved bulk solution containing iron moves through the TK201 second ion exchanger. Radiolabeling

[0100] In some embodiments, the eluent containing the target metal radionuclide is directly transferred into a reactor vial (e.g., second vessel) until needed for the radiolabeling. In some embodiments, the final volume of the [61Cu]CuCl2solution ranges from 1 to 5 mL (e.g., 3.2 ml) in 0.05 M HCl, resulting in a pH between 1 and 2 (e.g., 1 to 1.6) .

[0101] In some embodiments, after the crude solution has gone through valves 19 and 21 for purification, one or more metal impurities, such as, in this case, nickel, flows through valve 21 and into valve 22, where it is removed from the crude solution. In some embodiments, the nickel then flows out of valve 22 and into a waste vessel (e.g., fifth vessel) e.g. by means of tubing attached from valve 22 to a waste vessel. In some embodiments, the collected nickel is of sufficient purity that it can be recycled for future bombardment uses. For example, the collected nickel may have a chemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% Additional valves within the cassette can include lines (tubes) connected to additional waste vessels (e.g., as shown in FIG.14, removal of additional metals such as Cobalt, and additional solutions such as NaCl out of valve 25 via vacuum pressure and into a separate waste vessel (waste exhaust / vacuum pump of FIG. 14). In some embodiments, a Luer connector of manifold valve 25 is connected to a length of a tubing to a third port of a vessel. In some embodiments, this vessel is a waste vessel.

[0102] The remaining solution may be a purified metal radionuclide which may be eluted from the second exchanger and outputted from valve 23 into a vessel (e.g., second vessel or “reactor vial Cu-61 eluent” of FIG.14). 31 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0103] In some embodiments, an amount of the purified metal radionuclide is introduced back into the cassette manifold via inlet tube at valve 10. In some embodiments, the purified metal radionuclide moves from valve 10 through valve 9 and is then mixed with a buffer before flowing back into valve 7 to be outputted into a third vessel (e.g. reaction vial). In other embodiments, the purified metal radionuclide flows from valve 10 to valve 7 and is then outputted into a third vessel (e.g., reaction vial). The third vessel may be where the components needed to produce the radiopharmaceutical composition may be mixed. The third vessel may include the purified metal radionuclide, at least one buffer (e.g., already in the third vessel or a buffer at valve 9 will be outputted and introduced into the third vessel), optionally at least one pharmaceutically acceptable salt, and the precursor compound (e.g., chelator-functionalized PSMA I&T). In some embodiments, the pharmaceutically acceptable salts such as saline and / or ascorbic acid are added to the third vessel from valve 4.

[0104] As shown in FIG.14, the precursor compound may be inputted into the cassette at valve 8. In some embodiments, the precursor compound is inputted into the cassette manifold as a solution. In some embodiments, the precursor compound is in powder form, so during the step of radiolabeling the precursor compound, the precursor compound is mixed with a buffer in a vial connected to valve 8. For example, the precursor compound can be present in lyophilized form, and when ready for radiolabeling the precursor compound, the precursor compound is dissolved by adding an amount (e.g., 0.5-5 mL) of a buffer (e.g., 0.5 M NaOAc + 20 µg / L ascorbic acid) to the vial containing the precursor compound. Once mixed, the contents of the vial is transferred to the third vessel (e.g., reaction vessel). The buffer can flow from valve 9, through valve 8, and into the vial connected to valve 8. In some embodiments, the final precursor compound inputted into the cassette for radiolabeling is in solution. The precursor compound in solution may be inputted back into the cassette manifold at valve 8. The precursor compound may move from valve 8 and into valve 7 where it may be outputted into the third vessel. In some embodiments, once the components in the third vessel are adequately mixed, a radiopharmaceutical composition may be produced. In some embodiments, the resulting radiopharmaceutical composition may flow out of the third vessel and into the cassette manifold at valve 7, then flows from valve 7 and into valve 5. The radiopharmaceutical composition may flow out of valve 7 and pass through a filter and into a resulting product vial (fourth vessel). In some embodiments, the filter is configured to sterilize the radiopharmaceutical composition. 32 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 3.7. System

[0105] Aspects of the present disclosure include a system for purifying a metal radionuclide and radiolabeling a radionuclide with a precursor compound.

[0106] In one aspect, the system of the present disclosure includes an automated system comprising: a particle accelerator for irradiative bombardment (e.g., bombardment with protons, neutrons, or deuterons) of a target metal adhered to a niobium backing, wherein irradiative bombardment of the target metal produces a metal radionuclide; means for dissolving the metal radionuclide into solution to produce a crude solution comprising a mixture of metals, wherein the mixture of metals comprises the metal radionuclide and one or more metal impurities; and a cassette of the present disclosure.

[0107] In some embodiments, the metal radionuclide produced by irradiative bombardment of the target metal adhered to a niobium backing is described in International Application No. PCT / US2023 / 75064 (filed Sep.25, 2023), which is hereby incorporated by reference in its entirety. The composition of the starting material for irradiative bombardment (e.g., niobium coin with a target metal adhered thereto) is described herein and also in U.S. Provisional Application No.63 / 569,089 (filed Mar.22, 2024), e.g., in “Appendix A” therein, which is hereby incorporated by reference in its entirety.

[0108] The cassette of the present disclosure is attachable to a synthesis device, such as FASTLab, which cooperatively engages the cassette so as to be able to actuate each of the stopcocks and syringes to drive a source fluid with a radionuclide through the cassette for performance of a chemical synthesis process.

[0109] In some embodiments, the system comprises a synthetic device. The synthesis device can provide heat to a vessel of cassette, if needed, for chemical reactions. The synthesizer is programmed to operate pumps, syringes, valves, heating element, and controls the provision of nitrogen and application of vacuum to the cassette so as to direct the source fluid into mixing with the reagents, performing the chemical reactions, through the appropriate purification cartridges, and selectively pumping the output radionuclide, precursor compound, radiopharmaceutical composition and waste fluids into appropriate vial receptacles outside the cassette. In some embodiments, the fluid collected in the output vial is typically input into another system for either purification and / or dispensation. After product dispensation, the 33 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO internal components of cassette are typically flushed to remove latent radioactivity from the cassette.

[0110] The synthesizer includes a radioisotope delivery conduit which extends from a source of the radioisotope, typically either vial or the output line from a cyclotron to a delivery plunger. The delivery plunger is moveable by the synthesizer from a first raised position allowing the cassette to be attached to the synthesizer, to a second lowered position where the plunger is inserted into the housing at manifold valve 6. The plunger provides sealed engagement with the housing at manifold valve 6 so that the vacuum applied by the synthesizer to manifold will draw the radioisotope through the radioisotope delivery conduit and into manifold for processing. Additionally, prior to beginning the synthesis process, arms from the synthesizer will press the reagent vials onto the cannulas of manifold. The synthesis process may then commence.

[0111] In some embodiments, the cassette is mated to an automated synthesizer having rotatable arms which engage each of the stopcocks of valves 1-25 and can position each in a desired orientation throughout cassette operation. The synthesizer also includes a pair of spigots, one of each of which insert into ports of connectors at both ends of the manifold in fluid-tight connection. At least one of the spigots provide a source of nitrogen and an another spigot to provide a vacuum to manifold so as to assist in fluid transfer therethrough and to operate cassette in accordance with the present disclosure. The free ends of the syringe plungers are engaged by cooperating members from the synthesizer, which will then apply the reciprocating motion thereto within the syringes. A bottle containing water is fitted to the synthesizer then pressed onto a spike to provide access to a fluid for driving compounds under operation of the various- included syringes. In some embodiments, the one or more vessels can be placed within a well of the synthesizer and the product collection vessel and waste vessel are connected. 3.8. Pharmaceutical Compositions

[0112] Aspects of the present disclosure include methods for purifying a radionuclide (e.g., used interchangeably herein as a “radiotracer”) and preparing a pharmaceutical (e.g., radiopharmaceutical) composition comprising radiolabeling a radionuclide to a precursor compound to produce the pharmaceutical composition.

[0113] In one aspect, the present disclosure provides pharmaceutical compositions comprising a radiotracer ([61Cu]Cu-NODAGA-PSMA I&T) that has the structure 34 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO or is a

[0114] The pharmaceutical compositions are useful in the methods described herein, e.g., for generating radiographic images of subjects diagnosed with or suspected of having a PSMA- expressing tumor following administration of the pharmaceutical composition, e.g., by intravenous (i.v.) administration. Copper 61, also known as61Cu, has a half-life of 3.3 hours, which permits a broader distribution range and usage of61Cu-labelled radiotracers than68Ga-labelled or18F- labelled imaging agents. For example, pharmaceutical compositions containing61Cu-labelled radiotracers of the present disclosure have a distribution range of more than 700 miles, allowing less than 10 production sites to provide radioisotopes to the entire continental United States.

[0115] In certain embodiments, the radiotracer has the structureor is a 35 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0116] In certain embodiments, the pharmaceutical composition comprises the radiotracer in an amount ≥ 1 µg, e.g., ≥ 10 µg, ≥ 20 µg, ≥ 30 µg, ≥ 40 µg, ≥ 50 µg, ≥ 60 µg, ≥ 70 µg, or ≥ 80 µg.

[0117] In certain embodiments, the pharmaceutical composition comprises the radiotracer in an amount from 1 µg to 100 µg, e.g., from 20 µg to 90 µg, from 20 µg to 80 µg, from 20 µg to 70 µg, from 20 µg to 60 µg, from 20 µg to 50 µg, from 20 µg to 40 µg, from 20 µg to 30 µg, from 30 µg to 100 µg, from 30 µg to 90 µg, from 30 µg to 80 µg, from 30 µg to 70 µg, from 30 µg to 60 µg, from 30 µg to 50 µg, from 30 µg to 40 µg, from 40 µg to 100 µg, from 40 µg to 90 µg, from 40 µg to 80 µg, from 40 µg to 70 µg, from 40 µg to 60 µg, from 40 µg to 50 µg, from 50 µg to 100 µg, from 50 µg to 90 µg, from 50 µg to 80 µg, from 50 µg to 70 µg, from 50 µg to 60 µg, from 60 µg to 100 µg, from 60 µg to 90 µg, from 60 µg to 80 µg, from 60 µg to 70 µg, from 70 µg to 100 µg, from 70 µg to 90 µg, from 70 µg to 80 µg, from 80 µg to 100 µg, from 80 µg to 90 µg, or from 90 µg to 100. In certain embodiments, the pharmaceutical composition comprises 1 µg to 50 µg of the radiotracer, e.g., from 1 µg to 30 µg, from 1 µg to 10 µg, or from 1 µg to 5 µg.

[0118] In certain embodiments, the pharmaceutical composition is in the form of a liquid, e.g., a solution, such as an aqueous solution.

[0119] In certain embodiments, the pharmaceutical composition comprises an aqueous vehicle, i.e., a medium or carrier comprising at least a minimal amount of water, in which all the other components are dissolved. Exemplary aqueous vehicles include, e.g., deionized water, saline, phosphate buffer, citrate buffer, malate buffer, tartrate buffer, balanced salt solution, salts of organic acids, combinations of organic acids and salts of organic acids (e.g., tribasic sodium citrate and citric acid, malic acid and sodium malate, and potassium sodium tartrate and tartaric acid), and combinations thereof. In certain embodiments, the aqueous vehicle comprises saline solution, e.g., isotonic saline solution.

[0120] In certain embodiments, the pharmaceutical composition has a total volume of 2 to 15 mL, e.g., from 2 mL to 14 mL, from 2 mL to 12 mL, from 2 mL to 10 mL, from 2 mL to 8 mL, from 2 mL to 6 mL, from 2 mL to 4 mL, from 4 mL to 15 mL, from 4 mL to 14 mL, from 4 mL to 12 mL, from 4 mL to 10 mL, from 4 mL to 8 mL, from 4 mL to 6 mL, from 6 mL to 15 mL, from 6 mL to 14 mL, from 6 mL to 12 mL, from 6 mL to 10 mL, from 8 mL to 15 mL, from 8 mL to 14 mL, from 8 mL to 12 mL, from 8 mL to 10 mL, from 12 mL to 15 mL, or from 12 mL to 14 mL. In 36 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO certain embodiments, the pharmaceutical composition has a total volume from 2 mL to 5 mL or from 8 to 12 mL.

[0121] The total volume of the pharmaceutical composition comprises one or more unit doses for administration to the subject in the methods described herein, e.g., one dose, two doses, or three or more doses. In certain embodiments, the pharmaceutical composition comprises from 2 mL to 5 mL, corresponding to one unit dose for administration. In certain embodiments, the pharmaceutical composition comprises from 8 mL to 12 mL, corresponding to two unit doses for administration. 3.8.1. Properties

[0122] In certain embodiments, the pharmaceutical composition has an activity of ≥ 25 MBq, e.g., ≥ 30 MBq, ≥ 50 MBq, ≥ 75 MBq, ≥ 100 MBq, ≥ 150 MBq, ≥ 200 MBq, ≥ 250 MBq, ≥ 300 MBq, ≥ 350 MBq, ≥ 400 MBq, ≥ 450 MBq, ≥ 500 MBq, ≥ 750 MBq, or ≥ 1,000 MBq.

[0123] In certain embodiments, the pharmaceutical composition has an activity from 25 MBq to 1,500 MBq, e.g., from 25 MBq to 1,000 MBq, from 25 MBq to 750 MBq, from 25 MBq to 500 MBq, from 25 MBq to 300 MBq, from 25 MBq to 200 MBq, from 25 MBq to 100 MBq, from 50 MBq to 1,500 MBq, from 50 MBq to 1,000 MBq, from 50 MBq to 750 MBq, from 50 MBq to 500 MBq, from 50 MBq to 300 MBq, from 50 MBq to 200 MBq, from 50 MBq to 100 MBq. In certain embodiments, the pharmaceutical composition has an activity from 100 MBq to 300 MBq. In certain embodiments, the pharmaceutical composition has an activity from 100 MBq to 200 MBq.

[0124] In certain embodiments, the pharmaceutical composition has an activity from 700 MBq to 1,500 MBq, e.g., from 700 MBq to 1,200 MBq, from 700 MBq to 1,000 MBq, from 750 MBq to 1,500 MBq, from 750 MBq to 1,200 MBq, from 750 MBq to 1,000 MBq, from 1,000 MBq to 1,500 MBq, from 1,200 MBq to 1,500 MBq, or from 1,200 MBq to 1,500 MBq. In some embodiments, the pharmaceutical composition has an activity from between about 1,500 MBq to about 6,000 MBq.

[0125] In certain embodiments, the pharmaceutical composition has a radiotracer radiochemical purity of ≥ 90% at 12 hours after end of synthesis, e.g., ≥ 93%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%. 37 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0126] In certain embodiments, the pharmaceutical composition has a radiotracer radiochemical purity from 90% to 99% at 12 hours after end of synthesis, e.g., from 90% to 98%, from 90% to 97%, from 90% to 95%, from 90% to 93%, from 93% to 99%, from 93% to 98%, from 93% to 97%, from 93% to 95%, from 95% to 99%, from 95% to 98%, from 95% to 97%, from 97% to 99%, or from 98% to 99%. In certain embodiments, the pharmaceutical composition has a61[Cu]Cu radionuclidic purity at end of synthesis of ≥ 95%, e.g., ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%. In certain embodiments, the pharmaceutical composition has a61[Cu]Cu radionuclidic purity at end of synthesis of ≥ 97%.

[0127] In certain embodiments, the pharmaceutical composition has a61[Cu]Cu radionuclidic purity at end of synthesis of ≥ 98%, e.g., ≥ 99%, ≥ 99.5%, ≥ 99.6%, ≥ 99.7%, ≥ 99.8%, or ≥ 99.9%. In certain embodiments, the pharmaceutical composition has a61[Cu]Cu radionuclidic purity at end of synthesis of ≥ 99.99%.

[0128] In certain embodiments, the pharmaceutical composition has a radiocobalt activity content purity of the pharmaceutical composition at end of synthesis of ≤ 0.1%, e.g., ≤ 0.05%, ≤ 0.02%, ≤ 0.01%, ≤ 0.005% or ≤ 0.001%.

[0129] In certain embodiments, the pharmaceutical composition has at least one of a56[Co]Co specific activity or58[Co]Co specific activity at end of synthesis of ≤ 1,500 Bq / g, e.g., ≤ 1,200 Bq / g, ≤ 1,000 Bq / g, ≤ 800 Bq / g, ≤ 400 Bq / g, or ≤ 200 Bq / g.

[0130] In certain embodiments, the pharmaceutical composition has at least one of a56[Co]Co specific activity or58[Co]Co specific activity at end of synthesis from 200 Bq / g to 1,500 Bq / g, e.g., from 200 Bq / g to 1,200 Bq / g, from 200 Bq / g to 1,000 Bq / g, from 200 Bq / g to 800 Bq / g, from 200 to 600 Bq / g, or from 200 Bq / g to 400 Bq / g.

[0131] In certain embodiments, the pharmaceutical composition has a56[Co]Co specific activity of ≤ 100 Bq / g, e.g., ≤ 50 Bq / g, ≤ 25 Bq / g, ≤ 10 Bq / g, ≤ 8 Bq / g, ≤ 4 Bq / g, or ≤ 2 Bq / g.

[0132] In certain embodiments, the pharmaceutical composition has a56[Co]Co specific activity of from 1 Bq / g to 100 Bq / g, e.g., from 1 Bq / g to 50 Bq / g, from 1 Bq / g to 25 Bq / g, from 1 Bq / g to 10 Bq / g, from 1 Bq / g to 8 Bq / g, or from 1 Bq / g to 4 Bq / g.

[0133] In certain embodiments, the pharmaceutical composition has a58[Co]Co specific activity of ≤ 100 Bq / g, e.g., ≤ 50 Bq / g, ≤ 25 Bq / g, ≤ 10 Bq / g, ≤ 8 Bq / g, ≤ 4 Bq / g, or ≤ 2 Bq / g. 38 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0134] In certain embodiments, the pharmaceutical composition has a58[Co]Co specific activity of from 1 Bq / g to 100 Bq / g, e.g., from 1 Bq / g to 50 Bq / g, from 1 Bq / g to 25 Bq / g, from 1 Bq / g to 10 Bq / g, from 1 Bq / g to 8 Bq / g, or from 1 Bq / g to 4 Bq / g.

[0135] In certain embodiments, the pharmaceutical composition is characterized by a110mAg specific activity ≤ 0.1 Bq / g. In certain embodiments, the pharmaceutical composition is characterized by a108mAg specific activity ≤ 0.1 Bq / g. In certain embodiments, the pharmaceutical composition is characterized by a109Cd specific activity ≤ 0.1 Bq / g.

[0136] In certain embodiments, the pharmaceutical composition is characterized by at least two of: a110mAg specific activity ≤ 0.1 Bq / g, a108mAg specific activity ≤ 0.1 Bq / g, and a109Cd specific activity ≤ 0.1 Bq / g. In certain embodiments, the pharmaceutical composition is characterized by a110mAg specific activity of ≤ 0.1 Bq / g, a108mAg specific activity ≤ 0.1 Bq / g, and a109Cd specific activity ≤ 0.1 Bq / g.

[0137] In certain embodiments, the sum of the specific activities of the radionuclidic impurities in the pharmaceutical composition is ≤ 8,000 Bq / g, e.g., ≤ 5,000 Bq / g, ≤ 3,000 Bq / g, ≤ 1200 Bq / g, ≤ 1,000 Bq / g, ≤ 800 Bq / g, or ≤ 500 Bq / g.

[0138] In certain embodiments, the pharmaceutical composition comprises Al in an amount ≤ 1.2 ng / MBq. In certain embodiments, the pharmaceutical composition comprises Co in an amount ≤ 0.2 ng / MBq. In certain embodiments, the pharmaceutical composition comprises Fe in an amount ≤ 1.7 ng / MBq. In certain embodiments, the pharmaceutical composition comprises Pb in an amount ≤ 0.8 ng / MBq. In certain embodiments, the pharmaceutical composition comprises Zn in an amount ≤ 0.8 ng / MBq. In certain embodiments, the pharmaceutical composition comprises one or more of: an amount of Al ≤ 1.2 ng / MBq, an amount of Co ≤ 0.2 ng / MBq, an amount of Fe ≤ 1.7 ng / MBq, an amount of Pb ≤ 0.8 ng / MBq, or an amount of Zn ≤ 0.8 ng / MBq.

[0139] In certain embodiments, the pharmaceutical composition has an activity concentration ≥ 10 MBq / mL, e.g., ≥ 20 MBq / mL, ≥ 30 MBq / mL, ≥ 40 MBq / mL, ≥ 50 MBq / mL, ≥ 60 MBq / mL, ≥ 70 MBq / mL, ≥ 80 MBq / mL, or ≥ 90 MBq / mL.

[0140] In certain embodiments, the pharmaceutical composition has an activity concentration from 10 MBq / mL to 100 MBq / mL, e.g., from 10 MBq / mL to 50 MBq / mL, from 10 MBq / mL to 100 MBq / mL, or from 40 MBq / mL to 90 MBq / mL. 39 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0141] In certain embodiments, the apparent molar activity of the radiotracer is ≥ 1 MBq / nmol, e.g., ≥ 10 MBq / nmol, ≥ 20 MBq / nmol, ≥ 30 MBq / nmol, or ≥ 50 MBq / nmol. In certain embodiments, the apparent molar activity of the radiotracer is from 1 MBq / nmol to 50 MBq / nmol, e.g., from 1 MBq / nmol to 30 MBq / nmol, from 1 MBq / nmol to 20 MBq / nmol, from 1 MBq / nmol to 10 MBq / nmol, from 10 MBq / nmol to 50 MBq / nmol, from 10 MBq / nmol, to 30 MBq / nmol, from 10 MBq / nmol to 20 MBq / nmol, from 20 MBq / nmol to 50 MBq / nmol, from 20 MBq / nmol to 40 MBq / nmol, or from 20 MBq / nmol to 30 MBq / nmol.

[0142] In certain embodiments, the molar activity of the radiotracer is ≥ 1 MBq / nmol, e.g., ≥ 10 MBq / nmol, ≥ 20 MBq / nmol, ≥ 30 MBq / nmol, or ≥ 50 MBq / nmol. In certain embodiments, the molar activity of the radiotracer is from 1 MBq / nmol to 50 MBq / nmol, e.g., from 1 MBq / nmol to 30 MBq / nmol, from 1 MBq / nmol to 20 MBq / nmol, from 1 MBq / nmol to 10 MBq / nmol, from 10 MBq / nmol to 50 MBq / nmol, from 10 MBq / nmol, to 30 MBq / nmol, from 10 MBq / nmol to 20 MBq / nmol, from 20 MBq / nmol to 50 MBq / nmol, from 20 MBq / nmol to 40 MBq / nmol, or from 20 MBq / nmol to 30 MBq / nmol.

[0143] In certain embodiments, the pH of the pharmaceutical composition is from 5 to 7, e.g., from 5 to 6, from 5.5 to 6.5, or from 6 to 7. In certain embodiments, the pH of the pharmaceutical composition is 5, 6, or 7 + / - 0.1. 3.8.2. Excipients

[0144] In certain embodiments, the pharmaceutical composition comprises one or more excipients.

[0145] In certain embodiments, the pharmaceutical composition comprises one or more radiolytic inhibitors. Exemplary radiolytic inhibitors include, but are not limited to, ascorbic acid, gentisic acid, citric acid, N-tert-butyl-α-phenylnitrone (PBN), polyvinylpyrrolidone (PVP), ethanol, DMSA, cysteine, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinic acid, nicotinamide, salts of any of the foregoing, and combinations thereof.

[0146] In certain embodiments, the radiolytic inhibitor comprises ascorbic acid or a salt thereof. In certain embodiments, the radiolytic inhibitor comprises ascorbic acid. In certain embodiments, the radiolytic inhibitor comprises a salt of ascorbic acid, e.g., sodium ascorbate, calcium ascorbate, or potassium ascorbate. 40 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0147] In certain embodiments, the radiolytic inhibitor is present in the pharmaceutical composition in a concentration ≥ 1 μg / mL, e.g., ≥ 2 μg / mL, ≥ 3 μg / mL, ≥ 5 μg / mL, ≥ 8 μg / mL, ≥ 10 μg / mL, or ≥ 15 μg / mL.

[0148] In certain embodiments, the radiolytic inhibitor is present in the pharmaceutical composition in a concentration from 1 μg / mL to 15 μg / mL, e.g., from 3 μg / mL to 15 μg / mL, from 3 μg / mL to 10 μg / mL, from 5 μg / mL to 10 μg / mL, from 5 μg / mL to 15 μg / mL, from 5 μg / mL to 10 μg / mL, from 8 μg / mL to 15 μg / mL, from 8 μg / mL to 10 μg / mL, or from 10 μg / mL to 15 μg / mL.

[0149] In certain embodiments, the pharmaceutical composition comprises sodium chloride. In certain embodiments, sodium chloride is present in a concentration from 0.5 mg / mL to 50 mg / mL, e.g., from 5 mg / mL to 10 mg / mL, from 10 mg / mL to 30 mg / mL, or from 20 mg / mL to 50 mg / mL. In certain embodiments, the pharmaceutical composition comprises sodium chloride in a concentration from 1 mg / mL to 10 mg / mL or 1 mg / mL to 5 mg / mL.

[0150] In certain embodiments, the pharmaceutical composition comprises hydrochloric acid. In certain embodiments, the hydrochloric acid is present in the pharmaceutical composition in a concentration from 0.1 mg / mL to 1.0 mg / mL.

[0151] In certain embodiments, the pharmaceutical composition comprises sodium acetate. In certain embodiments, the sodium acetate is present in the pharmaceutical composition in a concentration from 5 mg / mL to 50 mg / mL, e.g., from 10 mg / mL to 25 mg / mL or from 15 mg / mL to 20 mg / mL.

[0152] In certain embodiments, the hydrochloric acid reacts with sodium acetate forming acetic acid and sodium chloride.

[0153] In certain embodiments, the pharmaceutical composition comprises 10-100 µg of the radiotracer, 3 μg / mL to 15 μg / mL of a radiolytic inhibitor (e.g., ascorbic acid or a salt thereof), and 1 mg / mL to 10 mg / mL sodium chloride.

[0154] In certain embodiments, the pharmaceutical composition comprises 10-100 µg of the radiotracer, 3 μg / mL to 15 μg / mL of a radiolytic inhibitor (e.g., ascorbic acid or a salt thereof), 1 mg / mL to 10 mg / mL sodium chloride, 0.1 mg / mL to 1.0 mg / mL hydrochloric acid; and 10 mg / mL to 25 mg / mL sodium acetate. 41 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0155] In some embodiments, the pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the pharmaceutical composition comprises mannitol.

[0157] In some embodiments, the pharmaceutical composition comprises ammonium acetate. 4. EXAMPLES 4.1. EXAMPLE 1: [61Cu]CuCl2Production

[0158] The production of the radionuclide was performed by irradiating a solid target of highly pure61Ni (purity > 99.42%) plated on a niobium coin backing with a proton beam.

[0159] Due to the relatively short half-lives (t1 / 268Ga = 68 min;18F = 110 min) and physical properties of the radionuclides, the key challenges in the PET tracer industry remain a) the imaging quality, b) reliability of supply and distribution of the radiopharmaceutical at low cost and c) low radiation burden to the patient. The distinctive advantage of using61Cu as a positron emitter, e.g., in a PET tracer, will not only ensure a) good imaging quality due to its physical properties (low mean positron energy) but also the possibility of delayed imaging, expected to improve the diagnostic sensitivity due to the washout of radioactivity from the background, thus improved image contrast, b) a large distribution radius due to its relatively long half-life (t1 / 261Cu = 205.5 min) while c) still keeping the radiation burden to the patient at a minimum. Provided herewith is an enabling description of new processes to produce highly pure61Cu, in the form of [61Cu]CuCl2, to be used in radiopharmaceutical applications, e.g., as a positron emitter in a PET tracer, in high activity concentration and volumes.

[0160] Trace metals and cold copper compete with61Cu to bind a chelator (for example, NODAGA) in this order: cold Cu(II) (i.e., stable isotopes) > Zn(II) > Fe(III) > Sn(IV) > Ti(IV) > Al(III.). The competition from these trace metals and cold copper decreases the tracer's radiolabeling yield and radiochemical purity significantly. Frequent sources of trace metals are the raw nickel metal powder itself, especially isotopically enriched nickel, reagents, and any metals in instruments used, such as iron. The purification process (ion-exchange columns) removes much of the trace metals except for cold (of particular relevance are stable isotopes69Cu and65Cu), which passes through into the product fraction by being the same element as the desired61Cu. One way of preventing cold copper contamination and the associated reduction in chemical purity is to pass 42 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO the dissolved nickel raw material (stable isotopes) through the process and separate the cold copper from the nickel before plating (see FIG. 8 for ICP-MS analysis). Table 1 displays the chemical purity of the [61Cu]CuCl2by either bombardment ofnatNi or61Ni on a niobium backing and the resulting impurity profile. Table 1. Chemical Purity of61Cu transmuted fromnatNi vs.61Ni. ng / MBq Cu-61 from nat-Ni Cu-61 from Ni-61 0.3 0.2 0.6 1.5 0.7 0.1 0.14.1.1.1 Preparation of Buffer Solution

[0161] Ammonium Chloride (4.6 g, Aldrich: 326372, Trace Select) was weighed into a clean (no metal) Falcon Tube (50 mL), and the previously cleaned magnetic stirring bar was added.6 mL of Trace Select water (Honeywell 95305) was added in one aliquot to flush walls of the Falcon in case any salt sticks to the Falcon tube walls.1 mL of ammonium hydroxide 28% (Sigma 338818) was added with a 1000 µL pipette with a respective pipette tip, 8x times. The lid of the Falcon was closed, and the Falcon is, in turns, vortexed (1-2 minutes) (immersion in an ultra-sonic bath was a possible alternative for 1-2 minutes) and shaken, until all salt was dissolved. The Falcon tube can also be warmed (e.g., by rolling between hands) to improve solubility, temperature (e.g., around 23°C, preferably between 23-25°C). After complete dissolution of the salt, the pH acceptance criteria, pH range 9.28 – 9.62, needs to be verified by pH measurement of the solution at RT, e.g., with and electronic pH meter. The Falcon tube was closed with parafilm and stored at room temperature. Prior to use, any solid salt formation was redissolved. 43 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 4.1.1.2 Preparation of Nickel Nitrate Plating Solution

[0162] A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was dried by placing it on a heating plate set to 150 °C. To the beaker was added 210 µg of natural (isotopic distribution) nickel (powder, Sigma-Aldrich <50 µm, 99.7% trace metals basis, essentially free from any impurities, except iron. The copper impurity amounts to < 0.3 ppm.) were weighed into the beaker and 4 mL of 65 % nitric acid were added using a pipette. The beaker was placed back on the active heating plate and the stirring was set to 300 rpm. Ensure the ventilation of the fume hood was functioning properly (evolution of NO2). During the dissolution, the solution turns green. The solution was reduced by evaporation to a volume of ^ 600 µL and taken from the heating plate to cool down to room temperature. The remaining solution was transferred to a 50 mL metal-free Falcon tube. The glass beaker was rinsed with a total of 2.8 mL of Trace Select water, in steps of 0.8 mL, 1 mL, and 1 mL, where each step was transferred to the Falcon tube before the adding the next washing fraction. Buffer solution (4 mL), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to the Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using sterile B-Braun syringes.

[0163] The following are example lots of60Ni and61Ni (certificate as provided by Isoflex, USA, March 2018): Table 2. Isotope 61Niµg <5044 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Content (ppm) <8 <50 <10 <10 20 30 50Isotope 61NiEnrichment 99.39%Ti <10Isotope60Ni Ti <10

[0164] The samples of natural nickel from Sigma-Aldrich were essentially free from any impurities, except iron. The copper impurity amounts to < 0.3 ppm. Additional suitable sources of natural Ni include: Nickel powder, <50 µm, 99.7% trace metals basis 45 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Nickel rod, diam.6.35 mm, =99.99% trace metals basis Nickel foil, thickness 0.5 mm, 99.98% trace metals 4.1.2. Electroplating the Backing Surface

[0165] A disc shaped niobium backing was obtained from high purity Nb as described herein and (28 mm x 1.0 mm) was cleaned with ethanol (high-purity) and inserted in a Comecer Electroplating Unit V21204. A platinum wire anode was positioned so that the distance relative to the coin surface was between about 1 and 3 mm, adjusted by a polymer spacer. The coin mass was determined to be 5.25 grams. Niobium backing (22 mm x 1.0 mm weighs 3.3 g). The plating solution was charged to the electrolyte container and attached to the apparatus. The voltage was set to 4.5V. The current reading after 5 min stabilization was 180 µA. The duty cycle for pump was set to 45%. The plating liquid turned from blue to transparent, slow decrease of current to 160 µA was observed over the period of 120 minutes. The plating process was stopped. The coin was taken out of the electrolytic cell and its weight was measured. The coin also underwent microscopic evaluation, FIGs.1 and 2 using a DINOLite digital microscope to observe the crystal structure and homogeneity of the surface. The coin (FIG.2) was stored in a metal-free Falcon tube under a nitrogen atmosphere. 4.1.3. Results of the Electroplating

[0166] Upon completion of electroplating, the coin underwent a microscopic evaluation using a DINOLite digital microscope to observe the crystal structure and homogeneity of the surface. As can be seen in FIG. 1 (panels A-C), a homogenous target coating having durable adhesion was obtained, see also FIG.2. 4.1.4. General Guidelines for High-purity [61Cu]CuCl2Production

[0167] The purpose of this example was to enable the bulk production of61Cu from the deuteron irradiation of natural nickel and / or enriched60Ni. This effort was a proof of concept, and, therefore, there were no benchmarked specifications for61Cu. However, we optimized target performance, target geometry / material use, irradiation parameters, and chemical processing methods to produce [61Cu]CuCl2 following enriched60Ni irradiation, or, scaled accordingly fornatNi irradiation. There were no pharmacopoeia specifications for radio-copper explicitly, however, test QC methods include assessment of radionuclidic purity and apparent molar activity (to demonstrate usability of the extracted [61Cu]CuCl2). 46 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0168] This example considers use of two different types of targets, natural nickel (natNi) targets and highly enriched Nickel-60 (60Ni) targets both of which were suitable for deuteron bombardment. However,natNi was cheap and available in high-purity while60Ni was still costly and required efficiency measures. If even higher yields were desired, target preparation efforts may be directly translated into the proton-based61Ni(p,n)61Cu route, however, given the cost of enriched61Ni (c.a. $25 USD / µg), such an approach imposes the need for target recycling.

[0169] The set of guidelines below enable all types of targets in the production of61Cu, including the production of high-purity [61Cu]CuCl2 from the Nb coins with a Zn or Ni (any isotopic enrichment) coating electroplated thereon as provided herein. Specific details are also provided for deuteron, and proton irradiations, respectively. This protocol was followed to generate the 61Cu-compositions evaluated in the following examples. Target Backing Flat coin - disc-shaped. The dimensions of the target backing form are: 70- –Attorney Ref: NCL-008WO Target Backing Niobium foil, 99.8% (metals basis), 1.0 mm (0.04 in) thick, annealed, Material Stock No.: 1025748 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Transfer system As the target can be automatically transferred to / from the cyclotron by compatibility means of a neumatic tar et transfer s stem it was critical that the ing matic and at fore, the l also clude d be a ng sited / or ader 8) ly raw thods49 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO used for preparingnatNi targets should ultimately be directly translatable to 60Ni61Ni At it the MS is to : 1 inAttorney Ref: NCL-008WO The amount suggested above were a good, albeit not strict, guide since chemical urification followin irradiation will in turn further remove t ince t- e y be8.0 ndcy) natNi cost lation nd re r51 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^ ≥70 mg or ≥89 mg / cm2(assuming 10 mm diameter) F t (i61Ni) ih t l ti l li it th d itd ing 61Cu y to ble e.g.52 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO irradiation. As these byproducts are chemically different from copper, such radionuclides may be removed during61Cu purification / processing. For s via ing s low e that t may able4.1.5. Purification and Characterization of [61Cu]CuCl2and waste streams

[0170] The solid target irradiated material was dissolved in a total volume of 7 mL of 6 M HCl with the addition of 30% hydrogen peroxide via a dissolution chamber.

[0171] Separation and purification was accomplished using a cassette-based FASTlab platform using a TBP (tributylphosphate-based) resin (1 mL) (particle size 50-100 µm; pre-packed, Triskem) then a weakly basic (tertiary amine; TK201) resin (2 mL) (particle size 50-100 µm; pre- packed, Triskem) each of which were pre-conditioned with H2O (7 mL) and HCl (10M, 7 mL). The cassette reagent vials were prepared using concentrated HCl (Optima Grade, Fischer Scientific), NaCl (ACS, Fischer Scientific) and milli-Q water (Millipore system, 18 MΩ-cm resistivity).6M HCl (2 x 4.2 mL), 5M NaCl in 0.05 M HCl (4.2 mL). The subsequent61Cu was then purified with two subsequent ion exchange resins in a FASTlab synthesis unit. 53 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 1) The acid-adjusted dissolution solution (approx.7 mL) was loaded over both columns in series and directed into a “Ni collection fraction”. The TBP resin acted as a guard column as it quantitatively retained Fe3+ions, while the Cu2+and Co2+complexes were quantitatively retained on the tertiary amine (TK201) resin. 2) Both columns were washed with 6M HCl (4 mL) to maximize Ni recovery for future recycling. 3) The TK201 column was washed with 4.5M HCl (5.5 mL) to elute the majority of cobalt salts. 4) The TK201 column was washed with 5M NaCl in 0.05M HCl (4 mL) to decrease residual acid on the resin and further remove any residual cobalt salts. 5) The TK201 column was washed with of 0.05M HCl (3 mL) to quantitatively elute the [61Cu]CuCl2.

[0172] The resulting [61Cu]CuCl2solution of the plated material has an average activity of 1.0 – 4.5 GBq. This activity was measured using a dose calibrator from Comecer and its radionuclidic purity by a gamma spectrometer at PSI in Switzerland.

[0173] Gamma spectrometry measurements were performed to identify any radionuclidic impurities, particularly long-lived radionuclides. These results indicate a 89.3% and 94% reduction in impurities fornatNi and61Ni on niobium backing materials with respect to silver backing materials when utilizing the methods disclosed herein. ICP-MS measurements were performed on the product of cold dissolutions by Labor Veritas in Switzerland to monitor elemental impurities present in product according to ICH-Q3D. All detected impurities were within regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, page 25).

[0174] The plating of highly enriched61Ni was also enabled with the same plating parameters as described above, for a higher yield and industrial production using proton irradiation (typically at 80 μΑ to 100 µA, 13 MeV protons for 1 hour to 2 hours and up to one half-life of61Cu). 4.1.6. Purity and activity evaluations of [61Cu]CuCl2compositions prepared fromnatNi(d,n)61Cu and60Ni(d,n)61Cu using Nb-backed coins.

[0175] This example presents information on the activity of the produced61Cu generated using the Nb backing, Ni electrodeposited coins of the present disclosure; alongside cobalt radioisotopes, 54 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO that were produced with deuteron irradiation using the coin comprising a natural nickel target and the coin comprising enriched60Ni as target, i.e.,natNi(d,n)61Cu and60Ni(d,n)61Cu, respectively. The irradiated materials were dissolved and purified as described above.

[0176] The obtained and purified61Cu product and waste generated during purification from the products of deuteron irradiation of natural nickel / Nb coin and60Ni / Nb coin, respectively, was processed and analyzed by gamma-spectrometry and presented below.

[0177] TENDL-2019 is based on thick target yield calculations using isotopic abundancy of natural nickel / Nb coin and enriched60Ni / Nb coin, respectively. 4.1.7. Radiocobalt Content

[0178] Table 5 contains activities of cobalt radioisotopes in the different fractions post FASTlab purification as a mean of three measurements (n=3 irradiations) usingnatNi / Nb target coin. The activities were extrapolated to a 3 h and 50 µA beam at EoB (end of bombardment) +2 h. The activity of [61Cu]CuCl2in these irradiations was determined experimentally and confirmed to be ~80% of TENDL-2019 based estimates.

[0179] Activity of produced61Cu for irradiation with deuteron at 8.4 MeV, 3 h at 50 µA at 80% efficiency (EoB+2 h): 3052 MBq. Also see FIG.3 for the change in cobalt radioisotopes with time along with the corresponding change in61Cu purity. Table 5: Cobalt isotopes:natNi / Nb target coin Radionuclide Cu fraction [Bq] Ni fraction [Bq] Co-waste I+II [Bq] Half-life [days] 56Co 118345 2696 2458071 77

[0180] Table 6 contains calculated activities of cobalt radioisotopes that would be obtained by using 99% enriched60Ni as target metal. The activities were extrapolated to a 3 h and 50 µA beam at EoB (end of bombardment) +2 h. The activity of61Cu was calculated accordingly.

[0181] The activity of produced61Cu with deuteron irradiation at 8.4 MeV, 3 h at 50 µA at 80% efficiency (EoB+2 h) was 11.552 MBq. Also see FIG.4 for the change in cobalt radioisotopes with time and the corresponding change in61Cu purity. 55 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 6: Cobalt isotopes: enriched60Ni / Nb target coin. Radionuclide61Cu fraction Separated Ni [Bq] Separated Co-waste Half-life [days] [Bq] I+II [Bq]

[0182] Based on measured activities (MBq) at different beam currents (µA) and timescales (5 – 60 minutes), the measured activity resulting from deuteron bombardment ofnatNi,60Ni and proton bombardment of61Ni using the process described herein was found to be approximately > 80% of the theoretical activity calculated using the TENDL-19 cross section database.

[0183] The activity of radiocobalt and other long-lived radionuclides was measured post-release (> 3 weeks after bombardment). The EOB activity of the long-lived impurities was then extrapolated.

[0184] In Table 7, the extrapolated radiocobalt activity content and61Cu purity of [61Cu]CuCl2solution produced bynatNi as target metal for a 50 µA, 3 h deuteron irradiation after FASTlab purification were presented. Table 7: Natural Ni / Nb Target Coin – Extrapolation of61Cu activity and purity in produced [61Cu]CuCl2solution. Co species u ides 56% 59% 86% 41% 31% 63%39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 6 213385 1330 50 96.332% 99.985% 0.01545% 7 213305 1081 48 95.750% 99.981% 0.01890% 09% 17% 34%. p pp action, assuming a product expiry time, e.g., >3 weeks post EoB. This value was lower than the limit allowed for Ga-68 cyclotron-produced as found in the Pharmacopeia (*0.1% at expiry for non-Ga radioisotopes):

[0186] The64Cu originating fromnatNi irradiation (content ~ 5% at expiry) will be the main impurity, reducing the radioisotopic purity of61Cu product at longer irradiation times or shelf-life (illustrated as the grey curve in FIG.3).

[0187] Table 8 and FIG.4 show the extrapolated radiocobalt activity content and61Cu purity of the produced [61Cu]CuCl2 solution after FASTlab purification. 57 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 8:60Ni / Nb Target coin – Extrapolation of61Cu activity and purity in produced [61Cu]CuCl2solution. Co species Hours61Cu64Cu % Purity PET activity in Cu % Purity % non-Cu lides 39% 71% 10% 59% 18% 90% 79% 88% 21% 84% 84%

[0188] Less than 0.01% non-Cu radioisotopes ( Co and Co) were left in the Cu fraction, assuming a product expiry time of 8 h post EoB. This value was ten times lower than the allowed limit for68Ga cyclotron-produced as found in the Pharmacopeia (0.1% at expiry for non-Ga radioisotopes*).

[0189] Less than 0.02%64Cu was left in the copper fraction at an expiry time of 8 h post EoB, one hundred times lower than the specification required for68Ga (2% Ga radioisotopes were allowed for68Ga).   4.1.9. Purity of produced [61Cu]CuCl2from Ni / Nb target coins: Comparison with Commercially Available Radionuclides

[0190] In Table 9, a comparison of the regulatory specifications on the purity of commercially available radionuclides are given along with the characteristics of the high purity [61Cu]CuCl2 produced from deuteron irradiation of natNi / Nb and enriched60Ni / Nb target coin (50 µA, 3 h) and after FASTlab purification described herein. 58 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 9: Comparison between commercially available radionuclides and [61Cu]CuCl2solution produced from irradiation ofnatNi / Nb coins and enriched60Ni / Nb coins. Radionuclide % Purity at % Max % Max other Dominant % % Max other EoB + 2 radioisotopes radioisotopes impurities Purity radioisotopes h r f m t E B + 2 t t x ir .15% .10% .01% 5% .02%

[0191] As the first notable comparison, cyclotron production of Ga from proton irradiation also produces long lived radionuclides, (see, e.g., Applied Radiation and Isotopes, 65(10), 1101–1107, IAEA-TECDOC-1863 Gallium-68 Cyclotron Production).notably65Zn (half-life=244 days) from the66Zn(p,pn)65Zn decay. With a roughly 0.365% of66Zn in an enriched68Zn starting target metal, about 770 Bq of65Zn will be produced from a 50 µA, 3 h beam with an energy of 13 MeV in a thick target (TENDL-2019 based calculations). Using natural Zn with 27.7% abundancy in66Zn, 58 kBq of65Zn will be produced in one run of 50 µA for 3 h beam.

[0192] Similar with [61Cu]CuCl2production, cyclotron production of [64Cu]CuCl2from proton irradiation also produces long-lived cobalt radionuclides, namely,55Co,57Co,58Co, and60Co. (See, e.g., Nuclear Medicine & Biology, Vol.24, pp.35-43, 1997; Applied Radiation and Isotopes 68 (2010) 5–13). By operating with a degraded beam of below 13 MeV,60Co (from64Ni(p,na)60Co) was reduced to 1 Bq per run of 50 µA, 3 h. With beam energies below 13 MeV,55Co, formed from 59 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO the58Ni(p,a)55Co reaction, will remain the main impurity (half-life=17.53 hours). The 170 Bq of the long-lived57Co was formed in about 170 Bq in these conditions mostly from60Ni(p,a)57Co.

[0193] Note: These estimates were computed from thick target yields using TENDL-2019 cross section data and isotopic abundancy of enriched64Ni as follows: 0.00376%58Ni, 0.00298%60Ni, 0.0058%61Ni, 0.135%62Ni, 99.858%64Ni. 4.1.10. Enriched61Ni as Target Metal on Nb backed coins

[0194] 61Cu was produced through the proton bombardment of61Ni electroplated Nb backed coin via cyclotron equipped with a solid target system irradiating a highly pure Niobium coin plated with highly pure61Ni (purity 99.42%). The proton beam currents used were up to 100 µA, and beam energy of 13 MeV. An aluminum beam degrader was used.

[0195] The solid target irradiated material was dissolved in a total volume of 7 mL of 6M HCl with the addition of 30% H2O2 in a heated dissolution chamber. The61Cu was purified from metal and radiometal impurities via a GE Healthcare FASTlab 2 module through a tributyl phosphate resin cartridge and a tertiary-amine-based weak ionic exchange resin containing long-chained alcohols. The product was finally eluted in an ISO class 5 environment in 3 mL 0.05 M HCl through a sterile filter Millex 4 mm Durapore PVDF 0.22 µm into a sterile evacuated vial. The vial was handled with care using the appropriate shielding and can be stored at room temperature until use using appropriate shielding for transport and handling. The properties of the [61Cu]CuCl2 solution were determined and are displayed below in Table 10. 60 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 10. [61Cu]CuCl2produced from61Ni. Parameter Test Method Specification Appearance Visual inspection Clear, colorless solution, free from t: q

[0196] As shown in Table 11 and FIG. 5, commercially available [61Cu]CuCl2 contains radionuclidic impurities, particularly high levels of56Co and58Co, in addition to110mAg and109Cd. Elimination of Ag and Cd isotopes from the Cu-61 product by replacing silver with niobium as backing material. There was a nine-fold reduction of56Co isotopes for natNi and >2000x reduction for Ni-61 (less shielding of radioactive waste is required). 50% reduction of long-lived cobalt isotopes (earlier final disposal of the produced waste) was also observed. It was clear from the data below, that the radionuclidic purity of [61Cu]CuCl2produced by the methods described above to be superior to previously known methods and products. The high levels of long-lived Co, Ag, and Cd radionuclides pose a radiation burden for the patient and a radioactive waste issue for 61 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO consumables that have come in contact with the [61Cu]CuCl2 product during radiopharmaceutical manufacturing and radiolabeling. Table 11. Detailed radionuclidic impurities present in commercially available61Cu compared to high-purity [61Cu]CuCl2of the present disclosure, expressed in Bq / g. Ext. Coins Present CoinsCoin nat-Ni on Ag nat-Ni on Nb61Ni on Nb2.31.2588.50.9N / DN / DN / De was an 83% decrease in radionuclidic impurities. When present in the [61Cu]CuCl2product, these impurities can cause a radiation burden for the patient, waste issues, and degrade the quality of, e.g., a radiotracer or radiopharmaceutical. They can also interfere with the chelation process by competing with61Cu, which affects the accurate radiolabeling of the tracer. An 89.3% reduction of impurities was observed upon changing the backing material from silver to the niobium backing provided herein and using the Ni plating methods described herein. And Additional reduction of 46% was observed when using Ni-61 as starting material. Table 12. Radionuclidic impurities in the produced [61Cu]CuCl2. Ext. Coins Present Coinsb ±0.2

[0198] Cq p y , EoB + 2 hours), long-lived radionuclidic impurities decay slower and, thus, increase in concentration in relation to 61Cu at longer timescales. Thus, the impurity profile may vary greatly based on the isotopic enrichment of the raw material, purity, method, and process of producing a coin, which influences the type and amount of radionuclidic impurities in the finished [61Cu]CuCl2product. 62 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0199] FIG. 7. contrasts the radionuclidic purity of [61Cu]CuCl2 solution produced with commercially available natNi target metal on a Ag backing compared to the radionuclidic purity of [61Cu]CuCl2solution produced by irradiation of Ni target metal electroplated according to the present disclosure on high purity Nb backing when assessed by gamma spectrometry in Bq / g (summed radionuclidic impurities) at t = 0h and at t = 12h. The presented data highlight the superior quality of the [61Cu]CuCl2solution when produced by irradiation of Ni target coatings electroplated according to the present disclosure on high purity Nb backing, where the purity after 12 hours is still well above the purity limits set by pharmacopeia for similar radionuclides for medical use. Table 13. Radionuclidic purity of commercially available61Cu compared to high-purity [61Cu]CuCl2of the present disclosure as measured at EoP and EoP + 12 hours. Ext. Coins Present Coinsnat-Ni on Nb 999 .999. . .

[0200] The experimental activities of61Cu produced after deuteron irradiation were about 80% of the theoretical yield as calculated from TENDL-2019 cross section data.

[0201] The main long-lived nuclides in the radioactive waste fraction from cyclotron production of61Cu were radiocobalt species of56Co,57Co,58Co, and60Co. It was calculated that, after four years,56Co,57Co, and58Co will have decayed below regulatory clearance limits, LL*, leaving only60Co. *Clearance limits (LL) means the value corresponding to the activity concentration level of a material below which handling of this material is no longer subject to mandatory licensing or supervision.

[0202] The yield and purity of [61Cu]CuCl2prepared with niobium coins was improved by plating the niobium coins with 99% enriched60Ni or61Ni. The purity of [61Cu]CuCl2 product was higher as64Cu was be formed as a radioisotopic impurity. Additionally, the56Co and60Co contents were reduced by a factor of 100.57Co amounts increased (but were low activity) and58Co amounts doubled (but decay below LL before56Co / 58Co). 63 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 4.1.12. Batch Control of [61Cu]CuCl2

[0203] Three representative batches of [61Cu]CuCl2 solution were manufactured as described above (by irradiating a solid target consisting of highly pure61Ni (purity > 99.42%) plated on a niobium coin backing with a proton beam) and tested. The results of these analyses are presented in Table 14. “End of Production” or “EoP” refers to the end of the preparation of [61Cu]CuCl2. Table 14: Analyses of three batches of [61Cu]CuCl2. Specification Results Batch - 1 2 3 mL l / mL 2.7264 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 4.1.13. Radionuclidic Purity

[0204] Radionuclidic purity is important in radiopharmacy since any radionuclidic impurities increase the radiation dose received by the patient and may also degrade the quality of any imaging procedure performed. For example, if significant levels of other radionuclides are present then biological distribution may be altered. Radionuclide samples contain some contaminants arising the production process or the decay of the primary radioisotope. Radionuclide impurities can occur as a result of the manufacturing process, for example, for nuclides produced by cyclotron there can be contaminants due to impurities in the target or by the energy of the reaction. In order to control the effects of these contaminants on the radiation dose received by the patient, limits are set on the maximum levels of contamination allowed. These limits are defined by governmental agencies, e.g., in pharmacopoeia monographs, and vary depending upon the radionuclide concerned and the physical decay characteristics of the likely contaminants. Measurement of radionuclidic purity may be performed high resolution using gamma-ray spectroscopy on samples well after bombardment. The activity of the long lived isotopes is then extrapolated back to EoB, EoP, or EoS or even at expiration. High activity emitted from long lived radionuclidic impurities greatly increases the cost and complexity of managing the disposal of all consumables that come into contact with the nuclide composition.

[0205] Through the deuteron irradiation of natural nickel and60Ni, and proton irradiation of61Ni, long-lived isotopes of cobalt are produced:56Co,57Co,58Co and60Co. Other long-lived radionuclides such as110mAg,108mAg and109Cd are produced through the irradiation of commonly used silver backing material, which are dissolved along with starting material during the purification process. Due to their long half-lives, the proportion of these radionuclides increases with time compared to the61Cu, decreasing the radionuclidic purity of the product, especially at later time points when usingnatNi as a starting material. Though most cobalt isotopes can be separated in the purification process, the110mAg,108mAg and109Cd end up in the61Cu fraction and nickel solution that is further used in recycling of irradiated target coating. The long-lived radionuclides become problematic when considering the radiation burden to the patient and the accumulation of radioactive waste. Third-party coin manufacturers did not publish the contamination from the non-niobium coin backings (e.g., silver). As provided by the present disclosure, the method of making and using coins comprising niobium represents an advantage, e.g., in view of the radionuclidic and chemical purity of samples produced following subatomic 65 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO particle bombardment, isolation, and purification. A detailed comparison of the known61Cu products (prepared via Ag backings and prior art methods of plating the target) to61Cu as provided by the present disclosure is provided below.

[0206] With these factors in mind, a niobium backing material was chosen due to its inert nature to acids at room temperature and at elevated temperatures. This characteristic allows the niobium backing material to resist the acid medium used during the dissolution and purification process. By doing so, higher radionuclidic and chemical purity can be achieved in the radiometal aqueous solution, eventually resulting in higher purity for the radiopharmaceutical prepared from the desired61Cu isotope. Although plating methods of niobium exist, the element has not yet been used for radionuclide production due to the poor adhesion of the plated Ni material (as discussed above). The Ni (or68Zn for the production of68Ga) requires sufficient adhesion for the coin to survive thermal loads (1200 W) during irradiation and pneumatic shuttle acceleration at 5 bar to 7 bar of pressure and abrupt stop at the head. On the other hand, however, the plated Ni (or Zn) must dissolve sufficiently during the dissolution and purification process. Attempts were made to plasma-coat niobium backings for plating nickel (Ni). However, this process resulted in losses and incomplete dissolution of Ni from the niobium backing. The thermal processes involved in plasma coating altered the grain structure of the niobium backing material, leading to a strong bond between the plated nickel and niobium. This strong bond made it difficult for the nickel to fully dissolve, causing losses. The plasma coating process itself resulted in very high losses in target coating, rendering the process not viable for use, especially with very expensive highly enriched target metals. The main reference to this summary is the IAEA documentation regarding cyclotron radionuclide production, IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS, REPORTS, No. 1. (INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2016) Additionally, a monetary evaluation regarding the procurement costs of niobium utilized as a backing material displays a 40% lower cost in comparison to commonly used backing materials such as gold, silver, and platinum where costs range from €80 to €120 per backing material (single coin).

[0207] Parallel to this, elements pertaining to the radiochemical purity of the radiolabeling process are controlled by manufacturing the plating solution under controlled conditions described herein. By procuring the plating solution from a raw base material of, e.g., nickel, the possibility of contamination is now independent from outside sources and suppliers. Such material and 66 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO equipment used in these cases are inert glass beakers and Falcon tubes (ensured to not contain any undesirable substances), TraceSelect pure water, pure reagents (trace-metal grade), inert coin adapter and electrolytic cell (on the electroplating unit), etc. Through this, the contaminants of trace metals can be minimized reduced or avoided all together. This difference between 99.9% purity and 99.99% purity plays a role in the resulting chemical purity of a radionuclide and therefore in the radiochemical purity of, e.g., a radiotracer or radiopharmaceutical prepared from the radionuclide, where the presence of cold Cu, Zn, Fe, Sn, Ti, or Al or any salt thereof are an issue as they will compete for binding to the chelator in the tracer along with the desired radionuclide (61Cu).

[0208] Robustness of plating was tested through a drop and scratch test. This assessment ensures that the electrodeposited substrate on the backing will survive mechanical impacts of the shuttling system and established an increased probability of survivability under the cyclotron beam.

[0209] In certain embodiments, coins were irradiated with 8.4 MeV deuterons for an average duration of 120 mins at a range of 40 μΑ to 45 μΑ or with 13.2 MeV deuterons at 40 µA to 45 µA using an ARTMS or GE shuttling system on a GE PET Trace cyclotron.

[0210] In certain embodiments, the coins were irradiated with 8.4 MeV deuterons for an average duration of 120 mins at a range of 40 μΑ to 45 μΑ or with 10 µA to 100 µA 13 MeV protons using an ARTMS or GE shuttling system on a GE PET Trace cyclotron.

[0211] Dissolution of Ni from the niobium backing was accomplished via the utilization of a dissolution system in 10 M HCl. The subsequent61Cu was then purified with two subsequent ion exchange resins in a FASTlab synthesis unit. The processing time for these purifications can reach up to 60 minutes.

[0212] The resulting [61Cu]CuCl2solution of the plated material has an average activity of 1.7 – 4.5 GBq. This activity was measured using a dose calibrator and its radionuclidic purity by a calibrated gamma spectrometer e.g., at PSI in Switzerland.

[0213] Gamma spectrometry measurements were performed to identify any radionuclidic impurities, particularly long-lived radionuclides. These results indicate an 89.3% and 94% reduction in impurities fornatNi and61Ni on niobium backing materials with respect to silver backing materials when utilizing the methods disclosed herein. ICP-MS measurements are 67 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO performed on the product of cold dissolutions by Labor Veritas in Switzerland to monitor elemental impurities present in the product according to ICH-Q3D. All detected impurities are within regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).

[0214] The plating of highly enriched61Ni was also enabled with the same plating parameters as described above, for a higher yield and industrial production using proton irradiation (typically at 10 μΑ to 100 µA, 13 MeV protons for 20 minutes to 2 hours and up to one half-life of61Cu).

[0215] Following automated transportation of the irradiated coin from the cyclotron to the hot cell docking station, the capsule was transferred to a QIS dissolution unit with tongs. The transmuted target metal was dissolved from the niobium backing material using 1:1 7M HCl: 30% H2O2(ultratrace analysis, Merck) (4 mL). The acid-peroxide mixture is circulated, immersing the coin and target metal surface to dissolve all irradiated elements at 2 mL / min for about 23 minutes at about 60 °C. When the target metal was fully dissolved, acidic solution containing the dissolved metal was withdrawn and the QIS system was flushed with 10M HCl (3 mL). The combined acidic solutions were then fed forward to the FASTlab purification unit.

[0216] For this reason, gamma spectrometry analyses were carried out on decayed samples (at least 10 half-lives of61Cu, corresponding at the earliest to 1.4 d after EoP). The analysis was performed using a high-purity germanium (HPGe) detector GEM30-70 from Ortec. 4.1.14. Activity concentration

[0217] The activity of the [61Cu]CuCl2solution was quantified using a dose calibrator following Ph. Eur.2.2.66 guidelines. The test was carried out at the end of the radionuclide production (EoP) using a certified dose calibrator, selecting the61Cu measuring channel. The weight of the [61Cu]CuCl2 solution was measured using an analytical scale. Assuming a density of the aqueous solution of 1.0 g / mL, the weight is converted into a volume. The activity concentration, expressed in GBq / mL, is then calculated by dividing the activity by the volume. 4.1.15. Apparent molar activity

[0218] The suitability of the [61Cu]CuCl2solution for radiolabeling was ensured by determining the apparent molar activity. This test assessed the impact of competing trace metals on61Cu chelation by quantifying the minimum amount of a given chelator required for efficient radiolabeling. The test can be performed with various chelators that can complex copper (e.g., 68 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO NOTA, DOTA, NODAGA). Among them, NODAGA has been assessed for61Cu molar activity. The test measures the percentage of complexation by radio-TLC after reacting a fixed amount of [61Cu]CuCl2solution with different amounts of chelator (titration). The results are then plotted (x axis (logarithmic): nmol of chelator; y axis: % of complexation), and a sigmoidal curve is obtained. The EC50 point is extrapolated, corresponding to the amount of chelator needed to achieve the 50% of complexation. The apparent molar activity is calculated by dividing the61Cu activity used extrapolated at the end of production (EoP) by 2 times the EC50value.

[0219] This test was not performed as a routine analysis, but when changes occur in 1) the grade of a chemical employed for the manufacturing of the [61Cu]CuCl2solution, 2) the quality of a consumable employed for the manufacturing of the [61Cu]CuCl2solution, 3) the target coin manufacturing process, and 4) if poor radiolabeling yields were observed. The AMA test is specific to a chelator and radiolabeling conditions (e.g., buffer concentration and pH) and has thus to be repeated when these parameters are modified. 4.1.16. pH

[0220] The pH value was determined by colorimetric evaluation using pH paper strips with a narrow range (pH interval 0 – 2.5) exposed to a 10 µL of the [61Cu]CuCl2solution. The color of the paper strips was compared to the reference color scale displayed on the strips container. 4.1.17. Radiochemical Purity (Radio-TLC)

[0221] The radiochemical purity of a [61Cu]CuCl2 solution prepared as described herein was determined by radio-TLC following Ph. Eur.2.2.66 guidelines. The test determined the percentage of61Cu present in the desired ionic form, namely as free Cu2+. The retention factor (Rf) was determined as the distance from the origin to the peak divided by the distance from the origin to the solvent front. Ionic [61Cu]Cu2+migrated to the solvent front (Rf= 0.8-1.0), while colloidal [61Cu]Cu(OH)2remained at the point of application (Rf= 0.0-0.2). The specification required that ≥ 99% of the whole radioactivity detected was present in the ionic form [61Cu]Cu2+.

[0222] For the test, 2 µL of the radioactive solution was applied at 1 cm away from the lower end of an iTLC paper plate (8 x 1 cm), consisting of glass microfiber chromatography paper impregnated with silica gel. After drying, the iTLC plate was placed in a glass chamber where it was run in a 0.1 M citrate buffer solution (pH 5). When the solvent front had reached a distance of 69 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO approximately 1 cm from the top of the iTLC plate, the plate was removed from the chamber and scanned using a PET miniGita Star from Elysia-Raytest, equipped with a β-sensitive detector and controlled by the software Gina Star from Elysia-Raytest. 4.1.18. Gamma spectrometry (Radionuclidic identity)

[0223] The radionuclidic identity of a [61Cu]CuCl2 solution prepared as described herein was confirmed by gamma spectrometry following Ph. Eur.2.2.66 guidelines. The presence of the main ^-photons with energy peaks characteristic of61Cu (listed in Table 15) was assessed. The table also lists the energy peak of the ^-photons belonging to58Co, which represents the main impurity detected in the test. The test was carried out at EoP using a Mucha Star multichannel analyser from Elysia-Raytest, equipped with a NaI detector, and controlled by the Gina Star from Elysia-Raytest software. Table 15: Energy peaks characteristic of61Cu and of its main impurity58Co. Peak Energy (keV) 4.1.19. Half-life (Radionuclidic identity)

[0224] The radionuclidic identity of a [61Cu]CuCl2solution prepared as described herein was further confirmed by half-life determination following Ph. Eur. 2.2.66 guidelines. The test was carried out at the end of the radionuclide production (EoP) using a certified dose calibrator from Comecer (model VDC-505), selecting the61Cu measuring channel. The specification required the measured half-life value to be within a predefined range of the accepted half-life value (20%). 70 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 4.1.20. LAL test (Bacterial endotoxin content)

[0225] The bacterial endotoxins were determined in a [61Cu]CuCl2 solution prepared as described herein by limulus amoebocyte lysate (LAL) test following Ph. Eur.2.6.14 guidelines. This system applies LAL kinetic chromogenic methodology that measures color intensity directly proportional to the endotoxin concentration in the sample. Each cartridge contained predefined amounts of LAL reagent, chromogenic substrate, and control standard endotoxin (CSE). The LAL reagent was mixed automatically by the device with the sample or the positive product control. The mixtures were incubated and then combined with the chromogenic substrate. For quantification, the optical density of the substrate was measured and analyzed against an internally archived standard curve. The analysis was performed in duplicate for the sample as well as for the positive product control. The system contained an internal printer to generate a report. 4.1.21. Bioburden

[0226] The bioburden of the aqueous [61Cu]CuCl2manufacturing process described hereinn was evaluated following Ph. Eur.2.6.12 guidelines. This test enables the detection and quantification of the viable microorganisms present in the system prior to terminal sterilization and represents a good reference point for evaluating the degree of safety of the process. The manufacturing process was performed in completeness but used non-irradiated target coins for radiation protection. The collected non-radioactive solution was analyzed by the Membrane-Filtration Method. Half of the sample was passed through a membrane filter with a pore size of 0.45 µm. The filter was placed onto Soybean-Casein Digest Agar and incubated to determine the total aerobic microbial count (TAMC). The other half of the sample was passed through a membrane filter with a pore size of 0.45 µm. The filter was then placed onto Sabouraud Dextrose Agar and incubated to determine the total yeast and mold count (TYMC). The bioburden was expressed in colony-forming units (CFU). 4.1.22. Control of Starting Material

[0227] Reagents and starting materials used to manufacture the radionuclide61Cu are provided in Table 16. The reagents employed in production were of TraceSelect grade to minimize the trace metal impurities. These impurities could impact radiolabeling, which may result in a poor complexation of61Cu with the chelator. 71 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 16: Materials used to purify and formulate [61Cu]CuCl2. Material Quality 61Ni 99.42% enrichment r r ion

[0228] At thined using an optical microscope (20x, 50x and 250x magnification). All the steps of the coin manufacturing were performed using TraceSelect grade chemicals and metal-free consumables. The target coins were stored in a cool, dark environment in metal-free sealed containers. 4.1.23. Impurities

[0229] The impurities present in the irradiated starting material can undergo a nuclear reaction, leading to the formation of undesired radioactive species, as summarized in Table 17. Due to the high isotopic purity of the61Ni (99.42% enrichment), these contaminations were limited. 72 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Table 17: Composition of the61Ni target coin plating and main nuclear reactions. 5861Ni (0.004%),60Ni (0.3%),61Ni (99.42%), Ni composition62Ni (0.3%),64Ni (0.004%)

[0230] ents used during the dissolution and purification stages are to be limited. These trace metal ions can impact the subsequent radiolabeling processes by interfering with the complexation of61Cu with the chelator. TraceSelect grade reagents and metal-free consumables are used with the aim of minimizing trace metal contamination.

[0231] A [61Cu]CuCl2solution may be characterized by apparent molar activity (AMA). Apparent molar activity assesses, for example, competing trace metal impurities of61Cu chelation by quantifying the minimum amount of a given chelator required for efficient radiolabeling.

[0232] An AMA test measures the percentage of complexation, by radio-TLC, after titrating a quantity of [61Cu]CuCl2 solution with different amounts of a chelator (e.g., DOTA, NODAGA, etc.).

[0233] The results were then plotted (x-axis (logarithmic): nmol of chelator; y-axis: % of complexation). The lowest nmol value of chelator corresponding to ≥ 95% complexation achieved was recorded. The experimental AMA value was then calculated according to the formula: ^^^^^^^^^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^where:^ Activity: indicates the activity present in the fixed amount of [61Cu]CuCl2 solution used for the titration decay corrected at the EoP (end of production; end of bombardment plus 1 hour). 73 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^nNODAGA: indicates the lowest nmol value of chelator for which ≥ 95% complexation was achieved. This test was performed to assess, for example: 1) the grade of a chemical employed for the manufacturing of the [61Cu]CuCl2 solution; 2) the quality of a consumable employed for the manufacturing of the [61Cu]CuCl2solution; 3) the target coin manufacturing process; or 4) in case poor radiolabeling yields were observed. AMA Test Procedure ^ The mobile phase was prepared as (0.1M sodium citrate) as follows: o Weigh 5.882 g of trisodium citrate dihydrate. o Add Suprapur water up to a volume of 200 mL. o Adjust the pH by adding HCl dropwise until it reaches a pH of 5. ^ Transfer an adequate amount of mobile phase into the TLC development chamber to cover a depth of 5 mm. ^ Prepare the sodium acetate solution (0.5 M in Ultrapur water) as follows: o Weigh 2.051 g of sodium acetate. o Add Ultrapur water up to a volume of 50 mL. o Apply 10 µL of the solution on a pH strip and check if the pH was 8. ^ A 5 mM stock solution of NODAGA was prepared in 0.5 M sodium acetate (Stock 1) as follows: o Weigh 3.1 mg of NODAGA. o Add Ultrapur water or equivalent up to a volume of 1.5 mL. o Store at -20°C after use. 74 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^ A 50 µM stock solution of NODAGA was prepared in 0.5 M sodium acetate (Stock 2) by mixing 10 µL of Stock 1 with 990 µL 0.5 M sodium acetate. Store at -20°C after use. ^ NODAGA test solutions S1-S2 were prepared for chelator titration as displayed in Table T1 by diluting Stock 2 with the listed volumes of sodium acetate 0.5 M. The test solution S0 was a blank solution (without the addition of NODAGA) of 100 µL of 0.5 M sodium acetate. Table T1: Preparation of solution 1 – 3 for chelator titration. Solution name Conc.NODAGA[nM] Volume stock 2 [µL] Volume sodium acetate [µL] S0 0 0 100e es so u o s, - , u o s o e - e e p epa e . sodium acetate according to the dilution scheme shown in Table . Table T2: Preparation of solution 4 - 10 for chelator titration. Solution name Conc.NODAGA[nM] Volume Sx [µL] Volume sodium acetate [µL] S 4 300 100 of S1 900^ A solution of 0.05 M HCl was prepared as follows: o Add 5 mL of Ultrapur water in a 15 mL Falcon tube. o Add 53 µL of 30% HCl to the falcon using a micropipette. o Add Ultrapur water up to 10 mL. o Spot 10 µL of the solution on a pH strip and confirm the pH is between 1.0 and 1.6. 75 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^ The [61Cu]CuCl2 solution was diluted with 0.05 M hydrochloric acid to reach a total volume of 1 mL with an activity concentration of 0.2 MBq / µL (EoP) according to the following formula: ^^^ Cu ൧CuCl solutio0.2 ^MBq / µL^ ଶn ^µL^ ൌ^^^^^^^^^^^^^MBq / µL^ ∗ 1000 µ^^.05 M hydrochloric acid for dilution ൌ 1000 µ^^ െ ^^^ Cu ൧CuClଶ solution to draw ^µL^where AC (EoP) is the activity concentration at EoP. ^ The solution were named “diluted Cu-61 solution”. See the example in Table . Table T3: [61Cu]CuCl2dilution examples. Activity Volume Activity Dilution for AMA eluted at [mL] concentration test uCl2L of uCl2L of uCl2L of ^ Add]CuCl2 solution (as prepared in Table T3), obtaining the reaction solutions listed in Table . Table T4: Reaction solutions. Reaction NODAGA Volume of Volume of Finale nNODAGA cNODAGA 1 M] 0 076 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO RS 8 S8 100 50 150 0.0015 10 RS 9 S9 100 50 150 0.0009 6 ^e eac o so u o s e e cu a e a oo e pe a u e o u es. ^ After incubation, perform TLC measurement on all the reaction solutions as follows: o Using a micropipette, spot 2 μL of each [61Cu]Cu-NODAGA reaction solution RS0-RS10 onto different pre-cut TLC paper. o Allow the TLC paper to dry for about 5 minutes or until there was no visible stain. o Place the TLC paper in the TLC chamber with the stained side on the bottom of the chamber. When the solvent front was about 1 cm from the top of the strip, remove the TLC paper from the TLC chamber with tweezers. o Mark the solvent front on the TLC paper strip with a pencil. o Measure the distance between the starting line and the solvent front with a ruler and let the strip dry completely. ^ After scanning the TLC plate, the software (e.g., Biochrom) will generate an evaluation report. Print the evaluation report and record the results. All data (i.e., RF, % of total activity, % of ROI) of the peaks must be documented. ^ Using the regions of interest (ROI) technique (drawing regions over distinct areas of activities), the % of complexation of [61Cu]Cu-NODAGA was expressed as a percentage of the total detected activity, as follows: ^^^^^^^^^^^^^^^^ ^^^^^^^^^^^ ^లభେ^ ^େ^ି^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^ ^^^େ^^େ^ି^^ୈ^ୋ^^%^ ൌ ୈ^ୋ^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^∗ 100Attorney Ref: NCL-008WO ^ The TLC scanner results were plotted (x-axis (logarithmic): nmol of NODAGA chelator; y-axis: % of complexation), and will follow a sigmoidal trend. An example of plot was given below in Figure . 120 100 10Figure T1:the nmol of titrating chelator and at y-axis the % of complexation obtained via radio-TLC. ^ The lowest value of nmol of chelator in correspondence of which ≥ 95% complexation is identified on the plot. An example was reported in Figure . 120 10Figure of chelator in correspondence of which ≥ 95% complexation was achieved (red arrow). The experimental AMA value was then calculated according to the formula: ^^^^^^^^^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ ൌ^^ேை^^ீ^^^^^^^^^^^ where: 78 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^ Activity: indicates the activity present in the fixed amount of [61Cu]CuCl2 solution used for the titration decay corrected at the EoP. ^ nNODAGA: indicates the lowest value of nmol of chelator where ≥ 95% complexation was achieved. 4.2. EXAMPLE 2: [61Cu]CuCl2Purification and ([61Cu]Cu-NODAGA-PSMA I&T) Production using a Cassette

[0234] This example provides sequential steps performed in the cassette of the present disclosure. The sequential steps are provided in the table below. Step: Nuclidium HCl then step mL b at 6 mL both ough / min79 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Cu Elution 3.2 mL of 0.05 M HCl, 1.4 ml / min through TK201 cartridge nted

[0235] The tables below shows a continuous flow sequence implemented in the cassette of the present disclosure. In this example, there was a continuous flow of the chemicals and consumable over the cartridges. The cartridges have their best performance at 0.7 mL / min, which was implemented in the current process.

[0236] The results of 11 Cu-61 production and purification in the tables below show runs for the non-continuous flow sequence in the cassette, and the continuous flow sequence implemented in the cassette. As shown, the yield of product was increased by 10% in the case of the continuous flow approach. Moreover, the activity in the nickel vial could be reduced from 0.67% to 0.22%, which further improved the recycling capabilities of the starting material. In addition, the increase in total yield of Cu-61, did not result in a noticeable increase of Cu-61 in the waste vial, indicating an improved retention of Cu-61 on the TK201 cartridge prior to the elution. Simulation runs with a dissolved nickel plating spiked with natural copper and cobalt are also provided, to simulate the retention of the different metals on the cartridges. The experiments simulated the loading of the cartridges as well as the elution of the different metals from the cartridges at different conditions. Table: Ni-61 non-continuous Cu-61 production activity uct % 4.6239973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 2 205.00 6.03 11.70 0.34 3220.00 79.64 3 284.60 8.41 12.70 0.37 3090.00 78.14 1.42 8.53 4.89 4.65 7.02 4.35 3.76 0.04 4.28 Tableactivity activity activity waste nickel vial Cu-61 vial Product 4.57 1.14 2.97 7.41 4.94 8.16 8.37 2.86 2.28 3.61 0.27 3.32 [023q p p radiolabeling cassette as described in the present disclosure are provided below.

[0238] The dissolution of the metal matrix (e.g., solution derived from the corrosive stripping of a niobium coin’s transmuted surface composition comprising radioactive metals) 81 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 1. Move 9.45M HCl from STVB1 to syringe S2 and dilute to 7M (2.3 ml) 2. move H2O230 % from STVB2 to Reservoir STVB4 (2ml) 3. Activity received at dissolution vessel (DV) 4. mix HCl 7M S2 and H2O2 in reservoir STVB4 (2.3 mL + 2 mL) 5. Suck mix from STVB4 to S2 and push to DV 6. Clean backbone of cassette 7. Move HCl from STVB1 to reservoir STVB4 (1.7 mL) 8. Move 9.45M HCl from STVB3 to syringe S2 and dilute to 7M HCl (2 ml) 9. Nickel dissolution + additional acid from STVB4 to DV 1.7 mL 9.45 M HCl

[0239] Conditioning of the separation columns 10. Precondition TBP+TK with H2O (6 mL) 11. Precondition TBP+TK with 9.45 HCl (4 mL)

[0240] Retrieval of the dissolved metal bulk 12. Transfer dissolved bulk from DV to reservoir STVB 13. Push 7M HCl from S2 to DV wash DV (2mL) 14. Transfer dissolved bulk from DV to reservoir STVB

[0241] Loading of the bulk on the cartridges and recovery of the starting material

[0242] Purification of the radionuclide (e.g.61Cu) 15. Nickel elution with 4 mL 6 M HCl; suck from V16 to S2 and push over TBP and TK201 into Nickel vial 16. Dry resins with N2 push for 800 mbar for 30 s 17. Clean backbone 18. Cobalt elution with 5 mL 4.5 M HCl; suck 6 M HCl from V14 to S2 and dilute with H2O from V15 and push over TK201 into waste 19. Dry resins with N2 push for 800 mbar for 30 s 20. Clean backbone 21. Recondition TK201 cartridge with NaCl 5 M in 0.05 M HCl (4,2 mL) suck from V13 to S2 and push over TK201 into waste 22. Dry resins with N2push for 800 mbar for 30 s 23. Clean backbone 82 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 24. Prepare 0.05 M HCl (5.65 mL) suck H2O from V15 to S2 and push to V16 to dilute 6 M HCl, suck from V16 to S2 and suck H2O from V15 to S2. Only 3.1 mL are used for Cu-61 elution. 25. Clean backbone

[0243] Elution of the radionuclide (e.g.61Cu) and transfer to the reactor vial

[0244] Cleaning of the purification section of the cassette and accompanying accessories

[0245] Dissolution of the tracer in its respective reaction solution 26. Dissolve a radiotracer precursor (e.g., 40 µg PSMA I&T) V8 in reaction solution V9 (6 mL Sodium acetate 0.5 M + 120 µg ascorbic acid). Move V9 into V11 push to V8. 27. Transfer the steps into the reaction vial Suck from V8 to V11 push to V7 and repeat.

[0246] Radiolabeling process, Transfer Cu-61 to reaction vial and mix solution (total 4 min) V10 to V11 push to V5 mix with N2450 mbar for 30 s.

[0247] Transfer of the drug product constituents (Tracer + reaction solution + 61Cu) to the reaction vial Sterile filtration and transfer to product vial V7 to V11 push to V5 2x (Tracer + reaction solution + 61Cu)

[0248] Radiolabeling and subsequent sterile filtration. Add 4 ml saline + 7.6 mg ascorbic acid Suck from V4 to V11 push to V5

[0249] Final product 13 mL

[0250] Radiolabeling and subsequent sterile filtration Element Before purification After purification83 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Mn 16.45 0.01 Y 0.0029 0.0034 Comparison of [

[0251] The table below shows the development of the continuous flow sequence after the cold testing phase. This means the runs below were all conducted with Cu-61 and the labeling is not included in these tests. The cold runs before were used without irradiated coins, to determine the functioning of the FASTlab sequence and to check that the pH and volumes were as desired. COIN Yield: Yield: Left on ID decay- uncorrected TK201 Changes made ution e ution ter n or sed the C) on of u ased again ing ther ml84 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 4.3. EXAMPLE 3 4.3.1. Comparison non-continuous vs continuous [61Cu]CuCl2Purification The two tables below, show the results of 11 Cu-61 production and purification runs once for the non-continuous flow sequence used during the past year, and the continuous flow sequence implemented during the past month. As can be seen, the yield of product was increased by 10% in the case of the continuous flow approach. Moreover, the activity in the nickel vial could be reduced from 0.67% to 0.22%, which further improves the recycling capabilities of the starting material. In addition, the increase in total yield of Cu-61, did not result in a noticeable increase of Cu-61 in the waste vial, indicating an improved retention of Cu-61 on the TK201 cartridge prior to the elution. Step Di l ti f l t d t i l 8 L 945 HCl 30% H O 31 of n the ^85 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Ni-61 non continuous activity w t / w t tivit nikl Nikl tivit C -61 Prd t vial 4,62 9,64 8,14 1,42 8,53 4,89 4,65 7,02 4,35 3,76 0,04 4,28activity waste / waste activity nickel Nickel activity Cu-61 Product vial 4,57 1,14 2,97 7,41 4,94 8,16 8,37 2,86 2,28 3,61 0,27 3,32... q p purification + labelling cassette invention. 1. The dissolution of the metal matrix 1. Move 9.45M HCl from STVB1 to syringe S2 86 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO move H2O230 % from STVB2 to Reservoir STVB4 (2ml) Activity received at dissolution vessel (DV) mix HCl 9,45M S2 and H2O2in reservoir STVB4 (2.3 mL + 2 mL) Suck mix from STVB4 to S2 and push to DV Clean backbone Move HCl from STVB1 to reservoir STVB4 (1.7 mL) Move 9.45M HCl from STVB3 to syringe S2 (2 ml) Nickel dissolution + additional acid from STVB4 to DV 1.7 mL 9.45 M HCloning of the separation columns Precondition TBP+TK with H2O (6 mL) Precondition TBP+TK with 9.45 HCl (4 mL) al of the dissolved metal bulk Transfer dissolved bulk from DV to reservoir STVB Push 9,45M HCl from S2 to DV wash DV (2mL) Transfer dissolved bulk from DV to reservoir STVB of the bulk on the cartridges and recovery of the starting material tion of the radionuclide (e.g.61Cu) Nickel elution with 4 mL 6 M HCl suck from V16 to S2 and push over TBP and TK201 into Nickel vial Dry resins with N2push for 800 mbar for 30 s Clean backbone Cobalt elution with 5 mL 4.5 M HCl suck 6 M HCl from V14 to S2 and dilute with H2O from V15 and push over TK201 into waste Dry resins with N2 push for 800 mbar for 30 s Clean backbone Recondition TK201 cartridge with NaCl 5 M in 0.05 M HCl (4,2 mL) suck from V13 to S2 and push over TK201 into waste Dry resins with N2 push for 800 mbar for 30 s Clean backbone 87 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 10. Prepare 0.05 M HCl (5.65 mL) suck H2O from V15 to S2 and push to V16 to dilute 6 M HCl, suck from V16 to S2 and suck H2O from V15 to S2. Only 3.1 mL are used for Cu-61 elution. 11. Clean backbone 6. Elution of the radionuclide (e.g.61Cu) and transfer to the reactor vial 7. Cleaning of the purification section of the cassette and accompanying accessories 8. Dissolution of the tracer in its respective reaction solution 1. Dissolve 40 µg PSMA I&T V8 in reaction solution V9 (6 mL Sodium acetate 0.5 M + 120 µg ascorbic acid) in two steps since peptide vial is too small. Move V9 into V11 push to V8. 2. Transfer the steps into the reaction vial Suck from V8 to V11 push to V7 and repeat. 9. Labelling process, Transfer Cu-61 to reaction vial and mix solution (total 4 min) V10 to V11 push to V5 mix with N2450 mbar for 30 s. 10. Transfer of the drug product constituents (Tracer + reaction solution +61Cu) to the reaction vial Sterile filtration and transfer to product vial V7 to V11 push to V5 2x (Tracer + reaction solution +61Cu) 11. Radio-labelling and subsequent sterile filtration. Add 4 ml saline + 7.6 mg ascorbic acid Suck from V4 to V11 push to V5 12. Final product 13 mL 5. METAL RADIONUCLIDE PROPERTIES AND COMPOSITIONS THEROF 5.1. Target Coin

[0252] An aspect of the present disclosure is the provision of a novel coin comprising a metal target for bombardment by subatomic particles to produce radionuclide compositions. In certain embodiments, a provided target coin is designed specifically for use in low energy, biomedical cyclotrons. In certain embodiments, a provided target coin is designed for use in biomedical cyclotrons. 88 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.1.1. Backing

[0253] In certain embodiments, the coin of the present disclosure comprises a backing. This backing has a mass and in certain embodiments has at least one backing surface upon which a targeting metal is deposited. The term “backing surface” as used herein refers to a single side of the backing that is or will be in contact with the target metal. In certain embodiments, the target metal is adhered to the backing, e.g., by electrodeposition. To describe this in another way, the target metal is adhered to the backing, for example, in the form of an electroplated coating or layer, this mass referred to herein simply as the “target” or “target metal.” After the target metal is adhered to the backing, the result is the coin.

[0254] In certain embodiments of the present disclosure, the backing comprises a chemically inert material, such as Nb, Ag, Pt, Au, Al, or W, particularly Nb. In certain embodiments of the present disclosure, the backing consists of a chemically inert material, such as Nb, Ag, Pt, Au, Al, or W, particularly Nb.

[0255] In certain embodiments, the backing is a Nb or Ag backing. In certain embodiments, the backing is a Ag backing. In certain embodiments, the backing is a Nb backing. In certain embodiments, the backing is a Pt backing. In certain embodiments, the backing is a Au backing. In certain embodiments, the backing is an Al backing. In certain embodiments, the backing is a W backing.

[0256] In certain embodiments, the backing is not a Ag backing. In certain embodiments, the backing is not a Pt backing. In certain embodiments, the backing is not a Au backing. In certain embodiments, the backing is not an Al backing. In certain embodiments, the backing is not a W backing.

[0257] In certain embodiments, the backing does not comprise Ag. In certain embodiments, the backing does not comprise Pt. In certain embodiments, the backing does not comprise Au. In certain embodiments does not comprise Al. In certain embodiments, the backing does not comprise W. 89 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.1.1.1 High-purity Nb

[0258] In certain embodiments of the present disclosure, the backing is a high purity Nb backing. In certain embodiments, the purity of Nb is ≥ 98.8%. In certain embodiments, the purity of Nb is ≥99.8%. In certain embodiments, the purity of Nb is 99 – 99.9%. In certain embodiments, purity of Nb is 99 – 99.99%. In certain embodiments, of the purity of Nb is 99 – 99.999%.

[0259] In certain embodiments, the purity of the Nb backing is ≥ 98.850 %, ≥ 98.900 %, ≥ 98.950 %, ≥ 990 %, ≥ 99.050 %, ≥ 99.100 %, ≥ 99.150 %, ≥ 99.200 %, ≥ 99.250 %, ≥ 99.300 %, ≥ 99.350 %, ≥ 99.400 %, ≥ 99.450 %, ≥ 99.500 %, ≥ 99.510 %, ≥ 99.520 %, ≥ 99.530 %, ≥ 99.540 %, ≥ 99.550 %, ≥ 99.560 %, ≥ 99.570 %, ≥ 99.580 %, ≥ 99.590 %, ≥ 99.600 %, ≥ 99.610 %, ≥ 99.620 %, ≥ 99.630 %, ≥ 99.640 %, ≥ 99.650 %, ≥ 99.660 %, ≥ 99.670 %, ≥ 99.680 %, ≥ 99.690 %, ≥ 99.700 %, ≥ 99.710 %, ≥ 99.720 %, ≥ 99.730 %, ≥ 99.740 %, ≥ 99.750 %, ≥ 99.760 %, ≥ 99.770 %, ≥ 99.780 %, ≥ 99.790 %, ≥ 99.800 %, ≥ 99.810 %, ≥ 99.820 %, ≥ 99.830 %, ≥ 99.840 %, ≥ 99.850 %, ≥ 99.853 %, ≥ 99.856 %, ≥ 99.859 %, ≥ 99.862 %, ≥ 99.865 %, ≥ 99.868 %, ≥ 99.871 %, ≥ 99.874 %, ≥ 99.877 %, ≥ 99.880 %, ≥ 99.883 %, ≥ 99.886 %, ≥ 99.889 %, ≥ 99.892 %, ≥ 99.895 %, ≥ 99.898 %, ≥ 99.901 %, ≥ 99.904 %, ≥ 99.907 %, ≥ 99.910 %, ≥ 99.913 %, ≥ 99.916 %, ≥ 99.919 %, ≥ 99.922 %, ≥ 99.925 %, ≥ 99.928 %, ≥ 99.931 %, ≥ 99.934 %, ≥ 99.937 %, ≥ 99.940 %, ≥ 99.943 %, ≥ 99.946 %, ≥ 99.949 %, ≥ 99.952 %, ≥ 99.955 %, ≥ 99.958 %, ≥ 99.961 %, ≥ 99.964 %, ≥ 99.967 %, ≥ 99.970 %, ≥ 99.973 %, ≥ 99.976 %, ≥ 99.979 %, ≥ 99.982 %, ≥ 99.985 %, ≥ 99.988 %, ≥ 99.991 %, ≥ 99.994 %, or ≥ 99.997 %. In certain embodiments, of the purity of the Nb backing is 99.810 %.

[0260] In certain embodiments, the Nb backing is characterized by limiting the amount of certain impurities, as described below.

[0261] In certain embodiments of the Nb backing, the amount of Fe in the backing is ≤ 30 ppm. In certain embodiments, the amount of Fe in the backing is ≤ 27 ppm, ≤ 28 ppm, ≤ 29 ppm, ≤ 30 ppm, ≤ 31 ppm, ≤ 32 ppm, ≤ 33 ppm, ≤ 34 ppm, ≤ 35 ppm, ≤ 36 ppm, ≤ 37 ppm, ≤ 38 ppm, ≤ 39 ppm, ≤ 40 ppm, ≤ 41 ppm, ≤ 42 ppm, ≤ 43 ppm, ≤ 44 ppm, ≤ 45 ppm, ≤ 46 ppm, ≤ 47 ppm, ≤ 48 ppm, ≤ 49 ppm, or ≤ 50 ppm.

[0262] In certain embodiments of the Nb backing, the amount of Ti in the backing is ≤ 60 ppm;, for example, Ti is ≤ 10 ppm. In certain embodiments, the amount of Ti in the backing is ≤ 5 ppm, 90 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ≤ 6 ppm, ≤ 7 ppm, ≤ 8 ppm, ≤ 9 ppm, ≤ 10 ppm, ≤ 11 ppm, ≤ 12 ppm, ≤ 13 ppm, ≤ 14 ppm, ≤ 15 ppm, ≤ 16 ppm, ≤ 17 ppm, ≤ 18 ppm, ≤ 19 ppm, ≤ 20 ppm, ≤ 21 ppm, ≤ 22 ppm, ≤ 23 ppm, ≤ 24 ppm, ≤ 25 ppm, ≤ 26 ppm, ≤ 27 ppm, ≤ 28 ppm, ≤ 29 ppm, ≤ 30 ppm, ≤ 31 ppm, ≤ 32 ppm, ≤ 33 ppm, ≤ 34 ppm, ≤ 35 ppm, ≤ 36 ppm, ≤ 37 ppm, ≤ 38 ppm, ≤ 39 ppm, ≤ 40 ppm, ≤ 41 ppm, ≤ 42 ppm, ≤ 43 ppm, ≤ 44 ppm, ≤ 45 ppm, ≤ 46 ppm, ≤ 47 ppm, ≤ 48 ppm, ≤ 49 ppm, ≤ 50 ppm, ≤ 51 ppm, ≤ 52 ppm, ≤ 53 ppm, ≤ 54 ppm, ≤ 55 ppm, ≤ 56 ppm, ≤ 57 ppm, ≤ 58 ppm, ≤ 59 ppm, ≤ 60 ppm, ≤ 61 ppm, ≤ 62 ppm, ≤ 63 ppm, ≤ 64 ppm, ≤ 65 ppm, ≤ 66 ppm, ≤ 67 ppm, ≤ 68 ppm, ≤ 69 ppm, ≤ 70 ppm, ≤ 71 ppm, ≤ 72 ppm, ≤ 73 ppm, or ≤ 74 ppm.

[0263] In certain embodiments of the Nb backing, the amount of Zn in the backing is ≤ 19 ppm; e.g., Zn is ≤ 10 ppm. In certain embodiments, the amount of Zn in the backing is ≤ 5 ppm, ≤ 6 ppm, ≤ 7 ppm, ≤ 8 ppm, ≤ 9 ppm, ≤ 10 ppm, ≤ 11 ppm, ≤ 12 ppm, ≤ 13 ppm, ≤ 14 ppm, ≤ 15 ppm, ≤ 16 ppm, ≤ 17 ppm, ≤ 18 ppm, ≤ 19 ppm, ≤ 20 ppm, ≤ 21 ppm, ≤ 22 ppm, ≤ 23 ppm, ≤ 24 ppm, ≤ 25 ppm, ≤ 26 ppm, ≤ 27 ppm, ≤ 28 ppm, ≤ 29 ppm, or ≤ 30 ppm.

[0264] In certain embodiments of the Nb backing, the amount of Cu in the backing is ≤ 5 ppm; e.g., Cu is ≤ 3 ppm. In certain embodiments, the amount of Cu in the backing is ≤ 0.5 ppm, ≤ 1 ppm, ≤ 1.5 ppm, ≤ 2 ppm, ≤ 2.5 ppm, ≤ 3 ppm, ≤ 3.5 ppm, ≤ 4 ppm, ≤ 4.5 ppm, ≤ 5 ppm, ≤ 5.5 ppm, ≤ 6 ppm, ≤ 6.5 ppm, ≤ 7 ppm, ≤ 7.5 ppm, or ≤ 8 ppm.

[0265] In certain embodiments of the Nb backing, the amount of Sn in the backing is ≤ 5 ppm. In certain embodiments, the amount of Sn in the backing is ≤ 0.5 ppm, ≤ 1 ppm, ≤ 1.5 ppm, ≤ 2 ppm, ≤ 2.5 ppm, ≤ 3 ppm, ≤ 3.5 ppm, ≤ 4 ppm, ≤ 4.5 ppm, ≤ 5 ppm, ≤ 5.5 ppm, ≤ 6 ppm, ≤ 6.5 ppm, ≤ 7 ppm, ≤ 7.5 ppm, ≤ 8 ppm, ≤ 8.5 ppm, ≤ 9 ppm, ≤ 9.5 ppm, ≤ 10 ppm, ≤ 10.5 ppm, ≤ 11 ppm, ≤ 11.5 ppm, ≤ 12 ppm, ≤ 12.5 ppm, or ≤ 13 ppm.

[0266] In certain embodiments of the Nb backing, the amount of Ni in the backing is < 5 ppm; e.g., Ni is < 1 ppm. In certain embodiments, the amount of Ni in the backing is ≤ 0.2 ppm, ≤ 0.4 ppm, ≤ 0.6 ppm, ≤ 0.8 ppm, ≤ 1 ppm, ≤ 1.2 ppm, ≤ 1.4 ppm, ≤ 1.6 ppm, ≤ 1.8 ppm, ≤ 2 ppm, ≤ 2.5 ppm, ≤ 3 ppm, ≤ 3.5 ppm, ≤ 4 ppm, ≤ 4.5 ppm, ≤ 5 ppm, ≤ 5.5 ppm, ≤ 6 ppm, ≤ 6.5 ppm, ≤ 7 ppm, ≤ 7.5 ppm, or ≤ 8 ppm. 91 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0267] In certain embodiments of the Nb backing, the amount of Al in the backing is ≤ 5 ppm. In certain embodiments, the amount of Al in the backing is ≤ 0.2 ppm, ≤ 0.4 ppm, ≤ 0.6 ppm, ≤ 0.8 ppm, ≤ 1 ppm, ≤ 1.2 ppm, ≤ 1.4 ppm, ≤ 1.6 ppm, ≤ 1.8 ppm, ≤ 2 ppm, ≤ 2.5 ppm, ≤ 3 ppm, ≤ 3.5 ppm, ≤ 4 ppm, ≤ 4.5 ppm, ≤ 5 ppm, ≤ 5.5 ppm, ≤ 6 ppm, ≤ 6.5 ppm, ≤ 7 ppm, ≤ 7.5 ppm, ≤ 8 ppm, ≤ 8.5 ppm, ≤ 9 ppm, ≤ 9.5 ppm, or ≤ 10 ppm.

[0268] In certain embodiments of the Nb backing, the amount of Fe in the backing is ≤ 50 ppm (e.g., ≤ 30 ppm), the amount of Ti in the backing is ≤ 60 ppm (e.g., ≤ 10 ppm), the amount of Zn in the backing is ≤ 19 ppm (e.g., ≤ 10 ppm), the amount of Cu in the backing is ≤ 5 ppm (e.g., ≤ 3 ppm), the amount of Sn in the backing is ≤ 13 ppm (e.g., ≤ 5 ppm), the amount of Ni in the backing is < 5 ppm (e.g., < 1 ppm), and / or the amount of Al in the backing is ≤ 5 ppm (e.g., 1 ppm), or any combination of the above.

[0269] In certain embodiments, the Nb backing is 99.8% pure, and comprises: C ≤ 24 ppm, H ≤ 1 ppm, Mo ≤ 2 ppm, Ni ≤ 4 ppm, Si ≤ 1 ppm, Ti ≤ 2 ppm, Zr ≤ 3 ppm, Fe ≤ 1 ppm, Hf ≤ 2 ppm, N ≤ 14 ppm, O ≤ 56 ppm, Ta ≤ 785 ppm, and W ≤ 4 ppm. In certain embodiments, the Nb backing is 99.9% pure and comprises: B ≤ 10 ppm, Ni ≤ 5 ppm, O ≤ 100 ppm, Si ≤ 100 ppm, Zr ≤ 10 ppm, Ta ≤ 500 ppm, H ≤ 10 ppm, W ≤ 100 ppm, C ≤ 25 ppm, Ni ≤ 20 ppm, Fe ≤ 30 ppm, Cu ≤ 5 ppm, Mo ≤ 10 ppm, and Ti ≤ 10 ppm. 5.1.1.2 Dimensions of the Backing

[0270] The backing according to the present disclosure is any two-dimensional shape without restriction and that has any thickness suitable for its intended use. In certain embodiments, the backing is a circle, an oval, or a geometric shape having from 3-10 sides, for example, a quadrilateral, such as a rectangle, square, trapezoid or parallelogram, a triangle, a composite of multiple geometric shapes, or an organic shape with irregular sides.

[0271] In certain embodiments, the backing has a circular cross-section (i.e., disc-shaped). In further such embodiments, the backing has a diameter of 35 – 15 mm, e.g., 28 mm, or 22 mm. Unless stated otherwise, the tolerance in diameter is ± 0.1 mm.

[0272] In certain embodiments, the backing has a thickness of 0.50- 3 mm or 1- 2 mm. In certain embodiments the backing has a thickness of 0.75 - 2.25 mm, 0.88 - 2.13 mm, 1 - 2 mm, 1.13 - 92 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 1.88 mm, 1.25 - 1.75 mm, or 1.38 - 1.63 mm. In certain embodiments, the backing has a thickness of 0.5 mm, 0.63 mm, 0.75 mm, 0.88 mm, 1 mm, 1.13 mm, 1.25 mm, 1.38 mm, 1.5 mm, 1.63 mm, 1.75 mm, 1.88 mm, 2 mm, 2.13 mm, 2.25 mm, 2.38 mm, 2.5 mm, 2.63 mm, 2.75 mm, 2.88 mm, or 3 mm.

[0273] In certain embodiments, the backing has a thickness of 1 mm to 2.5 mm. In certain embodiments, the backing thickness is 1.5 mm.

[0274] Unless stated otherwise, the tolerance in the backing thickness values reported herein is ± 0.05 mm.

[0275] In certain embodiments, the backing comprises a central disc-shaped groove. In further embodiments, the disc-shaped groove has a diameter of 10 mm and a depth of about 0.6 mm.

[0276] In certain embodiments, the surface of the backing material has a roughness (Ra) of 1.6 μm (micrometer). In certain embodiments, the surface of the backing material has an Ra of 1.5 μm. In certain embodiments, the surface of the backing material has an Ra of 1.4 μm. In certain embodiments, the surface of the backing material has an Ra of 1.3 μm. In certain embodiments, the surface of the backing material has an Ra of 1.2 μm. In certain embodiments, the surface of the backing material has an Ra of 1.1 μm. In certain embodiments, the surface of the backing material has an Ra of 1 μm. In certain embodiments, the surface of the backing material has an Ra of 0.9 μm. In certain embodiments, the surface of the backing material has an Ra of 0.8 μm. In certain embodiments, the surface of the backing material has an Ra of 0.7 μm. In certain embodiments, the surface of the backing material has an Ra of 0.6 μm. In certain embodiments, the surface of the backing material has an Ra of 0.5 μm. In certain embodiments, the surface of the backing material has an Ra of 0.4 μm. In certain embodiments, the surface of the backing material has an Ra of 0.3 μm. In certain embodiments, the surface of the backing material has an Ra of 0.2 μm. In certain embodiments, the surface of the backing material has an Ra of 0.1 μm.

[0277] Variations on the dimensions of the backing provided without tolerance values herein are according to ISO 27681:1989 General tolerances — Part 1: Tolerances for linear and angular dimensions without individual tolerance indications. 93 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.1.1.3 Backing Surface

[0278] In certain embodiments of the backing, and in particular, of the backing surface to which the target metal adheres, is free of oxides, for example, as evaluated by visual inspection. The presence of oxides is typically apparent as a discoloration that obscures the natural luster or color of the raw metal backing. In certain of these embodiments, any observed oxides are removed, e.g., by abrasion. Without being bound by theory, treatment of the backing surface with an abrasive method may further improve purity of the radionuclide product and / or to ensure sufficient adhesion of a target coating which in turn ensures target metal integrity during coin transfer and during particle bombardment.

[0279] In certain embodiments, the backing comprises Nb, wherein the backing surface is free or substantially free of oxides, particularly metal oxides. In certain embodiments, the Nb backing is new or unused, e.g., manufactured and stored to avoid exposure to oxidizing physical conditions. In certain embodiments, the backing is rolled out from a metal foil having a thickness greater than the desired thickness of the backing, thus imparting surface roughness.

[0280] In certain embodiments, the Nb backing surface has some oxidation, e.g., as observed by the presence discoloration of the natural luster or color of the raw metal surface. In related embodiments, the oxidation has been removed by physical abrasion, e.g., as described herein. 5.1.2. Target Metal

[0281] In certain embodiments, the target metal is the material to be irradiated (bombarded by, e.g., protons or deuterons) thereby producing radionuclide compositions of the present disclosure. In certain embodiments, impurities in the target metal are limited to certain levels described herein.

[0282] In certain embodiments, the target metal is electrodeposited, pressed, sintered, press- bonded, melted or physically deposited (through vapor or atomic deposition) onto the backing which acts as a stable carrier during the irradiation process. In certain embodiments, the target metal is in the form of a foil. In certain embodiments, the foil is a sheet or roll.

[0283] In certain embodiments, the electrodeposited target metal forms a target coating. In certain embodiments, the target coating covers only a portion of the backing surface, for 94 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO example, the center of the backing surface but not all the way to the perimeter of the backing surface. In certain embodiments, the target coating is prepared by electroplating the target metal from a plating solution, e.g., as described herein. In certain embodiments, a target coating is prepared by electroplating a target metal from a plating solution onto a backing surface.

[0284] In certain embodiments, the deposited target is a smooth and homogenous deposit with uniform thickness (with less than 25%, 20%, 15%, 12%, 10%, or 5% variability, particularly less than 15% variability) free of observable cracks or craters.

[0285] In certain embodiments, the maximum thickness of the target coating is 0.07 mm, 0.075 mm, 0.08 mm, 0.085 mm, 0.09 mm, 0.095 mm, 0.1 mm, 0.105 mm, 0.11 mm, 0.115 mm, 0.12 mm, 0.125 mm, 0.13 mm, or 0.135 mm. In certain embodiments, the maximum thickness of the target coating is 0.1 mm.

[0286] In certain embodiments, the minimum thickness of the target coating is 0.1 mm, 0.105 mm, 0.11 mm, 0.115 mm, 0.12 mm, 0.125 mm, 0.13 mm, 0.135 mm, 0.14 mm, 0.145 mm, 0.15 mm, 0.155 mm, 0.160 mm, 0.165 mm, 0.17 mm, 0.175 mm, or 0.18 mm. In certain embodiments, the minimum thickness of the target coating is 0.14 mm.

[0287] Unless otherwise indicated, the tolerance of the thickness measurements is ± 0.005 mm.

[0288] In certain embodiments, the amount of target metal deposited on the backing is 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg.

[0289]

[0066] In certain embodiments, the amount of target metal deposited on the backing is 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, or 80 mg. 95 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0290] Unless otherwise indicated, the tolerance of the mass measurements is ± 0.5 mg. 5.1.2.1 Nickel

[0291] In certain embodiments, the target metal is Ni. In certain embodiments, the target metal is natural Ni. Naturally occurring nickel is composed of five stable isotopes.58Ni is the most abundant isotope (68.077% natural abundance). The four minor (i.e., not most abundant) stable isotopes and their corresponding natural abundance is:60Ni (26.223%),61Ni (1.140%),62Ni (3.635%), and64Ni (0.926%).

[0292] In certain embodiments, the target metal is Ni and is isotopically enriched in a minor isotope selected from60Ni,61Ni,62Ni, and64Ni, relative to the minor isotope’s natural abundance in Ni.

[0293] In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 95% or more.

[0294] In certain embodiments, the target metal is Ni that is enriched in60Ni to 95% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 96% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 99% - 99.99%.

[0295] In certain embodiments, the target metal is Ni that is enriched in61Ni to 95% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 95% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 96% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 99% - 99.99%.

[0296] In certain embodiments, the target metal is Ni that is enriched in62Ni to 95% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 96% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 97% - 99.99%. In certain 96 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO embodiments, the target metal is Ni that is enriched in62Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 99% - 99.99%.

[0297] In certain embodiments, the target metal is Ni that is enriched in64Ni to 95% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 96% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 95%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 96%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 97%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 98%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 99%.

[0298] In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 97% or more. In certain embodiments, the target metal is Ni that is enriched in60Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 97% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 98% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in64Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 97% ± 1%.

[0299] In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 99% or more. In certain embodiments, the target metal is Ni that is enriched in60Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in62Ni to 99% - 99.99%. 97 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO In certain embodiments, the target metal is Ni that is enriched in64Ni to 99% - 99.99%. In certain embodiments, the target metal is Ni that is enriched in60Ni to 99% ± 0.5%. In certain embodiments, the target metal is Ni that is enriched in61Ni to 99% ± 0.5%.

[0300] Unless stated otherwise, the tolerance associated with a given enrichment value is ± 0.1%. 5.1.2.2 Zinc

[0301] In certain embodiments, the target metal is Zn. In certain embodiments, the target metal is isotopically enriched in68Zn relative to natural Zn. Natural Zn is composed of five stable isotopes with64Zn being the most abundant isotope (49.17% natural abundance). The minor isotopes along with their natural abundance are66Zn (27.73%),67Zn (4.04%),68Zn (18.45%), and70Zn (0.61%).

[0302] In certain embodiments, the target metal is Zn that is isotopically enriched in68Zn to 95% or more, e.g., 95% - 99.99%. In certain embodiments, the target metal is Zn and is isotopically enriched in68Zn to 99% or more. 5.1.2.3 Target Coating Purity

[0303] In aspects of the provided disclosure, the target coating, i.e., the electrochemically deposited material on the backing surface, is highly pure. In certain embodiments, nuclear bombardment of the present high-purity target coating provides a radionuclide composition of higher purity than if a lower purity target coating had been used. In certain embodiments, the target coating comprises one or more of: Cd ≤ 0.0005 ppm, Co ≤ 0.005 ppm, Pb ≤ 0.005 ppm, Cu ≤ 0.08 ppm, and Fe ≤ 0.15 ppm.

[0304]

[0082] In certain embodiments, the target metal is natural Ni having a chemical purity of 95% - 99.99%, e.g., 96% - 99.99%, 97% - 99.99%, 98% - 99.99%, or 99% - 99.99%.

[0305] In certain embodiments, the target metal is natural Ni having a chemical purity of ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, ≥ 99%.

[0306] In certain embodiments, the target metal is60Ni having a chemical purity of 95% - 99.99%, e.g., 96.% - 99.99%, 97% - 99.99%, 98% - 99.99%, or 99% - 99.99%. 98 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0307] In certain embodiments, the target metal is Ni that is enriched in61Ni having a chemical purity of 95% - 99.99%, e.g., 96% - 99.99%, 97% - 99.99%, 98% - 99.99%, or 99% - 99.99%.

[0308] In certain embodiments, the target metal is Ni that is enriched in62Ni having a chemical purity of 95% - 99.99%, e.g., 96% - 99.99%, 97% - 99.99%, 98% - 99.99%, or 99% - 99.99%.

[0309] In certain embodiments, the target metal is Ni that is enriched in64Ni having a chemical purity of 95% - 99.99%, e.g., 96% - 99.99%, 97% - 99.99%, 98% - 99.99%, or 99% - 99.99%. 5.1.3. Target Coating Dimensions

[0310] The dimensions of the target coating of the present disclosure are not particularly limited. The dimensions can be adjusted, e.g., according to the intended use of the coin. In certain embodiments, the surface area, mass, and thickness of the target coating are selected to accommodate various kinds of irradiation processes. In certain embodiments, the surface area (e.g., based on diameter for a circular coin), mass, and / or thickness of the target coating are selected to optimize, e.g., the activity yield and / or the radionuclidic purity of the produced radionuclide compositions, for example, on the basis of knowledge of the beam properties and reaction cross-sections provided by particular cyclotrons. 5.1.3.1 Target Coating Thickness

[0311] In certain embodiments, the target coating has a thickness of 5 to 250 µm, e.g., 5 to 200 µm, 5 to 180 µm, 5 to 170 µm, 5 to 160 µm, 5 to 150 µm, 5 to 140 µm, 5 to 130 µm, 5 to 120 µm, 5 to 110 µm, 20 to 150 µm, 50 to 150 µm, 75 to 150 µm, 90 to 150 µm, 50 to 130 µm, or 70 to 100 µm.

[0312] In certain embodiments, the target coating has a thickness of 40 to 250 µm, e.g., 50 to 250 µm, 60 to 250 µm, 70 to 250 µm, 80 to 250 µm, 90 to 250 µm, 100 to 250 µm, 110 to 250 µm, 120 to 250 µm, 130 to 250 µm, 140 to 250 µm, 150 to 250 µm, 160 to 250 µm, 170 to 250 µm, 180 to 250 µm, 190 to 250 µm, 200 to 250 µm, 220 to 250 µm, 50 to 220 µm, 50 to 200 µm, 50 to 180 µm, 50 to 160 µm, 50 to 150 µm, 50 to 140 µm, 50 to 130 µm, 50 to 120 µm, 50 to 110 µm, 50 to 100 µm, 50 to 90 µm, 50 to 80 µm, 50 to 70 µm, 100, 125, 150, 175, 200, 225, or 250 µm, 100 µm, 125 µm, 150 µm, 175 µm, 200 µm, 225 µm, 250 µm. 99 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.1.3.2 Target Coating Mass

[0313] In certain embodiments, the target coating has a mass of 40 mg or more. In certain embodiments, the target coating has a mass of 45 mg or more. In certain embodiments, the target coating has a mass of 50 mg or more. In certain embodiments, the target coating has a mass of 60 mg or more. In certain embodiments, the target coating has a mass of 30 to 200 mg, 30 to 180 mg, 30 to 160 mg, , 30 to 140 mg, 30 to 120 mg, 30 to 100 mg, 30 to 90 mg, 30 to 75 mg, 40 to 160 mg, 40 to 130 mg, 40 to 110 mg, 45 to 100 mg, 60 to 100 mg, 70 to 90 mg. In certain embodiments, the target coating has a mass of 75 to 85 mg, 65, 70, 75, 80, 85, or 90 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg. Unless otherwise stated, the tolerance in a provided mass value is ± 3 mg.

[0314] In certain embodiments, electroplating occurs in an electrolytic cell with a fixed anode. In these embodiments, a thicker target coating metal deposition occurs in the center of the backing. This thicker target coating material occurs where the cyclotron beam is most intense, providing a greater effective surface area and volume for direct bombardment, which in turn enhances activation efficiency and subsequently enhanced dissolution rate of the irradiated target coating. In certain embodiments, the target coating has a variability in the thickness of the target coating across the surface of the coating by about 25%, 20%, 15%, 12%, 10%, 5%, or less. In certain embodiments, the variability is 15% or less. In certain embodiments, the variability is 10% or less. For example, in certain embodiments, the thickness of the coating is 15% thicker in the center compared to the thickness at the edges of the coating.

[0315] In certain embodiments, the target coating is 5-30% thicker at the center compared to an average thickness of the coating around the perimeter, e.g., 5%, 7%, 10% or 12% to 15%, 17%, 20%, 25%, or 30% thicker, including 5-15%, 5-20%, 10-15%, 10-17%, 10-20%, 10-25%, 12- 15%, 12-17%, 15-20%, or 12-25%, particularly 10-15% thicker at the center compared to an average thickness of the coating around the perimeter.

[0316] In certain embodiments, the target coating is generally circular in shape, having a diameter of 3 cm or less, e.g., from 2.5 cm to about 0.75 cm. In certain embodiments, 95% of the target coating mass is within a radius of 2.5, 2.0, 1.5, 1.2, or 1 cm. In certain embodiments, the radius may vary by 10%, 7%, 5%, 3%, 2%, or 1%. 100 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.2. Target Diameter

[0317] In certain embodiments, the target coating is electrodeposited on a surface of a backing in a circular shape that has a diameter of 1 cm. In certain embodiments, the diameter is 5 mm to 1 cm, e.g., 5 mm to 500 mm, 5 mm to 250 mm, 5 mm to 100 mm, 10 mm - 50 mm, 10 mm - 25 mm, 8 mm - 15 mm. In certain embodiments, the target coating is a circular shape and has a diameter of 10 mm or 13 mm ± 1mm.

[0318] In certain embodiments, the target coating material remains intact on the surface of the coin after being transferred to and from the cyclotron, such as by means of a pneumatic coin transfer system. An advantage of the present coins is that the electroplated target coating is sufficiently durable to remain adhered to the backing under conditions of direct air flow and abrupt mechanical movements incurred during coin transfer.

[0319] In certain embodiments, the target coating remains adhered to the backing during pneumatic transfer both to and from the cyclotron. Such a pneumatic system is typically fed by a compressed air connection of 6-7 bar, and at minimum, 360 SLPM flow. Such a system is “push- push”, and therefore, compressed air is typically blown on both the front and rear sides of the coin, respectively, depending on the direction of transfer. In certain embodiments, the target coating remains adhered to the backing after the coin comes to an abrupt stop as it reaches the target station or hot cell.

[0320] In certain embodiments, suitable tests that indicate target coating durability include the following, whereby the total plating mass loss for all tests combined should be negligible (e.g. <2%w / w): Visual inspection, gentle knocking / tapping on a countertop on top of white paper to check for loosening of target coating grains, gently rubbing an acid-washed Teflon spatula against the deposited target coating and checking for loosening of target coating grains, and / or placing and gently pressing down on a piece of Scotch tape against the target coating.

[0321] If there is access to the cyclotron apparatus, it is recommended to transfer the coin back / forth multiple times and ensure target coating stability (i.e., no mass loss). Such a test may be performed with or without a degrader (e.g., a 500 µm thin sheet of Al of at least the same dimensions as the target coating or greater) in place. 101 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.3. Methods of Preparing a Coin

[0322] In a further aspect of the present disclosure, a method is provided for preparing a coin comprising a target metal according to the present disclosure as described herein, wherein the method comprises the steps of electroplating the dissolved target metal from a plating solution onto the backing surface; wherein the plating solution has a pH of 9.5 - 10.7. 5.3.1. Obtaining / Preparing the Backing

[0323] In certain embodiments, the backing is comprised of a corrosion-resistant material. In certain embodiments, the backing comprises Nb, Ag, Pt, Au, Al, or W. In certain embodiments, the backing comprises Nb or Ag. In certain embodiments, the backing consists of Nb.

[0324] In certain embodiments, the backing comprises high-purity Nb as described herein, and is used, for example in preparing high-purity radionuclide compositions.

[0325] In further embodiments of these methods, the method further comprises a step of abrading the backing surface. The method of abrading is not particularly limited and includes any kind of mechanical abrasion. In certain embodiments, the entire area of the backing surface to be electroplated is abraded, e.g., to ensure adhesion of the target coating and / or to remove any oxides or discoloration, which may interfere with the electroplating. In certain embodiments, the abrading is performed with a vibrational tumbler. In certain embodiments, the abrading is performed with a corundum grinding stone. In certain embodiments, the abrasion is performed with a Bosh Impact 12 hand grinder (pink corundum abrasive grit size 60) at 50 rpm for a duration of roughly 45 to 60 seconds to cover a surface area of about 650-550 mm2. 5.3.2. Preparing the Plating Solution

[0326] An aspect of the present disclosure is that by utilizing a basic solution for the plating solution, a higher anode-cathode potential can be achieved that reduces plating times, e.g., to < 3 hours compared to the 24 hours of commercially available platings. In addition, the presence of ammonia in the plating solution leads to a lower rate of hydrogen evolution, resulting in a more homogenous and uniform crystal structure and uniform micropores in structure of a target metal coating, e.g., plated layer of Ni or Zn. Without being bound by any particular theory, it is 102 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO thought that this can be attributed to the chemical nature of NH3 and its tendency to receive hydrogen atoms to form NH4+.

[0327] In certain embodiments, a mass of 40 to 100 mg of target metal (e.g.,natNi,60Ni, or61Ni) is electroplated onto a backing surface to be used in a single bombardment session. In certain embodiments, a mass of 50 to 100 mg of target metal is electroplated onto a backing surface to be used in a single bombardment session to obtain a radionuclide, e.g., of61Cu or68Ga, particularly61Cu.

[0328] In an aspect of the present disclosure, a plating solution having a basic pH is provided. In certain embodiments, the pH of the plating solution is from 9 to 11, e.g., 9.5 - 10.7 or 10 - 10.4. In certain embodiments, the plating solution has a pH of 9.5 - 10.7. In certain embodiments, the plating solution has a pH of 10 - 10.4. Unless indicated otherwise, the tolerance of any pH value of the plating solution is ± 0.1.

[0329] In certain embodiments, preparing the plating solution comprises the step of dissolving the target metal starting material, e.g., metal powder, in nitric acid.

[0330] In certain embodiments, electroplating the target metal is from a plating solution wherein the plating solution comprises nitrate ions. In certain embodiments, the plating solution comprises or is prepared using aqueous HNO3. In certain embodiments, the plating solution does not comprise sulfate ions.

[0331] In certain embodiments, the method further comprises the step of preparing a plating solution.

[0332] In certain embodiments, preparing the plating solution comprises dissolving the target metal starting material. In certain embodiments, the plating solution is prepared by combining the target metal and a molar excess of HNO3.In certain embodiments, the HNO3is in the form of 65% nitric acid (aqueous) and is added to the plating solution in excess of 40 grams HNO3 per gram target metal (e.g., HNO3:Ni 40 g:1g).

[0333] In certain embodiments, a mass of 20 to 200 mg of target metal (e.g.,natNi,60Ni, or61Ni) is dissolved in the plating solution. In certain embodiments, a mass of 50 to 100 mg of target 103 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO metal is dissolved in the plating solution. In certain embodiments, the mass of target metal dissolved in the plating solution is 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In certain embodiments, a mass of 50 mg of target metal is dissolved in the plating solution. In certain embodiments, a mass of 100 mg of target metal is dissolved in the plating solution. Unless otherwise stated, the target mass has a tolerance of ± 3 mg.

[0334] In certain embodiments, preparing the plating solution comprises preparing a buffer solution by combining ammonium chloride and ammonium hydroxide in water. In certain embodiments, the plating solution is an ammonium buffer solution. In certain embodiments, the plating solution is or comprises ammonium ions. In certain embodiments, the buffer solution has a pH of 9.2 – 9.40, e.g., 9.28 – 9.30. In certain embodiments, the buffer solution has a pH of about 9.3 (at room temperature).

[0335] In certain embodiments, preparing the plating solution comprises adding a buffer solution to the plating solution comprising ammonium ions. In certain embodiments, a plating solution is prepared by contacting a metal salt with a buffer solution. In certain embodiments, a plating solution is prepared by contacting a metal nitrate with a buffer solution. In certain embodiments, a plating solution is prepared by contacting nickel nitrate with a buffer solution. In certain embodiments, a plating solution comprises a metal salt dissolved in a buffer solution. In certain embodiments, a plating solution comprises a nickel salt dissolve in a buffer solution. In certain embodiments, the plating solution comprises dissolved metal ions. In certain embodiments, the plating solution comprises dissolved metal ions for electrodeposition. In certain embodiments, the plating solution comprises ammonium ions and a dissolved metal for electrodeposition. In certain embodiments, the plating solution comprises nickel ions. In certain of these embodiments, the plating solution comprises the dissolved target metal.

[0336] In certain embodiments, the plating solution comprisesnatNi and / or60Ni or a salt thereof. In certain embodiments, the plating solution comprisesnatNi or a salt thereof. In certain 104 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO embodiments, the plating solution comprises60Ni or a salt thereof. In certain embodiments, the plating solution comprises61Ni or a salt thereof.

[0337] In certain embodiments, the plating solution has a pH of 8.5 to 11. In certain embodiments, the pH of the plating solution is 8 to 10.8. In certain embodiments, the pH is 8.10 to 10.6, 8.2 to 10.5, 8.3 to 10.4, 8.5 to 10.3, 8.6 to 10.25, 8.7 to 10.2, 8.5 to 10.15, 8.5 to 10.1, 8.5 to 10, 8.5 to 9.9, 8.5 to 9.80, 8.5 to 9.6, 8.5 to 9.50, 8.5 to 9.4, 8.5 to 9.3, 8.5 to 9.2, 8.5 to 9.1, or 8.5 to 9. In certain embodiments, the plating solution has a pH of 9, 9.50, 10, 10.05, 10.10, 10.15, 10.20, 10.25, 10.30, 10.35, 10.40, 10.50, 10.60, or 10.70, 9, 10, 10.05, 10.10, 10.15, 10.20, 10.25, 10.30, 10.35, or 10.40.

[0338] In certain embodiments, the step of preparing the plating solution further comprises adjusting the pH of the plating solution, e.g., after addition of the buffer, by adding an effective amount of NH4OH to achieve a particular pH value for the plating solution.

[0339] In further embodiments, the step of adjusting the pH of the plating solution further adding NH4OH, e.g., dropwise, to the plating solution until a desired pH is reached. 5.3.3. Purity of Electroplating Solution

[0340] An aspect of the present disclosure is the provision of a high-purity plating solution for use in the production of high-purity radionuclide compositions. Frequent sources of trace metals are the target metal starting material itself, especially enriched nickel, reagents and instruments used. Iron is common and requires careful consideration to be reduced from the environment in which the plating solution is prepared. Reagents are selected to reduce impurities.

[0341] In certain embodiments of the provided methods, the target metal is selected from those described in this disclosure. In certain embodiments, the target metal used to prepare the plating solution (i.e., target metal source material) is in the form of a metal salt, oxide or elemental metal. In certain of these embodiments, metal oxide or metal (e.g., rod, granules, powder) is at least 98% pure, based on trace metals analysis. In certain embodiments, the target metal source material is at least 99.9% pure based on trace metals analysis. In certain embodiments, the target metal source material is at least 99.99% pure based on trace metals analysis. In certain 105 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO embodiments, the target metal source material comprises no more than 150 ppm sum trace metal impurities.

[0342] In certain embodiments, the method of preparing a coin further comprises a method of purifying the plating solution prior to the electroplating step. In certain embodiments, purifying the plating solution is according to known methods to reduce dissolved Cu, Zn, Fe, Co, Sn, Ti, and / or Al from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu, Zn, Fe, Sn, Ti, and / or Al from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu, Zn, and / or Fe from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu from solutions.

[0343] . In certain embodiments, the plating solution comprises Cu ≤ 0.1 ppm, Cu ≤ 0.2 ppm, Cu ≤ 0.3 ppm, Cu ≤ 0.4 ppm, Cu ≤ 0.5 ppm, Cu ≤ 0.6 ppm, Cu ≤ 0.7 ppm, Cu ≤ 0.8 ppm, Cu ≤ 0.9 ppm, Cu ≤ 10 ppm, Cu ≤ 10.1 ppm, Cu ≤ 10.2 ppm, Cu ≤ 10.3 ppm, Cu ≤ 10.4 ppm, Cu ≤ 10.5 ppm, Cu ≤ 10.6 ppm, Cu ≤ 10.7 ppm, Cu ≤ 10.8 ppm, Cu ≤ 10.9 ppm, Cu ≤ 11 ppm, Cu ≤ 12 ppm, Cu ≤ 13 ppm, Cu ≤ 14 ppm, Cu ≤ 15 ppm, Cu ≤ 16 ppm, Cu ≤ 17 ppm, Cu ≤ 18 ppm, Cu ≤ 19 ppm, or Cu ≤ 20 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.1 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.2 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.3 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.4 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.5 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.6 ppm. In certain embodiments, the plating solution comprises Cu ≤ 0.7 ppm. In a particular embodiment, the plating solution comprises Cu ≤ 0.1 ppm.

[0344] In certain embodiments of the provided methods, the plating solution comprises Fe ≤ 10 ppm. In certain embodiments, the plating solution comprises Fe ≤ 1 ppm, Fe ≤ 5 ppm, Fe ≤ 10 ppm, Fe ≤ 15 ppm, Fe ≤ 20 ppm, Fe ≤ 25 ppm, Fe ≤ 30 ppm, Fe ≤ 32 ppm, or Fe ≤ 35 ppm. In certain embodiments, the plating solution comprises Fe ≤ 1 ppm. In certain embodiments, the plating solution comprises Fe ≤ 5 ppm. In certain embodiments, the plating solution comprises Fe ≤ 10 ppm. In certain embodiments, the plating solution comprises Fe ≤ 15 ppm. In certain embodiments, the plating solution comprises Fe ≤ 20 ppm. In certain embodiments, the plating 106 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO solution comprises Fe ≤ 25 ppm. In certain embodiments, the plating solution comprises Fe ≤ 30 ppm. In certain embodiments, the plating solution comprises Fe ≤ 32 ppm. In certain embodiments, the plating solution comprises Fe ≤ 35 ppm.

[0345] In certain embodiments of the provided methods, the below identified elements are limited to the provided thresholds. That is, in certain embodiments, the plating solution comprises one or more of the following: Ga, Lu, Pb, and / or Y are individually ≤ 0.1 ppm; Zn and / or Co are individually ≤ 0.3 ppm; Cd, Cr, Al, Mn, Mo, Sn, Ti, and / or V are individually ≤ 1 ppm; and Family I and / or II elements are individually ≤ 1000 ppm.

[0346] In certain embodiments, the highest grades of reagents should be used, to avoid trace metal contamination of the target coating, as more than a tenth of a microgram per 100 mg of target metal (that is, 1 ppm of the target metal) is already a significant contamination that may render the coin unusable for production of high-purity radionuclides. In the case of the production of radiocopper it is not accepted to add more than 0.1 ppm of cold Cu as this would reduce the purity of the prepared radionuclide composition.

[0347] In certain embodiments of the provided methods of preparing the plating solution, the maximum level of impurities allowed to be added by this process to the target metal starting material (refer to trace metal analysis of supplied starting material) are: ^ Copper (Cu) ≤ 0.1 ppm; ^ High affinity metals (Ga, Lu, Pb, Y) are individually ≤ 0.1 ppm; ^ Zinc and cobalt (Zn, Co) are individually ≤ 0.3 ppm; ^ Transition and other metals (Cd, Cr, Al, Mn, Mo, Sn, Ti, V, etc.) are individually ≤ 1 ppm; ^ Iron (Fe) ≤ 10 ppm; and ^ Family I and II (K, Ba, Mg, Be, etc.) are individually ≤.1000 ppm.

[0348] In certain embodiments of the provided methods of preparing the plating solution impart only very small amounts of impurities to the solution. In these embodiments, the maximum level 107 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO of impurities added by this process to the target metal starting material (e.g.,natNi and enriched Ni isotopes) in comparison to the trace metal analysis of supplied starting material are limited to: ^ Silver (Ag): ≤ 0.2 ppm; ^ Cobalt (Co): ≤ 0.5 ppm; ^ Chromium (Cr): ≤ 0.2 ppm; ^ Copper (Cu): ≤ 0.3 ppm; ^ Iron (Fe): ≤ 32 ppm; ^ Potassium (K): ≤ 0.2 ppm; ^ Magnesium (Mg): ≤ 0.1 ppm; ^ Manganese (Mn): ≤ 0.1 ppm; ^ Sodium (Na): ≤ 3.2 ppm; and ^ Titanium (Ti): ≤ 0.1 ppm.

[0349] In certain embodiments of the provided methods of preparing the plating solution, the maximum level of impurities tolerated by this process to the target metal (e.g.,natZn andxxZn isotopes) starting material (refer to trace metal analysis of supplied starting material) are one or more of the following: ^ High-affinity metals (Ga, Cu, Lu, Pb, Y): are individually ≤ 0.1 ppm; ^ Zinc and cobalt (Zn, Co) are individually ≤ 0.3 ppm; ^ Transition and other metals (Ca, Cd, Cr, Al, Mn, Mo, Sn, Ti, V….) are individually ≤ 1 ppm; ^ Iron (Fe): are individually ≤ 10 ppm; and ^ Family I and II (K, Ba, Mg, Be, etc.): are individually ≤ 1000 ppm. 5.3.4. Electroplating

[0350] In certain embodiments, the electroplating occurs at a current of 100 to 380 µA. In certain embodiments, the electroplating occurs at a current of 100 to 360 µA, of 100 to 340 µA, of 100 to 320 µA, of 100 to 300 µA, of 100 to 280 µA, of 100 to 260 µA, of 100 to 240 µA, of 100 to 220 µA, of 100 to 210 µA, of 100 to 200 µA, of 100 to 180 µA, of 100 to 170 µA, of 100 to 160 µA, of 120 to 380 µA, of 140 to 380 µA, of 160 to 380 µA, of 180 to 380 µA, of 200 to 380 µA, of 220 to 380 µA, of 240 to 380 µA, of 260 to 380 µA, of 280 to 380 µA, of 300 to 380 µA, of 108 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 320 to 380 µA, of 120 to 350 µA, of 120 to 320 µA, of 120 to 300 µA, of 120 to 280 µA, of 120 to 260 µA, of 120 to 240 µA, of 120 to 220 µA, of 120 to 200 µA. In certain embodiments, the electroplating occurs at a current of 120 to 180 µA, of 130 to 170 µA, of 140 to 170 µA, of 150 to 170 µA. In certain embodiments, the electroplating occurs at a current of 155 to 165 µA. In certain embodiments, the electroplating occurs at a current of 140, 145, 150, 155, 160, 165, 170, 175, or 180 µA. In certain embodiments, the electroplating occurs at a current of 140 µA. In certain embodiments, the electroplating occurs at a current of 145 µA. In certain embodiments, the electroplating occurs at a current of 150 µA. In certain embodiments, the electroplating occurs at a current of 155 µA. In certain embodiments, the electroplating occurs at a current of 160 µA. In certain embodiments, the electroplating occurs at a current of 165 µA. In certain embodiments, the electroplating occurs at a current of 170 µA. In certain embodiments, the electroplating occurs at a current of 175 µA. In certain embodiments, the electroplating occurs at a current of 180 µA. Unless indicated otherwise, the tolerance of any provided current value is ± 0.3 µA.

[0351] In certain embodiments, the electroplating occurs at a voltage of 2.5-6.5 V. In certain embodiments, the electroplating occurs at a voltage of 3.5–6 V. In certain embodiments, the electroplating occurs at a voltage of 3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, 5.0, 5.25, 5.50, 5.75, or 6 V, or within a range defined by any two of these values. For example, the electroplating occurs at a voltage of 4.25-5.25 V or from 4.5-5.5 V. In certain embodiments, the electroplating occurs at a voltage of 5.5 V. Unless indicated otherwise, the tolerance of any provided voltage value is ± 0.2 V.

[0352] In certain embodiments, the electroplating occurs at a temperature of 15-30°C. In certain embodiments, the electroplating occurs at a temperature of 20-25°C. Unless indicated otherwise, the tolerance of any provided temperature value is ± 0.5°C.

[0353] In certain embodiments, the electroplating occurs in a cycle time of ≤ 5 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤ 4 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤ 3 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤ 2 hours. In certain embodiments, the electroplating occurs in a cycle 109 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO time of ≤ 90 minutes. In these embodiments a cycle can comprise plating a single coin, two coins, three coins or more in a batch process.

[0354] In certain embodiments, the electroplating occurs under one or more conditions selected from: a voltage of 3.5 – 5.5 V; temperature of 20-25°C; and a cycle time of ≤ 3 hours. In certain embodiments, the electroplating occurs under two or more conditions selected from: a voltage of 3.5 – 5.5 V; temperature of 20-25°C; and a cycle time of ≤ 3 hours. In certain embodiments, the electroplating occurs under all three conditions selected from: a voltage of 3.5 – 5.5 V; temperature of 20-25°C; and a cycle time of ≤ 3 hours.

[0355] In certain embodiments, the electroplating occurs with a plating solution volume of 30, 25, 20, 15, 12, 10, 7, or 5 mL or less, in particular 10 mL or less.

[0356] In certain embodiments, the electroplating occurs in an electrolytic cell comprising a fixed anode. In certain embodiments, the anode is selected from a graphite anode and a platinum anode. In certain embodiments, the anode is 99.999% trace metal free by weight. In certain embodiments, the anode is a platinum anode. In certain embodiments, the platinum anode is in the form of a wire or foil. 5.4. Methods of Making a High-Purity Radionuclide Composition

[0357] An aspect of the disclosure provided herein is the provision of a method of making a high-purity radionuclide composition. The method comprises: irradiation of the target metal of the coin in a particle accelerator according to the present disclosure to produce an irradiated target coating; and isolation of the produced high-purity radionuclide composition.

[0358] In certain embodiments, the coin comprises a high-purity Nb backing as described herein. In further embodiments, the coin comprises a target coating prepared as described herein.

[0359] An overview of a production process for preparing a copper radionuclidexCu (e.g.,60Cu,61Cu,62Cu, or64Cu) is given below: (1) Coin production as provided herein comprising the use of one of a natural or highly enriched nickel isotope (natNi,60Ni,61Ni,62Ni, or64Ni) or a highly enriched zinc isotope (64Zn or68Zn) as target metal present as a target coating adhered to a high-purity Nb backing 110 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ^ (2) Target coating irradiation with protons or deuterons through a particle accelerator, such as a cyclotron ^^ (3) Dissolution from the coin the irradiated target coating (containingxCu / Ni orxCu / Zn) using an acidic medium, such as 10 M HCl ^^ (4) Purification ofxCu from Ni or Zn starting material through ion-exchange resins and a purification unit ^^ (5) Transfer of [xCu]CuCl2 for characterization and use in labeling or dispensing.

[0360] In certain embodiments of the method of producing high-purity radionuclides, isolating comprises dissolving the irradiated target coating in aqueous HCl solution to obtain a radionuclide chloride solution, such as a [xCu]CuCl2 aqueous solution. In certain of these embodiments, the aqueous HCl solution is a 10 M HCl solution. 5.4.1. Bombardment

[0361] Highly pure compositions comprising positron emitting isotopes of copper suitable for medical use, e.g., in diagnostic imaging or through a Positron Emission Tomography (PET) scan, such as60Cu,61Cu,62Cu, and64Cu, can be produced by the deuteron or proton bombardment of a coin prepared according to the present disclosure (e.g., highly pure Nb backing with a target coating comprising stable nickel or zinc isotopes) through a particle accelerator. Certain embodiments of the nuclear reactions and corresponding production routes possible using a small hospital cyclotron are as listed in Table 1 below: Table 1: Production methods of positron-emitting copper isotopes,60Cu,61Cu,62Cu,64Cu, and67Cu. 111 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Isotope Reaction Incident beam Typical target Reference energy (MeV) metal enrichment (%) a, a, , 2), . embodiments, the radionuclide is61Cu. In certain embodiments, the radionuclide is prepared according tonatNi(d,n)61Cu. In certain embodiments, the radionuclide is prepared according to 60Ni(d,n)61Cu. In certain embodiments, the radionuclide is prepared according to61Ni(p,n)61Cu.

[0363] In certain embodiments, the radionuclide is64Cu. In certain embodiments, the radionuclide is prepared according to64Ni(p,n)64Cu.

[0364] In certain embodiments, the radionuclide is67Cu. In certain embodiments, the radionuclide is prepared according to68Zn(p,2p)67Cu or70Zn(p,^)67Cu. 5.4.1.1 Bombardment Time

[0365] In certain embodiments of the method of producing high-purity radionuclides, the irradiation occurs for one half-life of the radionuclide. In certain of these embodiments, the irradiation is from 60-220 minutes. In certain embodiments, the irradiation is from 30-200 minutes. In certain embodiments, the irradiation is from 50-180 minutes. In certain embodiments, the irradiation is from 60-180 minutes. In certain embodiments, the irradiation is from 80-180 minutes. In certain embodiments, the irradiation is from 90-180 minutes. In certain embodiments, the irradiation is from 100-180 minutes. In certain embodiments, the irradiation is from 110-180 minutes. In certain embodiments, the irradiation is from 120-180 minutes. In certain embodiments, the irradiation is from 30-160 minutes. In certain embodiments, the 112 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO irradiation is from 30-140 minutes. In certain embodiments, the irradiation is from 30-120 minutes. In certain embodiments, the irradiation is from 30-110 minutes. In certain embodiments, the irradiation is from 30-100 minutes. In certain embodiments, the irradiation is from 30-90 minutes. In certain embodiments, the irradiation is from 30-80 minutes. In certain embodiments, the irradiation is from 30-70 minutes. In certain embodiments, the irradiation is from 30-60 minutes. In certain embodiments, the irradiation is 30, 45, 60, 75, 90, 105, 120, 135, 150, or 165 minutes. In certain embodiments, the irradiation is 30 minutes. In certain embodiments, the irradiation is 45 minutes. In certain embodiments, the irradiation is 60 minutes. In certain embodiments, the irradiation is 30 minutes. In certain embodiments, the irradiation is 75 minutes. In certain embodiments, the irradiation is 90 minutes. In certain embodiments, the irradiation is 105 minutes. In certain embodiments, the irradiation is 120 minutes. In certain embodiments, the irradiation is 135 minutes. In certain embodiments, the irradiation is 150 minutes. In certain embodiments, the irradiation is 165 minutes. In certain embodiments, the irradiation is 200 minutes. In certain embodiments, the irradiation is 220 minutes. 5.4.1.2 Bombardment Particles

[0366] In certain embodiments of the method of producing high-purity radionuclides, irradiation comprises: bombarding the target metal with protons, deuterons, or alpha particles. In certain embodiments, the bombardment beam is selected from protons, deuterons, alpha particles, and photons. In certain embodiments, the bombardment beam is selected from protons, deuterons, electrons, and photons. In certain embodiments, the bombardment beam is selected from protons and deuterons. In certain embodiments, the bombardment beam is selected from protons and deuterons. In certain embodiments, the bombardment beam comprises deuterons. In certain embodiments, the bombardment beam comprises protons. In certain embodiments, the bombardment beam comprises alpha particles. In certain embodiments, the bombardment beam comprises photons. 5.4.1.3 Deuteron Bombardment Energy

[0367] In certain embodiments of the method of producing high-purity radionuclides, the target metal is bombarded with deuterons having a beam energy ≤ 9, 3-9, or 8-9 MeV. In certain 113 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO embodiments, the beam energy is 1-10 MeV, 3-9 MeV, 5-9 MeV, 6-9 MeV, 7-9 MeV, 8-9 MeV, 8.1 MeV, 8.2 MeV, 8.3 MeV, 8.4 MeV, 8.5 MeV, 8.6 MeV, 8.7 MeV, 8.8 MeV, or 8.9 MeV. 5.4.1.4 Deuteron Bombardment Current

[0368] In certain embodiments of producing high-purity radionuclides, the target metal is bombarded with deuterons with beam current ≤ 100 µA, e.g., 10-100 µA, 10-60 µA, 10-50 µA, 20-60 µA, 30-60 µA, 40-60 µA, 20-50 µA, 30-50 µA, 35-50 µA, 40-60 µA, 40-55 µA, 40-50 µA, or 40-45 µA.

[0369] In certain of these embodiments, the target metal comprisesnatNi,60Ni, or61Ni. In these embodiments, the high-purity radionuclide composition comprises61Cu.

[0370] In certain embodiments of the method of producing high-purity radionuclides, the target metal is bombarded with deuterons having one or both of a beam energy ≤ 9 MeV and / or a beam current ≤ 100 µA. 5.4.1.5 Proton Bombardment Energy

[0371] In certain embodiments, the target metal is bombarded with protons having a beam energy of 7-20 MeV, e.g., 7-18 MeV, 7-16 MeV, 7-14 MeV, 7-12 MeV, 7-10 MeV, 8-18 MeV, 9-18 MeV, 10-18 MeV, 11-18 MeV, 12-18 MeV, 13-18 MeV, 8-16 MeV, 9-15 MeV, 10-14 MeV, 11-14 MeV, 12-14 MeV, 13-14 MeV, 13.1 MeV, 13.2 MeV, 13.3 MeV, 13.4 MeV, 13.5 MeV, 13.6 MeV, 13.7 MeV, 13.8 MeV, or 13.9 MeV. 5.4.1.6 Proton Bombardment Current

[0372] In certain embodiments, the target metal is bombarded with protons having a beam current of 10-150 µA, e.g., 10-140 µA, 10-130 µA, 10-120 µA, 10-110 µA, 10-100 µA, 10-90 µA, 10-80 µA, 20-150 µA, 30-150 µA, 50-150 µA, 60-150 µA, 70-150 µA, 80-150 µA, 90-150 µA, 100-150 µA, 110-150 µA, 75 µA, 80 µA, 85 µA, 90 µA, or 100 µA.

[0373] In certain of these embodiments, the target metal comprises61Ni and the radionuclide is a61Cu radionuclide. In certain of these embodiments, the target metal comprises60Ni and the radionuclide is a60Cu radionuclide. In certain of these embodiments, the target metal comprises64Ni and the radionuclide is a64Cu radionuclide. In certain of these embodiments, the target 114 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO metal comprises64Zn and the radionuclide is a61Cu radionuclide. In certain of these embodiments, the target metal comprises68Zn and the radionuclide is a64Cu radionuclide.

[0374] In certain embodiments, the radionuclide is prepared according tonatNi(d,n)61Cu.

[0375] In certain embodiments, the radionuclide is prepared according to60Ni(d,n)61Cu.

[0376] In certain embodiments, the radionuclide is prepared according to61Ni(p,n)61Cu.

[0377] In certain embodiments, the radionuclide is prepared according to64Zn(p,α)61Cu.

[0378] In certain embodiments, the radionuclide is64Cu. In certain embodiments, the radionuclide is prepared according to64Ni(p,n)64Cu, e.g., on a particle accelerator such as a medical cyclotron.

[0379] In certain embodiments, the radionuclide is prepared according to68Zn(p,αn)64Cu. 5.4.2. Purification

[0380] In certain embodiments, separation and purification of the high-purity radionuclide (for example, as a [xCu]CuCl2aqueous solution) is accomplished using a cassette-based FASTlab platform. In certain embodiments, a TBP (tributylphosphate-based) resin is used, e.g., (1 mL) (particle size 50-100 µm; pre-packed, Triskem ®). In certain embodiments, a weakly basic resin is used, e.g., (tertiary amine; TK201) (2 mL) (particle size 50-100 µm; pre-packed, Triskem®). In certain embodiments, the resin is pre-conditioned with H2O (7 mL) and HCl (10M, 7 mL). In certain embodiments, cassette reagent vials were prepared using concentrated HCl (Optima Grade, Fischer Scientific), NaCl (ACS, Fischer Scientific) and / or milli-Q water (Millipore system, 18 MΩ-cm resistivity), e.g., 6M HCl (2 x 4.2 mL), 5M NaCl in 0.05 M HCl (4.2 mL). In certain embodiments, the obtained61Cu was then purified with two subsequent ion exchange resins in a FASTlab synthesis unit. In certain embodiments the acid-adjusted dissolution solution (approx.7 mL) was loaded over both columns in series and directed into a “Ni collection fraction”. In certain embodiments a TBP resin is implemented as a guard column as it quantitatively retained Fe3+ions, while the Cu2+and Co2+complexes were quantitatively retained on the tertiary amine (TK201) resin. In certain embodiments, both columns are used and washed with 6M HCl (4 mL) to maximize Ni recovery for future recycling. In certain embodiments, the 115 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO TK201 column was washed with HCl, e.g., 4.5M (5.5 mL) to elute most cobalt salts into the waste stream. In certain embodiments, the TK201 column is washed with HCl, e.g., 5M NaCl in 0.05M (4 mL) to decrease residual acid on the resin and further remove any residual cobalt salts. In certain embodiments, the TK201 column was washed with HCl, e.g., of 0.05M (3 mL) to quantitatively elute the [61Cu]CuCl2. 5.5. Radionuclide Compositions

[0381] In a further aspect of the present disclosure is the provision of a radionuclide composition, e.g., of [61Cu]CuCl2. In various embodiments, a radionuclide composition is produced by the bombardment of a target metal by subatomic particles, e.g., irradiated with protons, deuterons, electrons, or alpha particles, particularly protons or deuterons.

[0382] In certain embodiments, the radionuclide composition is in the form of an aqueous solution, e.g., an aqueous solution that comprises a radionuclide in a salt, such as [61Cu]CuCl2. In certain embodiments, a radioactive composition is dissolved in a HCl solution.

[0383] In various embodiments, the radionuclide composition is in the form of a lyophilized halide salt. In various embodiments, the radionuclide composition is in the form of a lyophilized chloride salt. 5.5.1. Radionuclidic Purity

[0384] The term “radionuclidic purity” refers to the ratio of the radionuclide, expressed as a percentage of total radioactivity content of a radionuclide containing composition. As reported herein, unless otherwise specified, radionuclidic purity is determined by high resolution gamma spectroscopy (e.g., high-purity germanium (HPGe) detector) on a sample after expiration, e.g. >8 hours or >3 weeks) and is then extrapolated (e.g., using the TENDLE-2019 database according to procedures well known in the art), and reported herein as the value at the end of synthesis (EoB+2 hours ) of the radionuclide.

[0385] Radionuclidic purity at “end of synthesis” or “EoS” refers to a measurement at the time the final radionuclide composition is obtained, e.g., after dissolution and optional purification. Unless otherwise stated, EoS is EoB plus 90 minutes. 116 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0386] Various methods for purifying produced copper radioisotopes are known to those of skill in the art, see for example, INTERNATIONAL ATOMIC ENERGY AGENCY, Production of Emerging Radionuclides towards Theranostic Applications: copper-61, Scandium-43 and -44, and Yttrium-86, IAEA-TECDOC-1955, IAEA, Vienna (2021) and the references cited therein. For example, trialkylphosphate and ion exchange-based purification schemes relevant to Cu, such as either61Cu or64Cu purification, are generally applicable.

[0387] In various embodiments, the radionuclide composition has a radionuclidic purity at end of synthesis (EoB plus 90 minutes) of ≥ 95.0%. In certain embodiments, the high-purity composition comprises a6xCu radionuclide, e.g.,61Cu ,64Cu, or67Cu. In certain embodiments, the high-purity composition comprises64Cu, for example, for use as a diagnostic agent. In other embodiments, the high-purity composition comprises67Cu for use as a therapeutic agent. In certain embodiments, the high-purity composition comprises61Cu, for example, for use in radiolabeling a radiotracer for medical use, such as in diagnostic imaging.

[0388] In various embodiments, the high-purity composition comprises61Cu and has a radionuclidic purity at end of synthesis of ≥ 97.0%.

[0389] In certain embodiments, the radionuclide composition, e.g., a high-purity radionuclide, comprising61Cu,64Cu, or67Cu, particularly61Cu, is characterized by one or more of the following purity requirements: 110mAg ≤ 0.1 Bq / g; 108mAg ≤ 0.1 Bq / g; and 109Cd ≤ 0.1 Bq / g.

[0390] Considering radiocobalt impurities, the64Ni(p,α) reaction produces61Co (t½ = 1.649h), with other radiocobalt impurities (e.g.,55Co, etc.) arising largely from the small quantities of other (A ≠ 64) Ni isotopes in the isotopically enriched starting material. In the context of61Cu, however, among other reactions on other Ni isotopes, the dominant61Ni(p,α) and60Ni(d,α) reactions will give rise to long lived58Co (t½ = 70.86 d) producing 0.05% and 0.11% of58Co relative activity compared with61Cu, respectively. As such, efficient purification of the radionuclide composition from radiocobalt by-products may prove to be even more important in 117 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO the context of61Cu purification. In considering QC of61Cu, Section 2.6 of the IAEA Radioisotopes and Radiopharmaceuticals Reports No.1 [INTERNATIONAL ATOMIC ENERGY AGENCY, Cyclotron produced radionuclides: Emerging positron emitters for medical applications:64Cu and124I, Radioisotopes and Radiopharmaceuticals Reports 1, IAEA, Vienna (2016) 63, incorporated herein in its entirety] presents in great detail on64Cu radionuclidic purity, and apparent molar activity.

[0391] In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or60Ni, or via the proton irradiation of61Ni, wherein the composition comprises one or more of the following: 56Co ≤ 1500 Bq / g; 57Co ≤ 100 Bq / g; 58Co ≤ 15000 Bq / g; and 60Co ≤ 15 Bq / g.

[0392] In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or60Ni, or via the proton irradiation of61Ni, wherein the composition comprises two or more of the following: 56Co ≤ 1500 Bq / g; 57Co ≤ 100 Bq / g; 58Co ≤ 15000 Bq / g; 60Co ≤ 15 Bq / g; and / or having two or more of the following: 110mAg ≤ 1 Bq / g; 108mAg ≤ 1 Bq / g; and 109Cd ≤ 1 Bq / g.

[0393] In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or60Ni, or via the proton irradiation of61Ni, wherein the radionuclide is not a Cu radionuclide and the composition comprises one or more of the following: 118 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 110mAg ≤ 0.1 Bq / g; 108mAg ≤ 0.1 Bq / g; and 109Cd ≤ 0.1 Bq / g. 5.5.2. Chemical Purity

[0394] The term “chemical purity,” as used herein, is understood to represent the molar percent of the identified or desired radionuclide to all metals in the sample. The radionuclide compositions prepared by the disclosed methods herein exhibit high chemical purity, which facilitates the production of radiopharmaceuticals with high radiochemical purity.

[0395] Radiochemical purity, as understood herein, is the ratio or percent of radioactivity from the desired radionuclide in the radiopharmaceutical to the total radioactivity of the sample that includes the radiopharmaceutical. Non-radioactive isotopes of metals (“cold” metals) will not contribute to the total radioactivity of a sample, but they can compete with the desired radionuclide for inclusion in the radiopharmaceutical, e.g., competing for chelation sites in the radiopharmaceutical.

[0396] In certain embodiments, the radionuclide composition according to the present disclosure has a chemical purity of ≥ 99.0% by mole. In certain embodiments, the radionuclide composition is prepared according to the methods provided herein.

[0397] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by one or more of the following: Fe ≤ 2 mg / L; 69Cu and65Cu together are ≤ 1 mg / L; Zn ≤ 2 mg / L; Sn ≤ 0.01 mg / L; Ti ≤ 0.01 mg / L; Al ≤ 2 mg / L; As ≤ 1 mg / L; Ni ≤ 1 mg / L; and wherein any one of Cr, Cd, Co, and Y is ≤ 0.1 mg / mL. 119 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0398] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Fe ≤ 2 mg / L. In some embodiments, the radionuclide composition is an aqueous solution characterized by comprising Fe ≤ 2 mg / L, ≤ 1.9 mg / L, ≤ 1.8 mg / L, ≤ 1.7 mg / L, ≤ 1.6 mg / L, ≤ 1.5 mg / L, ≤ 1.4 mg / L, ≤ 1.3 mg / L, ≤ 1.2 mg / L, ≤ 1.1 mg / L, ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, or ≤ 0.1 mg / L.

[0399] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by the sum of69Cu and65Cu ≤ 1 mg / L. In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by the sum of69Cu and65Cu ≤ 1 mg / L, ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, or ≤ 0.01 mg / L.

[0400] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Ni ≤ 1 mg / L, ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, or ≤ 0.01 mg / L.

[0401] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Zn ≤ 2 mg / L, ≤ 1.9 mg / L, ≤ 1.8 mg / L, ≤ 1.7 mg / L, ≤ 1.6 mg / L, ≤ 1.5 mg / L, ≤ 1.4 mg / L, ≤ 1.3 mg / L, ≤ 1.2 mg / L, ≤ 1.1 mg / L, ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, or ≤ 0.1 mg / L.

[0402] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Sn ≤ 0.1 mg / L, ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0403] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Ti ≤ 0.1 mg / L, ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 120 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0404] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Al ≤ 2 mg / L, ≤ 1.9 mg / L, ≤ 1.8 mg / L, ≤ 1.7 mg / L, ≤ 1.6 mg / L, ≤ 1.5 mg / L, ≤ 1.4 mg / L, ≤ 1.3 mg / L, ≤ 1.2 mg / L, ≤ 1.1 mg / L, ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, or ≤ 0.1 mg / L.

[0405] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising As ≤ 1 mg / L, ≤ 0.9 mg / L, ≤ 0.8 mg / L, ≤ 0.7 mg / L, ≤ 0.6 mg / L, ≤ 0.5 mg / L, ≤ 0.4 mg / L, ≤ 0.3 mg / L, ≤ 0.2 mg / L, ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0406] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Cr ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0407] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Cd ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0408] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Co ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L. 121 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0409] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Y ≤ 0.1 mg / L ≤ 0.09 mg / L, ≤ 0.08 mg / L, ≤ 0.07 mg / L, ≤ 0.06 mg / L, ≤ 0.05 mg / L, ≤ 0.04 mg / L, ≤ 0.03 mg / L, ≤ 0.02 mg / L, ≤ 0.01 mg / L, ≤ 0.009 mg / L, ≤ 0.008 mg / L, ≤ 0.007 mg / L, ≤ 0.006 mg / L, ≤ 0.005 mg / L, ≤ 0.004 mg / L, ≤ 0.003 mg / L, ≤ 0.002 mg / L, or ≤ 0.001 mg / L.

[0410] In certain embodiments, trace metal analysis is conducted by ICP-MS, e.g., > 3weeks.

[0411] In certain embodiments, the sum of impurities in the radionuclide composition is ≤ 15 µg / GBq.

[0412] In certain embodiments, the radionuclide composition is characterized by Cu ≤ 1.5 µg / GBq, e.g., ≤ 1.0 µg / GBq; or ≤ 0.5 µg / GBq.

[0413] In certain embodiments, the radionuclide composition is characterized by Al ≤ 3.0 µg / GBq, e.g., ≤ 2.5 µg / GBq; or ≤ 2 µg / GBq.

[0414] In certain embodiments, the radionuclide composition is characterized by Co ≤ 2 µg / GBq, e.g., ≤ 1.5 µg / GBq; or ≤ 1 µg / GBq.

[0415] In certain embodiments, the radionuclide composition is characterized by Fe ≤ 4 µg / GBq, e.g., ≤ 3.5 µg / GBq; or ≤ 3 µg / GBq.

[0416] In certain embodiments, the radionuclide composition is characterized by Pb ≤ 3 µg / GBq, e.g., ≤ 2.5 µg / GBq; or ≤ 2 µg / GBq.

[0417] In certain embodiments, the radionuclide composition is characterized by Ni ≤ 3 µg / GBq, e.g., ≤ 2.50 µg / GBq; or ≤ 2 µg / GBq.

[0418] In certain embodiments, the radionuclide composition is characterized by Zn ≤ 2 µg / GBq, e.g., ≤ 1.5 µg / GBq; or ≤ 1 µg / GBq. 5.5.3. Copper Isotopes

[0419] Highly pure radiocopper compositions comprising60Cu,61Cu,62Cu,64Cu, or67Cu are produced through the deuteron, proton, electron, or alpha particle bombardment of a coin 122 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO prepared as described herein. In certain embodiments, the coin comprises a highly pure Nb backing, a target metal (e.g., a nickel isotope or a mixture thereof, or a zinc isotope, or mixture thereof) through a particle accelerator such as a cyclotron as described herein.

[0420] In certain embodiments, a high-purity copper radionuclide composition is obtained according to any one of the target metals, isotope enrichment levels, and incident beam energy described in in Characterization of a [61Cu]CuCl2 solution

[0421] Radionuclidic solutions provided by the methods and materials described herein are characterized according to various properties and attributes. In some embodiments, for example, activity concentration can be determined by a dose calibrator; pH value can be determined by pH paper; radiochemical purity can be determined by radio thin-layer chromatography; radionuclidic purity and / or identity can be determined by gamma spectrometry; and chemical purity can be determined by inductively couple plasma mass spectrometry (ICP-MS). Among the non-limiting characterization profiles of radionuclidic and radiochemical compositions of the present disclosure, high-purity [61Cu]CuCl2 may be measured according to some of the properties below. 5.5.4. Appearance

[0422] In certain embodiments, composition comprising a radioactive copper salt (e.g., [61Cu]CuCl2) as provided herein is characterized by a color or mixture of colors. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color blue. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color green. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color turquoise. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is colorless. 5.5.5. Activity

[0423] In certain embodiments, the radionuclide composition as described herein, is further characterized by one or more of: an activity concentration of 0.01-23.33 GBq / mL at calibration; a molar activity of 10 – 580 MBq / nmol at calibration; and an activity at end of synthesis of > 500 MBq. An embodiment, as described above, further characterized by one or more of: an activity concentration of > 25 MBq / mL at calibration, a molar activity of 10 – 580 MBq / nmol at calibration, and an activity at the end of synthesis of > 150 MBq. 123 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0424] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of ≥ 500 MBq, ≥ 490 MBq, ≥ 480 MBq, ≥ 470 MBq, ≥ 460 MBq, ≥ 450 MBq, ≥ 440 MBq, ≥ 430 MBq, ≥ 420 MBq, ≥ 410 MBq, ≥ 400 MBq, ≥ 390 MBq, ≥ 380 MBq, ≥ 370 MBq, ≥ 360 MBq, ≥ 350 MBq, ≥ 340 MBq, ≥ 330 MBq, ≥ 320 MBq, ≥ 310 MBq, ≥ 300 MBq, ≥ 290 MBq, ≥ 280 MBq, ≥ 270 MBq, ≥ 260 MBq, ≥ 250 MBq, ≥ 240 MBq, ≥ 230 MBq, ≥ 220 MBq, ≥ 210 MBq, ≥ 200 MBq, ≥ 190 MBq, ≥ 180 MBq, ≥ 170 MBq, ≥ 160 MBq, ≥ 150 MBq, ≥ 140 MBq, ≥ 130 MBq, ≥ 120 MBq, ≥ 110 MBq, ≥ 100 MBq, ≥ 90 MBq, ≥ 80 MBq, ≥ 70 MBq, ≥ 60 MBq, ≥ 50 MBq, ≥ 40 MBq, ≥ 30 MBq, ≥ 20 MBq, or ≥ 10 MBq.

[0425] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of > 500 MBq.

[0426] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of > 150 MBq. 5.5.5.1 Activity Concentration

[0427] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of 50 - 400 MBq / mL, 55 - 395 MBq / mL, 60 - 390 MBq / mL, 65 - 385 MBq / mL, 70 - 380 MBq / mL, 75 - 375 MBq / mL, 80 - 370 MBq / mL, 85 - 365 MBq / mL, 90 - 360 MBq / mL, 95 - 355 MBq / mL, 100 - 350 MBq / mL, 105 - 345 MBq / mL, 110 - 340 MBq / mL, 115 - 335 MBq / mL, 120 - 330 MBq / mL, 125 - 325 MBq / mL, 130 - 320 MBq / mL, 135 - 315 MBq / mL, 140 - 310 MBq / mL, 145 - 305 MBq / mL, 150 - 300 MBq / mL, 155 - 295 MBq / mL, 160 - 290 MBq / mL, 165 - 285 MBq / mL, 170 - 280 MBq / mL, 175 - 275 MBq / mL, 180 - 270 MBq / mL, 185 - 265 MBq / mL, 190 - 260 MBq / mL, 195 - 255 MBq / mL, 200 - 250 MBq / mL, 205 - 245 MBq / mL, 210 - 240 MBq / mL, 215 - 235 MBq / mL, or 220 - 230 MBq / mL.

[0428] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of ≥ 400 MBq / mL, ≥ 395 MBq / mL, ≥ 390 MBq / mL, ≥ 385 MBq / mL, ≥ 380 MBq / mL, ≥ 375 MBq / mL, ≥ 370 MBq / mL, ≥ 365 MBq / mL, ≥ 360 MBq / mL, ≥ 355 MBq / mL, ≥ 350 MBq / mL, ≥ 345 MBq / mL, ≥ 340 MBq / mL, ≥ 335 MBq / mL, ≥ 330 MBq / mL, ≥ 325 MBq / mL, ≥ 320 MBq / mL, ≥ 315 MBq / mL, ≥ 310 MBq / mL, ≥ 305 MBq / mL, ≥ 300 MBq / mL, ≥ 295 MBq / mL, ≥ 290 MBq / mL, ≥ 285 MBq / mL, ≥ 280 MBq / mL, ≥ 275 MBq / mL, ≥ 270 MBq / mL, ≥ 265 MBq / mL, ≥ 260 MBq / mL, ≥ 255 MBq / mL, ≥ 250 124 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO MBq / mL, ≥ 245 MBq / mL, ≥ 240 MBq / mL, ≥ 235 MBq / mL, ≥ 230 MBq / mL, ≥ 225 MBq / mL, ≥ 220 MBq / mL, ≥ 215 MBq / mL, ≥ 210 MBq / mL, ≥ 205 MBq / mL, ≥ 200 MBq / mL, ≥ 195 MBq / mL, ≥ 190 MBq / mL, ≥ 185 MBq / mL, ≥ 180 MBq / mL, ≥ 175 MBq / mL, ≥ 170 MBq / mL, ≥ 165 MBq / mL, ≥ 160 MBq / mL, ≥ 155 MBq / mL, ≥ 150 MBq / mL, ≥ 145 MBq / mL, ≥ 140 MBq / mL, ≥ 135 MBq / mL, ≥ 130 MBq / mL, ≥ 125 MBq / mL, ≥ 120 MBq / mL, ≥ 115 MBq / mL, ≥ 110 MBq / mL, ≥ 105 MBq / mL, ≥ 100 MBq / mL, ≥ 95 MBq / mL, ≥ 90 MBq / mL, ≥ 85 MBq / mL, ≥ 80 MBq / mL, ≥ 75 MBq / mL, ≥ 70 MBq / mL, ≥ 65 MBq / mL, ≥ 60 MBq / mL, ≥ 55 MBq / mL, ≥ 50 MBq / mL, ≥ 45 MBq / mL, or ≥ 40 MBq / mL.

[0429] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of ≥ 30 MBq / mL, ≥ 29 MBq / mL, ≥ 28 MBq / mL, ≥ 27 MBq / mL, ≥ 26 MBq / mL, ≥ 25 MBq / mL, ≥ 24 MBq / mL, ≥ 23 MBq / mL, ≥ 22 MBq / mL, ≥ 21 MBq / mL, ≥ 20 MBq / mL, ≥ 19 MBq / mL, ≥ 18 MBq / mL, ≥ 17 MBq / mL, ≥ 16 MBq / mL, ≥ 15 MBq / mL, ≥ 14 MBq / mL, ≥ 13 MBq / mL, ≥ 12 MBq / mL, ≥ 11 MBq / mL, ≥ 10 MBq / mL, ≥ 9 MBq / mL, ≥ 8 MBq / mL, ≥ 7 MBq / mL, ≥ 6 MBq / mL, ≥ 5 MBq / mL, ≥ 4 MBq / mL, ≥ 3 MBq / mL, ≥ 2 MBq / mL, or ≥ 1 MBq / mL.

[0430] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01 - 25 GBq / mL.

[0431] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01 - 30 GBq / mL, 0.50 - 29.50 GBq / mL, 1 - 29 GBq / mL, 1.50 - 28.50 GBq / mL, 2 - 28 GBq / mL, 2.50 - 27.50 GBq / mL, 3 - 27 GBq / mL, 3.50 - 26.50 GBq / mL, 4 - 26 GBq / mL, 4.50 - 25.50 GBq / mL, 5 - 25 GBq / mL, 5.50 - 24.50 GBq / mL, 6 - 24 GBq / mL, 6.50 - 23.50 GBq / mL, 7 - 23 GBq / mL, 7.50 - 22.50 GBq / mL, 8 - 22 GBq / mL, 8.50 - 21.50 GBq / mL, 9 - 21 GBq / mL, 9.50 - 20.50 GBq / mL, 10 - 20 GBq / mL, 10.50 - 19.50 GBq / mL, 11 - 19 GBq / mL, 11.50 - 18.50 GBq / mL, 12 - 18 GBq / mL, 12.50 - 17.50 GBq / mL, 13 - 17 GBq / mL, 13.50 - 16.50 GBq / mL, 14 - 16 GBq / mL, or 14.50 - 15.50 GBq / mL.

[0432] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01 - 3 GBq / mL, 0.05 - 2.95 GBq / mL, 0.10 - 2.90 GBq / mL, 0.15 - 2.85 GBq / mL, 0.20 - 2.80 GBq / mL, 0.25 - 2.75 GBq / mL, 0.30 - 2.70 GBq / mL, 0.35 - 2.65 GBq / mL, 0.40 - 2.60 GBq / mL, 0.45 - 2.55 GBq / mL, 0.50 - 2.50 GBq / mL, 0.55 - 2.45 GBq / mL, 125 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 0.60 - 2.40 GBq / mL, 0.65 - 2.35 GBq / mL, 0.70 - 2.30 GBq / mL, 0.75 - 2.25 GBq / mL, 0.80 - 2.20 GBq / mL, 0.85 - 2.15 GBq / mL, 0.90 - 2.10 GBq / mL, 0.95 - 2.05 GBq / mL, 1 - 2 GBq / mL, 1.05 - 1.95 GBq / mL, 1.10 - 1.90 GBq / mL, 1.15 - 1.85 GBq / mL, 1.20 - 1.80 GBq / mL, 1.25 - 1.75 GBq / mL, 1.30 - 1.70 GBq / mL, 1.35 - 1.65 GBq / mL, 1.40 - 1.60 GBq / mL, or 1.45 - 1.55 GBq / mL.

[0433] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.25 - 0.50 GBq / mL, 0.50 - 0.75 GBq / mL, 0.75 - 1 GBq / mL, 1 - 1.25 GBq / mL, 1.25 - 1.50 GBq / mL, 1.50 - 1.75 GBq / mL, 1.75 - 2 GBq / mL, 2 - 2.25 GBq / mL, 2.25 - 2.50 GBq / mL, 2.50 - 2.75 GBq / mL, 2.75 - 3 GBq / mL, 3 - 3.25 GBq / mL, 3.25 - 3.50 GBq / mL, 3.50 - 3.75 GBq / mL, 3.75 - 4 GBq / mL, 4 - 4.25 GBq / mL, 4.25 - 4.50 GBq / mL, 4.50 - 4.75 GBq / mL, 4.75 - 5 GBq / mL, 5 - 5.25 GBq / mL, 5.25 - 5.50 GBq / mL, 5.50 - 5.75 GBq / mL, 5.75 - 6 GBq / mL, 6 - 6.25 GBq / mL, 6.25 - 6.50 GBq / mL, 6.50 - 6.75 GBq / mL, 6.75 - 7 GBq / mL, 7 - 7.25 GBq / mL, 7.25 - 7.50 GBq / mL, 7.50 - 7.75 GBq / mL, 7.75 - 8 GBq / mL, 8 - 8.25 GBq / mL, 8.25 - 8.50 GBq / mL, 8.50 - 8.75 GBq / mL, 8.75 - 9 GBq / mL, 9 - 9.25 GBq / mL, 9.25 - 9.50 GBq / mL, 9.50 - 9.75 GBq / mL, 9.75 - 10 GBq / mL, 10 - 10.25 GBq / mL, 10.25 - 10.50 GBq / mL, 10.50 - 10.75 GBq / mL, 10.75 - 11 GBq / mL, 11 - 11.25 GBq / mL, 11.25 - 11.50 GBq / mL, 11.50 - 11.75 GBq / mL, 11.75 - 12 GBq / mL, 12 - 12.25 GBq / mL, 12.25 - 12.50 GBq / mL, 12.50 - 12.75 GBq / mL, 12.75 - 13 GBq / mL, 13 - 13.25 GBq / mL, 13.25 - 13.50 GBq / mL, 13.50 - 13.75 GBq / mL, 13.75 - 14 GBq / mL, 14 - 14.25 GBq / mL, 14.25 - 14.50 GBq / mL, 14.50 - 14.75 GBq / mL, 14.75 - 15 GBq / mL, 15 - 15.25 GBq / mL, 15.25 - 15.50 GBq / mL, 15.50 - 15.75 GBq / mL, 15.75 - 16 GBq / mL, 16 - 16.25 GBq / mL, 16.25 - 16.50 GBq / mL, 16.50 - 16.75 GBq / mL, 16.75 - 17 GBq / mL, 17 - 17.25 GBq / mL, 17.25 - 17.50 GBq / mL, 17.50 - 17.75 GBq / mL, 17.75 - 18 GBq / mL, 18 - 18.25 GBq / mL, 18.25 - 18.50 GBq / mL, 18.50 - 18.75 GBq / mL, 18.75 - 19 GBq / mL, 19 - 19.25 GBq / mL, 19.25 - 19.50 GBq / mL, 19.50 - 19.75 GBq / mL, 19.75 - 20 GBq / mL, 20 - 20.25 GBq / mL, 20.25 - 20.50 GBq / mL, 20.50 - 20.75 GBq / mL, 20.75 - 21 GBq / mL, 21 - 21.25 GBq / mL, 21.25 - 21.50 GBq / mL, 21.50 - 21.75 GBq / mL, 21.75 - 22 GBq / mL, 22 - 22.25 GBq / mL, 22.25 - 22.50 GBq / mL, 22.50 - 22.75 GBq / mL, 22.75 - 23 GBq / mL, 23 - 23.25 GBq / mL, 23.25 - 23.50 GBq / mL, 23.50 - 23.75 GBq / mL, 23.75 - 24 GBq / mL, 24 - 24.25 GBq / mL, 24.25 - 24.50 GBq / mL, 24.50 - 24.75 GBq / mL, or 24.75 - 25 GBq / mL. 126 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.5.5.2 Molar Activity

[0434] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10 – 600 MBq / nmol, 25 - 600 GBq / nmol, 50 - 600 GBq / nmol, 75 - 600 GBq / nmol, 100 - 600 GBq / nmol, 125 - 600 GBq / nmol, 150 - 600 GBq / nmol, 175 - 600 GBq / nmol, 200 - 600 GBq / nmol, 225 - 600 GBq / nmol, 250 - 600 GBq / nmol, 275 - 600 GBq / nmol, 300 - 600 GBq / nmol, 325 - 600 GBq / nmol, 350 - 600 GBq / nmol, 375 - 600 GBq / nmol, 400 - 600 GBq / nmol, 425 - 600 GBq / nmol, 450 - 600 GBq / nmol, 475 - 600 GBq / nmol, 500 - 600 GBq / nmol, 525 - 600 GBq / nmol, 550 - 600 GBq / nmol, or 575 - 600 GBq / nmol.

[0435] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10 - 25 GBq / nmol, 10 - 50 GBq / nmol, 10 - 75 GBq / nmol, 10 - 100 GBq / nmol, 10 - 125 GBq / nmol, 10 - 150 GBq / nmol, 10 - 175 GBq / nmol, 10 - 200 GBq / nmol, 10 - 225 GBq / nmol, 10 - 250 GBq / nmol, 10 - 275 GBq / nmol, 10 - 300 GBq / nmol, 10 - 325 GBq / nmol, 10 - 350 GBq / nmol, 10 - 375 GBq / nmol, 10 - 400 GBq / nmol, 10 - 425 GBq / nmol, 10 - 450 GBq / nmol, 10 - 475 GBq / nmol, 10 - 500 GBq / nmol, 10 - 525 GBq / nmol, 10 - 550 GBq / nmol, 10 - 575 GBq / nmol, 25 - 600 GBq / nmol, 50 - 575 GBq / nmol, 75 - 550 GBq / nmol, 100 - 525 GBq / nmol, 125 - 500 GBq / nmol, 150 - 475 GBq / nmol, 175 - 450 GBq / nmol, 200 - 425 GBq / nmol, 225 - 400 GBq / nmol, 250 - 375 GBq / nmol, 275 - 350 GBq / nmol, or 300 - 325 GBq / nmol.

[0436] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10 - 150 MBq / nmol, 20 - 150 MBq / nmol, 30 - 150 MBq / nmol, 40 - 150 MBq / nmol, 50 - 150 MBq / nmol, 60 - 150 MBq / nmol, 70 - 150 MBq / nmol, 80 - 150 MBq / nmol, 90 - 150 MBq / nmol, 100 - 150 MBq / nmol, 110 - 150 MBq / nmol, 120 - 150 MBq / nmol, 130 - 150 MBq / nmol, 140 - 150 MBq / nmol, 10 - 140 MBq / nmol, 10 - 130 MBq / nmol, 10 - 120 MBq / nmol, 10 - 110 MBq / nmol, 10 - 100 MBq / nmol, 10 - 90 MBq / nmol, 10 - 80 MBq / nmol, 10 - 70 MBq / nmol, 10 - 60 MBq / nmol, 10 - 50 MBq / nmol, 10 - 40 MBq / nmol, 10 - 30 MBq / nmol, 10 - 20 MBq / nmol, 10 - 80 MBq / nmol, 20 - 90 MBq / nmol, 30 - 100 MBq / nmol, 40 - 110 MBq / nmol, 50 - 120 MBq / nmol, 60 - 130 MBq / nmol, or 70 - 140 MBq / nmol. 127 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO

[0437] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 molar activity concentration at calibration of 10 - 150 MBq / nmol. 5.5.6. pH

[0438] In certain embodiments, composition comprising [61Cu]CuCl2 as provided herein is characterized by a pH of 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, or 1.7.

[0439] In certain embodiments, the pH of a [61Cu]CuCl2 solution is 1-1.6. In certain embodiments, the pH is 1.05-1.55, 1.10-1.45, 1.15-1.35, 1.20-1.25.

[0440] In certain embodiments, the pH of a [61Cu]CuCl2 solution is from 0.11 to 1.7, 0.12 to 1.69, 0.13 to 1.68, 0.14 to 1.67, 0.15 to 1.66, 0.16 to 1.65, 0.17 to 1.64, 0.18 to 1.63, 0.19 to 1.62, 0.2 to 1.61, 0.21 to 1.6, 0.22 to 1.59, 0.23 to 1.58, 0.24 to 1.57, 0.25 to 1.56, 0.26 to 1.55, 0.27 to 1.54, 0.28 to 1.53, 0.29 to 1.52, 0.3 to 1.51, 0.31 to 1.5, 0.32 to 1.49, 0.33 to 1.48, 0.34 to 1.47, 0.35 to 1.46, 0.36 to 1.45, 0.37 to 1.44, 0.38 to 1.43, 0.39 to 1.42, 0.4 to 1.41, 0.41 to 1.4, 0.42 to 1.39, 0.43 to 1.38, 0.44 to 1.37, 0.45 to 1.36, 0.46 to 1.35, 0.47 to 1.34, 0.48 to 1.33, 0.49 to 1.32, 0.5 to 1.31, 0.51 to 1.3, 0.52 to 1.29, 0.53 to 1.28, 0.54 to 1.27, 0.55 to 1.26, 0.56 to 1.25, 0.57 to 1.24, 0.58 to 1.23, 0.59 to 1.22, 0.6 to 1.21, 0.61 to 1.2, 0.62 to 1.19, 0.63 to 1.18, 0.64 to 1.17, 0.65 to 1.16, 0.66 to 1.15, 0.67 to 1.14, 0.68 to 1.13, 0.69 to 1.12, 0.7 to 1.11, 0.71 to 1.1, 0.72to1.09, 0.73 to 1.08, 0.74 to 1.07, 0.75 to 1.06, 0.76 to 1.05, 0.77 to 1.04, 0.78 to 1.03, 0.79 to 1.02, 0.8 to 1.01, 0.81 to 1, 0.82 to 0.99, 0.83 to 0.98, or 0.84 to 0.97. 128 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.5.7. Radionuclidic purity

[0441] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a radionuclidic purity of ≥ 99.99%, ≥ 99.98%, ≥ 99.97%, ≥ 99.96%, ≥ 99.95%, ≥ 99.94%, ≥ 99.93%, ≥ 99.92%, ≥ 99.91%, ≥ 99.90%, ≥ 99.89%, ≥ 99.88%, ≥ 99.87%, ≥ 99.86%, ≥ 99.85%, ≥ 99.84%, ≥ 99.83%, ≥ 99.82%, ≥ 99.81%, ≥ 99.80%, ≥ 99.79%, ≥ 99.78%, ≥ 99.77%, ≥ 99.76%, ≥ 99.75%, ≥ 99.74%, ≥ 99.73%, ≥ 99.72%, ≥ 99.71%, ≥ 99.70%, ≥ 99.69%, ≥ 99.68%, ≥ 99.67%, ≥ 99.66%, ≥ 99.65%, ≥ 99.64%, ≥ 99.63%, ≥ 99.62%, ≥ 99.61%, ≥ 99.60%, ≥ 99.59%, ≥ 99.58%, ≥ 99.57%, ≥ 99.56%, ≥ 99.55%, ≥ 99.54%, ≥ 99.53%, ≥ 99.52%, ≥ 99.51%, ≥ 99.50%, ≥ 99.49%, ≥ 99.48%, ≥ 99.47%, ≥ 99.46%, ≥ 99.45%, ≥ 99.44%, ≥ 99.43%, ≥ 99.42%, ≥ 99.41%, ≥ 99.40%, ≥ 99.39%, ≥ 99.38%, ≥ 99.37%, ≥ 99.36%, ≥ 99.35%, ≥ 99.34%, ≥ 99.33%, ≥ 99.32%, ≥ 99.31%, ≥ 99.30%, ≥ 99.29%, ≥ 99.28%, ≥ 99.27%, ≥ 99.26%, ≥ 99.25%, ≥ 99.24%, ≥ 99.23%, ≥ 99.22%, ≥ 99.21%, ≥ 99.20%, ≥ 99.19%, ≥ 99.18%, ≥ 99.17%, ≥ 99.16%, ≥ 99.15%, ≥ 99.14%, ≥ 99.13%, ≥ 99.12%, ≥ 99.11%, ≥ 99.10%, ≥ 99.09%, ≥ 99.08%, ≥ 99.07%, ≥ 99.06%, ≥ 99.05%, ≥ 99.04%, ≥ 99.03%, ≥ 99.02%, ≥ 99.01%, ≥ 99.00%, ≥ 98.99%, ≥ 98.98%, ≥ 98.97%, ≥ 98.96%, ≥ 98.95%, ≥ 98.94%, ≥ 98.93%, ≥ 98.92%, ≥ 98.91%, ≥ 98.90%, ≥ 98.89%, ≥ 98.88%, ≥ 98.87%, ≥ 98.86%, ≥ 98.85%, ≥ 98.84%, ≥ 98.83%, ≥ 98.82%, ≥ 98.81%, ≥ 98.80%, ≥ 98.79%, ≥ 98.78%, ≥ 98.77%, ≥ 98.76%, ≥ 98.75%, ≥ 98.74%, ≥ 98.73%, ≥ 98.72%, ≥ 98.71%, ≥ 98.70%, ≥ 98.69%, ≥ 98.68%, ≥ 98.67%, ≥ 98.66%, ≥ 98.65%, ≥ 98.64%, ≥ 98.63%, ≥ 98.62%, ≥ 98.61%, ≥ 98.60%, ≥ 98.59%, ≥ 98.58%, ≥ 98.57%, ≥ 98.56%, ≥ 98.55%, ≥ 98.54%, ≥ 98.53%, ≥ 98.52%, ≥ 98.51%, ≥ 98.50%, ≥ 98.49%, ≥ 98.48%, ≥ 98.47%, ≥ 98.46%, ≥ 98.45%, ≥ 98.44%, ≥ 98.43%, ≥ 98.42%, ≥ 98.41%, ≥ 98.40%, ≥ 98.39%, ≥ 98.38%, ≥ 98.37%, ≥ 98.36%, ≥ 98.35%, ≥ 98.34%, ≥ 98.33%, ≥ 98.32%, ≥ 98.31%, ≥ 98.30%, ≥ 98.29%, ≥ 98.28%, ≥ 98.27%, ≥ 98.26%, ≥ 98.25%, ≥ 98.24%, ≥ 98.23%, ≥ 98.22%, ≥ 98.21%, ≥ 98.20%, ≥ 98.19%, ≥ 98.18%, ≥ 98.17%, ≥ 98.16%, ≥ 98.15%, ≥ 98.14%, ≥ 98.13%, ≥ 98.12%, ≥ 98.11%, ≥ 98.10%, ≥ 98.09%, ≥ 98.08%, ≥ 98.07%, ≥ 98.06%, ≥ 98.05%, ≥ 98.04%, ≥ 98.03%, ≥ 98.02%, ≥ 98.01%, ≥ 98.00%, ≥ 97.99%, ≥ 97.98%, ≥ 97.97%, ≥ 97.96%, ≥ 97.95%, ≥ 97.94%, ≥ 97.93%, ≥ 97.92%, ≥ 97.91%, ≥ 97.90%, ≥ 97.89%, ≥ 97.88%, ≥ 97.87%, ≥ 97.86%, ≥ 97.85%, ≥ 97.84%, ≥ 97.83%, ≥ 97.82%, ≥ 97.81%, ≥ 97.80%, ≥ 97.79%, ≥ 97.78%, ≥ 97.77%, ≥ 97.76%, ≥ 97.75%, ≥ 97.74%, ≥ 97.73%, ≥ 97.72%, ≥ 97.71%, ≥ 97.70%, ≥ 97.69%, ≥ 97.68%, ≥ 97.67%, ≥ 97.66%, ≥ 97.65%, ≥ 97.64%, ≥ 97.63%, ≥ 97.62%, ≥ 97.61%, ≥ 97.60%, ≥ 97.59%, ≥ 97.58%, ≥ 97.57%, 129 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ≥ 97.56%, ≥ 97.55%, ≥ 97.54%, ≥ 97.53%, ≥ 97.52%, ≥ 97.51%, ≥ 97.50%, ≥ 97.49%, ≥ 97.48%, ≥ 97.47%, ≥ 97.46%, ≥ 97.45%, ≥ 97.44%, ≥ 97.43%, ≥ 97.42%, ≥ 97.41%, ≥ 97.40%, ≥ 97.39%, ≥ 97.38%, ≥ 97.37%, ≥ 97.36%, ≥ 97.35%, ≥ 97.34%, ≥ 97.33%, ≥ 97.32%, ≥ 97.31%, ≥ 97.30%, ≥ 97.29%, ≥ 97.28%, ≥ 97.27%, ≥ 97.26%, ≥ 97.25%, ≥ 97.24%, ≥ 97.23%, ≥ 97.22%, ≥ 97.21%, ≥ 97.20%, ≥ 97.19%, ≥ 97.18%, ≥ 97.17%, ≥ 97.16%, ≥ 97.15%, ≥ 97.14%, ≥ 97.13%, ≥ 97.12%, ≥ 97.11%, ≥ 97.10%, ≥ 97.09%, ≥ 97.08%, ≥ 97.07%, ≥ 97.06%, ≥ 97.05%, ≥ 97.04%, ≥ 97.03%, ≥ 97.02%, ≥ 97.01%, or ≥ 97%. 5.5.8. Long Lived Radionuclidic impurities

[0442] In certain embodiments of a method of producing high-purity radionuclides as provided herein, comprising the step of isolating a desired radionuclide the method further comprises the step of purifying a radionuclide salt solution to decrease amounts of chemical impurities. In certain of these embodiments, purifying includes anion / cation exchange chromatography. In certain embodiments, purifying comprises alkyl phosphate resin chromatography. In certain embodiments, purifying comprises weak cation exchange chromatography. In certain embodiments, purifying comprises decreasing the specific activity (e.g., in Bq / g) of certain radionuclides below a certain threshold.

[0443] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a56Cospecific activity of ≤ 1500 Bq / g, ≤ 1450 Bq / g, ≤ 1400 Bq / g, ≤ 1350 Bq / g, ≤ 1300 Bq / g, ≤ 1250 Bq / g, ≤ 1200 Bq / g, ≤ 1150 Bq / g, ≤ 1100 Bq / g, ≤ 1050 Bq / g, ≤ 1000 Bq / g, ≤ 950 Bq / g, ≤ 900 Bq / g, ≤ 850 Bq / g, ≤ 800 Bq / g, ≤ 750 Bq / g, ≤ 700 Bq / g, ≤ 650 Bq / g, ≤ 600 Bq / g, ≤ 550 Bq / g, ≤ 500 Bq / g, ≤ 450 Bq / g, ≤ 400 Bq / g, ≤ 350 Bq / g, ≤ 300 Bq / g, ≤ 250 Bq / g, ≤ 200 Bq / g, ≤ 150 Bq / g, ≤ 100 Bq / g, or ≤ 50 Bq / g.

[0444] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a57Cospecific activity of ≤ 100 Bq / g, ≤ 95 Bq / g, ≤ 90 Bq / g, ≤ 85 Bq / g, ≤ 80 Bq / g, ≤ 75 Bq / g, ≤ 70 Bq / g, ≤ 65 Bq / g, ≤ 60 Bq / g, ≤ 55 Bq / g, ≤ 50 Bq / g, ≤ 45 Bq / g, ≤ 40 Bq / g, ≤ 35 Bq / g, ≤ 30 Bq / g, ≤ 25 Bq / g, ≤ 20 Bq / g, ≤ 15 Bq / g, ≤ 10 Bq / g, ≤ 5 Bq / g, ≤ 4.6 Bq / g, ≤ 4.5 Bq / g, ≤ 4.4 Bq / g, ≤ 4.3 Bq / g, ≤ 4.2 Bq / g, ≤ 4.1 Bq / g, ≤ 4 Bq / g, ≤ 3.9 Bq / g, ≤ 3.8 Bq / g, ≤ 3.7 Bq / g, ≤ 3.6 Bq / g, ≤ 3.5 Bq / g, ≤ 3.4 Bq / g, ≤ 3.3 Bq / g, ≤ 3.2 Bq / g, ≤ 3.1 Bq / g, ≤ 3 Bq / g, ≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 130 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0445] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a58Cospecific activity of ≤ 1500 Bq / g, ≤ 1450 Bq / g, ≤ 1400 Bq / g, ≤ 1350 Bq / g, ≤ 1300 Bq / g, ≤ 1250 Bq / g, ≤ 1200 Bq / g, ≤ 1150 Bq / g, ≤ 1100 Bq / g, ≤ 1050 Bq / g, ≤ 1000 Bq / g, ≤ 950 Bq / g, ≤ 900 Bq / g, ≤ 850 Bq / g, ≤ 800 Bq / g, ≤ 750 Bq / g, ≤ 700 Bq / g, ≤ 650 Bq / g, ≤ 600 Bq / g, ≤ 575 Bq / g, ≤ 550 Bq / g, ≤ 525 Bq / g, ≤ 500 Bq / g, ≤ 475 Bq / g, ≤ 450 Bq / g, ≤ 425 Bq / g, ≤ 400 Bq / g, ≤ 375 Bq / g, ≤ 350 Bq / g, ≤ 325 Bq / g, ≤ 300 Bq / g, ≤ 275 Bq / g, ≤ 250 Bq / g, ≤ 225 Bq / g, ≤ 200 Bq / g, ≤ 175 Bq / g, ≤ 150 Bq / g, ≤ 125 Bq / g, ≤ 100 Bq / g, ≤ 75 Bq / g, ≤ 50 Bq / g, or ≤ 25 Bq / g.

[0446] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a60Cospecific activity of ≤ 15 Bq / g,≤ 14 Bq / g,≤ 13 Bq / g,≤ 12 Bq / g,≤ 11 Bq / g,≤ 10 Bq / g,≤ 9 Bq / g,≤ 8 Bq / g,≤ 7 Bq / g,≤ 6 Bq / g,≤ 5 Bq / g,≤ 4 Bq / g,≤ 3 Bq / g,≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0447] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a108mAgspecific activity of ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, ≤ 0.1 Bq / g.

[0448] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a110mAgspecific activity of ≤ 5 Bq / g, ≤ 4.9 Bq / g, ≤ 4.8 Bq / g, ≤ 4.7 Bq / g, ≤ 4.6 Bq / g, ≤ 4.5 Bq / g, ≤ 4.4 Bq / g, ≤ 4.3 Bq / g, ≤ 4.2 Bq / g, ≤ 4.1 Bq / g, ≤ 4 Bq / g, ≤ 3.9 Bq / g, ≤ 3.8 Bq / g, ≤ 3.7 Bq / g, ≤ 3.6 Bq / g, ≤ 3.5 Bq / g, ≤ 3.4 Bq / g, ≤ 3.3 Bq / g, ≤ 3.2 Bq / g, ≤ 3.1 Bq / g, ≤ 3 Bq / g, ≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 131 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0449] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a109Cdspecific activity of ≤ 15 Bq / g, ≤ 14 Bq / g, ≤ 13 Bq / g, ≤ 12 Bq / g, ≤ 11 Bq / g, ≤ 10 Bq / g, ≤ 9 Bq / g, ≤ 8 Bq / g, ≤ 7 Bq / g, ≤ 6 Bq / g, ≤ 5 Bq / g, ≤ 4 Bq / g, ≤ 3 Bq / g, ≤ 2 Bq / g, or ≤ 1 Bq / g. 5.5.9. Radiochemical identity

[0450] In certain embodiments, the presence and / or quantity of61Cuis characterized by γ- photons. In certain embodiments,61Cuis characterized by γ-photons with energy peak at: 511 ± 20 keV. In certain embodiments,61Cuis characterized by γ-photons with energy peak at: 511 ± 20 keV and 283 keV ± 20 keV. In certain embodiments,61Cuis characterized by γ-photons with energy peak at: 511 ± 20 keV, 283 keV ± 20 keV, and 656 keV ± 20 keV. In certain embodiments,61Cuis characterized by γ-photons with energy peak at: 511 ± 20 keV (eventually sum peak at 1022 keV ± 20 keV), 283 keV ± 20 keV and 656 keV ± 20 keV. 5.5.10. Chemical purity

[0451] In certain embodiments,61Cucan be characterized by other chemical impurities. In certain embodiments, non-radioactive (cold) elements are present in a [61Cu]CuCl2 solution. In certain embodiments, cold elements are present and quantified by ICP-MS (inductively coupled plasma mass spectrometry). In some embodiments,61Cuis a transmutation product provided by methods described in the present disclosure. In some embodiments, transmutation of a target metal (e.g.,natNi,60Ni,or61Ni) provides61Cuin varying levels of radiochemical purity. 5.5.10.1 Aluminum

[0452] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising aluminum (e.g., non-radioactive)in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 132 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.5.10.2 Cobalt

[0453] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising cobalt (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.5.10.3 Copper

[0454] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising copper (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.5.10.4 Iron

[0455] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising iron (e.g., non-radioactive) in an amount ≤ 3 ng / MBq, ≤ 2.9 ng / MBq, ≤ 2.8 ng / MBq, ≤ 2.7 ng / MBq, ≤ 2.6 ng / MBq, ≤ 2.5 ng / MBq, ≤ 2.4 ng / MBq, ≤ 2.3 ng / MBq, ≤ 2.2 ng / MBq, ≤ 2.1 ng / MBq, ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.5.10.5 Lead

[0456] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising lead (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 133 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.5.10.6 Nickel

[0457] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising nickel (e.g., non-radioactive) in an amount ≤ 4.5 ng / MBq, ≤ 4.4 ng / MBq, ≤ 4.3 ng / MBq, ≤ 4.2 ng / MBq, ≤ 4.1 ng / MBq, ≤ 4 ng / MBq, ≤ 3.9 ng / MBq, ≤ 3.8 ng / MBq, ≤ 3.7 ng / MBq, ≤ 3.6 ng / MBq, ≤ 3.5 ng / MBq, ≤ 3.4 ng / MBq, ≤ 3.3 ng / MBq, ≤ 3.2 ng / MBq, ≤ 3.1 ng / MBq, ≤ 3 ng / MBq, ≤ 2.9 ng / MBq, ≤ 2.8 ng / MBq, ≤ 2.7 ng / MBq, ≤ 2.6 ng / MBq, ≤ 2.5 ng / MBq, ≤ 2.4 ng / MBq, ≤ 2.3 ng / MBq, ≤ 2.2 ng / MBq, ≤ 2.1 ng / MBq, ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.5.10.7 Zinc

[0458] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising zinc (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. below; wherein the irradiation occurs in a cyclotron (e.g., a medical cyclotron). 5.6. Characterization of a [61Cu]CuCl2solution

[0459] Radionuclidic solutions provided by the methods and materials described herein are characterized according to various properties and attributes. In some embodiments, for example, activity concentration can be determined by a dose calibrator; pH value can be determined by pH paper; radiochemical purity can be determined by radio thin-layer chromatography; radionuclidic purity and / or identity can be determined by gamma spectrometry; and chemical purity can be determined by inductively couple plasma mass spectrometry (ICP-MS). Among the non-limiting characterization profiles of radionuclidic and radiochemical compositions of the present disclosure, high-purity [61Cu]CuCl2 may be measured according to some of the properties below. 134 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.6.1. Appearance

[0460] In certain embodiments, composition comprising a radioactive copper salt (e.g., [61Cu]CuCl2) as provided herein is characterized by a color or mixture of colors. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color blue. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color green. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color turquoise. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is colorless. 5.6.2. Activity

[0461] In certain embodiments, the radionuclide composition as described herein, is further characterized by one or more of: an activity concentration of 0.01-23.33 GBq / mL at calibration; a molar activity of 10 – 580 MBq / nmol at calibration; and an activity at end of synthesis of > 500 MBq. An embodiment, as described above, further characterized by one or more of: an activity concentration of > 25 MBq / mL at calibration,a molar activity of 10 – 580 MBq / nmol at calibration, and an activity at the end of synthesis of > 150 MBq.

[0462] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of ≥ 500 MBq, ≥ 490 MBq, ≥ 480 MBq, ≥ 470 MBq, ≥ 460 MBq, ≥ 450 MBq, ≥ 440 MBq, ≥ 430 MBq, ≥ 420 MBq, ≥ 410 MBq, ≥ 400 MBq, ≥ 390 MBq, ≥ 380 MBq, ≥ 370 MBq, ≥ 360 MBq, ≥ 350 MBq, ≥ 340 MBq, ≥ 330 MBq, ≥ 320 MBq, ≥ 310 MBq, ≥ 300 MBq, ≥ 290 MBq, ≥ 280 MBq, ≥ 270 MBq, ≥ 260 MBq, ≥ 250 MBq, ≥ 240 MBq, ≥ 230 MBq, ≥ 220 MBq, ≥ 210 MBq, ≥ 200 MBq, ≥ 190 MBq, ≥ 180 MBq, ≥ 170 MBq, ≥ 160 MBq, ≥ 150 MBq, ≥ 140 MBq, ≥ 130 MBq, ≥ 120 MBq, ≥ 110 MBq, ≥ 100 MBq, ≥ 90 MBq, ≥ 80 MBq, ≥ 70 MBq, ≥ 60 MBq, ≥ 50 MBq, ≥ 40 MBq, ≥ 30 MBq, ≥ 20 MBq, or ≥ 10 MBq.

[0463] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity at end of synthesis of > 500 MBq.

[0464] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity at end of synthesis of > 150 MBq. 135 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.6.2.1 Activity Concentration

[0465] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of 50 - 400 MBq / mL, 55 - 395 MBq / mL, 60 - 390 MBq / mL, 65 - 385 MBq / mL, 70 - 380 MBq / mL, 75 - 375 MBq / mL, 80 - 370 MBq / mL, 85 - 365 MBq / mL, 90 - 360 MBq / mL, 95 - 355 MBq / mL, 100 - 350 MBq / mL, 105 - 345 MBq / mL, 110 - 340 MBq / mL, 115 - 335 MBq / mL, 120 - 330 MBq / mL, 125 - 325 MBq / mL, 130 - 320 MBq / mL, 135 - 315 MBq / mL, 140 - 310 MBq / mL, 145 - 305 MBq / mL, 150 - 300 MBq / mL, 155 - 295 MBq / mL, 160 - 290 MBq / mL, 165 - 285 MBq / mL, 170 - 280 MBq / mL, 175 - 275 MBq / mL, 180 - 270 MBq / mL, 185 - 265 MBq / mL, 190 - 260 MBq / mL, 195 - 255 MBq / mL, 200 - 250 MBq / mL, 205 - 245 MBq / mL, 210 - 240 MBq / mL, 215 - 235 MBq / mL, or 220 - 230 MBq / mL.

[0466] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of ≥ 400 MBq / mL, ≥ 395 MBq / mL, ≥ 390 MBq / mL, ≥ 385 MBq / mL, ≥ 380 MBq / mL, ≥ 375 MBq / mL, ≥ 370 MBq / mL, ≥ 365 MBq / mL, ≥ 360 MBq / mL, ≥ 355 MBq / mL, ≥ 350 MBq / mL, ≥ 345 MBq / mL, ≥ 340 MBq / mL, ≥ 335 MBq / mL, ≥ 330 MBq / mL, ≥ 325 MBq / mL, ≥ 320 MBq / mL, ≥ 315 MBq / mL, ≥ 310 MBq / mL, ≥ 305 MBq / mL, ≥ 300 MBq / mL, ≥ 295 MBq / mL, ≥ 290 MBq / mL, ≥ 285 MBq / mL, ≥ 280 MBq / mL, ≥ 275 MBq / mL, ≥ 270 MBq / mL, ≥ 265 MBq / mL, ≥ 260 MBq / mL, ≥ 255 MBq / mL, ≥ 250 MBq / mL, ≥ 245 MBq / mL, ≥ 240 MBq / mL, ≥ 235 MBq / mL, ≥ 230 MBq / mL, ≥ 225 MBq / mL, ≥ 220 MBq / mL, ≥ 215 MBq / mL, ≥ 210 MBq / mL, ≥ 205 MBq / mL, ≥ 200 MBq / mL, ≥ 195 MBq / mL, ≥ 190 MBq / mL, ≥ 185 MBq / mL, ≥ 180 MBq / mL, ≥ 175 MBq / mL, ≥ 170 MBq / mL, ≥ 165 MBq / mL, ≥ 160 MBq / mL, ≥ 155 MBq / mL, ≥ 150 MBq / mL, ≥ 145 MBq / mL, ≥ 140 MBq / mL, ≥ 135 MBq / mL, ≥ 130 MBq / mL, ≥ 125 MBq / mL, ≥ 120 MBq / mL, ≥ 115 MBq / mL, ≥ 110 MBq / mL, ≥ 105 MBq / mL, ≥ 100 MBq / mL, ≥ 95 MBq / mL, ≥ 90 MBq / mL, ≥ 85 MBq / mL, ≥ 80 MBq / mL, ≥ 75 MBq / mL, ≥ 70 MBq / mL, ≥ 65 MBq / mL, ≥ 60 MBq / mL, ≥ 55 MBq / mL, ≥ 50 MBq / mL, ≥ 45 MBq / mL, or ≥ 40 MBq / mL.

[0467] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity concentration at calibration of ≥ 30 MBq / mL, ≥ 29 MBq / mL, ≥ 28 MBq / mL, ≥ 27 MBq / mL, ≥ 26 MBq / mL, ≥ 25 MBq / mL, ≥ 24 MBq / mL, ≥ 23 MBq / mL, ≥ 22 MBq / mL, ≥ 21 MBq / mL, ≥ 20 MBq / mL, ≥ 19 MBq / mL, ≥ 18 MBq / mL, ≥ 17 MBq / mL, ≥ 16 MBq / mL, ≥ 15 MBq / mL, ≥ 14 MBq / mL, ≥ 13 MBq / mL, ≥ 12 MBq / mL, ≥ 11 MBq / mL, ≥ 10 MBq / mL, ≥ 9 MBq / mL, ≥ 8 136 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO MBq / mL, ≥ 7 MBq / mL, ≥ 6 MBq / mL, ≥ 5 MBq / mL, ≥ 4 MBq / mL, ≥ 3 MBq / mL, ≥ 2 MBq / mL, or ≥ 1 MBq / mL.

[0468] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity concentration at calibration of 0.01 - 25 GBq / mL.

[0469] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01 - 30 GBq / mL, 0.50 - 29.50 GBq / mL, 1 - 29 GBq / mL, 1.50 - 28.50 GBq / mL, 2 - 28 GBq / mL, 2.50 - 27.50 GBq / mL, 3 - 27 GBq / mL, 3.50 - 26.50 GBq / mL, 4 - 26 GBq / mL, 4.50 - 25.50 GBq / mL, 5 - 25 GBq / mL, 5.50 - 24.50 GBq / mL, 6 - 24 GBq / mL, 6.50 - 23.50 GBq / mL, 7 - 23 GBq / mL, 7.50 - 22.50 GBq / mL, 8 - 22 GBq / mL, 8.50 - 21.50 GBq / mL, 9 - 21 GBq / mL, 9.50 - 20.50 GBq / mL, 10 - 20 GBq / mL, 10.50 - 19.50 GBq / mL, 11 - 19 GBq / mL, 11.50 - 18.50 GBq / mL, 12 - 18 GBq / mL, 12.50 - 17.50 GBq / mL, 13 - 17 GBq / mL, 13.50 - 16.50 GBq / mL, 14 - 16 GBq / mL, or 14.50 - 15.50 GBq / mL.

[0470] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity concentration at calibration of 0.01 - 3 GBq / mL, 0.05 - 2.95 GBq / mL, 0.10 - 2.90 GBq / mL, 0.15 - 2.85 GBq / mL, 0.20 - 2.80 GBq / mL, 0.25 - 2.75 GBq / mL, 0.30 - 2.70 GBq / mL, 0.35 - 2.65 GBq / mL, 0.40 - 2.60 GBq / mL, 0.45 - 2.55 GBq / mL, 0.50 - 2.50 GBq / mL, 0.55 - 2.45 GBq / mL, 0.60 - 2.40 GBq / mL, 0.65 - 2.35 GBq / mL, 0.70 - 2.30 GBq / mL, 0.75 - 2.25 GBq / mL, 0.80 - 2.20 GBq / mL, 0.85 - 2.15 GBq / mL, 0.90 - 2.10 GBq / mL, 0.95 - 2.05 GBq / mL, 1 - 2 GBq / mL, 1.05 - 1.95 GBq / mL, 1.10 - 1.90 GBq / mL, 1.15 - 1.85 GBq / mL, 1.20 - 1.80 GBq / mL, 1.25 - 1.75 GBq / mL, 1.30 - 1.70 GBq / mL, 1.35 - 1.65 GBq / mL, 1.40 - 1.60 GBq / mL, or 1.45 - 1.55 GBq / mL.

[0471] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2activity concentration at calibration of 0.25 - 0.50 GBq / mL, 0.50 - 0.75 GBq / mL, 0.75 - 1 GBq / mL, 1 - 1.25 GBq / mL, 1.25 - 1.50 GBq / mL, 1.50 - 1.75 GBq / mL, 1.75 - 2 GBq / mL, 2 - 2.25 GBq / mL, 2.25 - 2.50 GBq / mL, 2.50 - 2.75 GBq / mL, 2.75 - 3 GBq / mL, 3 - 3.25 GBq / mL, 3.25 - 3.50 GBq / mL, 3.50 - 3.75 GBq / mL, 3.75 - 4 GBq / mL, 4 - 4.25 GBq / mL, 4.25 - 4.50 GBq / mL, 4.50 - 4.75 GBq / mL, 4.75 - 5 GBq / mL, 5 - 5.25 GBq / mL, 5.25 - 5.50 GBq / mL, 5.50 - 5.75 GBq / mL, 5.75 - 6 GBq / mL, 6 - 6.25 GBq / mL, 6.25 - 6.50 GBq / mL, 6.50 - 6.75 GBq / mL, 6.75 - 7 GBq / mL, 7 - 7.25 GBq / mL, 7.25 - 7.50 GBq / mL, 7.50 - 7.75 GBq / mL, 7.75 - 8 GBq / mL, 8 - 137 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 8.25 GBq / mL, 8.25 - 8.50 GBq / mL, 8.50 - 8.75 GBq / mL, 8.75 - 9 GBq / mL, 9 - 9.25 GBq / mL, 9.25 - 9.50 GBq / mL, 9.50 - 9.75 GBq / mL, 9.75 - 10 GBq / mL, 10 - 10.25 GBq / mL, 10.25 - 10.50 GBq / mL, 10.50 - 10.75 GBq / mL, 10.75 - 11 GBq / mL, 11 - 11.25 GBq / mL, 11.25 - 11.50 GBq / mL, 11.50 - 11.75 GBq / mL, 11.75 - 12 GBq / mL, 12 - 12.25 GBq / mL, 12.25 - 12.50 GBq / mL, 12.50 - 12.75 GBq / mL, 12.75 - 13 GBq / mL, 13 - 13.25 GBq / mL, 13.25 - 13.50 GBq / mL, 13.50 - 13.75 GBq / mL, 13.75 - 14 GBq / mL, 14 - 14.25 GBq / mL, 14.25 - 14.50 GBq / mL, 14.50 - 14.75 GBq / mL, 14.75 - 15 GBq / mL, 15 - 15.25 GBq / mL, 15.25 - 15.50 GBq / mL, 15.50 - 15.75 GBq / mL, 15.75 - 16 GBq / mL, 16 - 16.25 GBq / mL, 16.25 - 16.50 GBq / mL, 16.50 - 16.75 GBq / mL, 16.75 - 17 GBq / mL, 17 - 17.25 GBq / mL, 17.25 - 17.50 GBq / mL, 17.50 - 17.75 GBq / mL, 17.75 - 18 GBq / mL, 18 - 18.25 GBq / mL, 18.25 - 18.50 GBq / mL, 18.50 - 18.75 GBq / mL, 18.75 - 19 GBq / mL, 19 - 19.25 GBq / mL, 19.25 - 19.50 GBq / mL, 19.50 - 19.75 GBq / mL, 19.75 - 20 GBq / mL, 20 - 20.25 GBq / mL, 20.25 - 20.50 GBq / mL, 20.50 - 20.75 GBq / mL, 20.75 - 21 GBq / mL, 21 - 21.25 GBq / mL, 21.25 - 21.50 GBq / mL, 21.50 - 21.75 GBq / mL, 21.75 - 22 GBq / mL, 22 - 22.25 GBq / mL, 22.25 - 22.50 GBq / mL, 22.50 - 22.75 GBq / mL, 22.75 - 23 GBq / mL, 23 - 23.25 GBq / mL, 23.25 - 23.50 GBq / mL, 23.50 - 23.75 GBq / mL, 23.75 - 24 GBq / mL, 24 - 24.25 GBq / mL, 24.25 - 24.50 GBq / mL, 24.50 - 24.75 GBq / mL, or 24.75 - 25 GBq / mL. 5.6.2.2 Molar Activity

[0472] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2molar activity concentration at calibration of 10 – 600 MBq / nmol, 25 - 600 GBq / nmol, 50 - 600 GBq / nmol, 75 - 600 GBq / nmol, 100 - 600 GBq / nmol, 125 - 600 GBq / nmol, 150 - 600 GBq / nmol, 175 - 600 GBq / nmol, 200 - 600 GBq / nmol, 225 - 600 GBq / nmol, 250 - 600 GBq / nmol, 275 - 600 GBq / nmol, 300 - 600 GBq / nmol, 325 - 600 GBq / nmol, 350 - 600 GBq / nmol, 375 - 600 GBq / nmol, 400 - 600 GBq / nmol, 425 - 600 GBq / nmol, 450 - 600 GBq / nmol, 475 - 600 GBq / nmol, 500 - 600 GBq / nmol, 525 - 600 GBq / nmol, 550 - 600 GBq / nmol, or 575 - 600 GBq / nmol.

[0473] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10 - 25 GBq / nmol, 10 - 50 GBq / nmol, 10 - 75 GBq / nmol, 10 - 100 GBq / nmol, 10 - 125 GBq / nmol, 10 - 150 GBq / nmol, 10 - 175 GBq / nmol, 10 - 200 GBq / nmol, 10 - 225 GBq / nmol, 10 - 250 GBq / nmol, 10 138 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO - 275 GBq / nmol, 10 - 300 GBq / nmol, 10 - 325 GBq / nmol, 10 - 350 GBq / nmol, 10 - 375 GBq / nmol, 10 - 400 GBq / nmol, 10 - 425 GBq / nmol, 10 - 450 GBq / nmol, 10 - 475 GBq / nmol, 10 - 500 GBq / nmol, 10 - 525 GBq / nmol, 10 - 550 GBq / nmol, 10 - 575 GBq / nmol, 25 - 600 GBq / nmol, 50 - 575 GBq / nmol, 75 - 550 GBq / nmol, 100 - 525 GBq / nmol, 125 - 500 GBq / nmol, 150 - 475 GBq / nmol, 175 - 450 GBq / nmol, 200 - 425 GBq / nmol, 225 - 400 GBq / nmol, 250 - 375 GBq / nmol, 275 - 350 GBq / nmol, or 300 - 325 GBq / nmol.

[0474] In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10 - 150 MBq / nmol, 20 - 150 MBq / nmol, 30 - 150 MBq / nmol, 40 - 150 MBq / nmol, 50 - 150 MBq / nmol, 60 - 150 MBq / nmol, 70 - 150 MBq / nmol, 80 - 150 MBq / nmol, 90 - 150 MBq / nmol, 100 - 150 MBq / nmol, 110 - 150 MBq / nmol, 120 - 150 MBq / nmol, 130 - 150 MBq / nmol, 140 - 150 MBq / nmol, 10 - 140 MBq / nmol, 10 - 130 MBq / nmol, 10 - 120 MBq / nmol, 10 - 110 MBq / nmol, 10 - 100 MBq / nmol, 10 - 90 MBq / nmol, 10 - 80 MBq / nmol, 10 - 70 MBq / nmol, 10 - 60 MBq / nmol, 10 - 50 MBq / nmol, 10 - 40 MBq / nmol, 10 - 30 MBq / nmol, 10 - 20 MBq / nmol, 10 - 80 MBq / nmol, 20 - 90 MBq / nmol, 30 - 100 MBq / nmol, 40 - 110 MBq / nmol, 50 - 120 MBq / nmol, 60 - 130 MBq / nmol, or 70 - 140 MBq / nmol.

[0475] In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2molar activity concentration at calibration of 10 - 150 MBq / nmol. 5.6.3. pH

[0476] In certain embodiments, composition comprising [61Cu]CuCl2as provided herein is characterized by a pH of 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 139 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, or 1.7.

[0477] In certain embodiments, the pH of a [61Cu]CuCl2solution is 1-1.6. In certain embodiments, the pH is 1.05-1.55, 1.10-1.45, 1.15-1.35, 1.20-1.25.

[0478] In certain embodiments, the pH of a [61Cu]CuCl2 solution is from 0.11 to 1.7, 0.12 to 1.69, 0.13 to 1.68, 0.14 to 1.67, 0.15 to 1.66, 0.16 to 1.65, 0.17 to 1.64, 0.18 to 1.63, 0.19 to 1.62, 0.2 to 1.61, 0.21 to 1.6, 0.22 to 1.59, 0.23 to 1.58, 0.24 to 1.57, 0.25 to 1.56, 0.26 to 1.55, 0.27 to 1.54, 0.28 to 1.53, 0.29 to 1.52, 0.3 to 1.51, 0.31 to 1.5, 0.32 to 1.49, 0.33 to 1.48, 0.34 to 1.47, 0.35 to 1.46, 0.36 to 1.45, 0.37 to 1.44, 0.38 to 1.43, 0.39 to 1.42, 0.4 to 1.41, 0.41 to 1.4, 0.42 to 1.39, 0.43 to 1.38, 0.44 to 1.37, 0.45 to 1.36, 0.46 to 1.35, 0.47 to 1.34, 0.48 to 1.33, 0.49 to 1.32, 0.5 to 1.31, 0.51 to 1.3, 0.52 to 1.29, 0.53 to 1.28, 0.54 to 1.27, 0.55 to 1.26, 0.56 to 1.25, 0.57 to 1.24, 0.58 to 1.23, 0.59 to 1.22, 0.6 to 1.21, 0.61 to 1.2, 0.62 to 1.19, 0.63 to 1.18, 0.64 to 1.17, 0.65 to 1.16, 0.66 to 1.15, 0.67 to 1.14, 0.68 to 1.13, 0.69 to 1.12, 0.7 to 1.11, 0.71 to 1.1, 0.72to1.09, 0.73 to 1.08, 0.74 to 1.07, 0.75 to 1.06, 0.76 to 1.05, 0.77 to 1.04, 0.78 to 1.03, 0.79 to 1.02, 0.8 to 1.01, 0.81 to 1, 0.82 to 0.99, 0.83 to 0.98, or 0.84 to 0.97. 5.6.4. Radionuclidic purity

[0479] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by a radionuclidic purity of ≥ 99.99%, ≥ 99.98%, ≥ 99.97%, ≥ 99.96%, ≥ 99.95%, ≥ 99.94%, ≥ 99.93%, ≥ 99.92%, ≥ 99.91%, ≥ 99.90%, ≥ 99.89%, ≥ 99.88%, ≥ 99.87%, ≥ 99.86%, ≥ 99.85%, ≥ 99.84%, ≥ 99.83%, ≥ 99.82%, ≥ 99.81%, ≥ 99.80%, ≥ 99.79%, ≥ 99.78%, ≥ 99.77%, ≥ 99.76%, ≥ 99.75%, ≥ 99.74%, ≥ 99.73%, ≥ 99.72%, ≥ 99.71%, ≥ 99.70%, ≥ 99.69%, ≥ 99.68%, ≥ 99.67%, ≥ 99.66%, ≥ 99.65%, ≥ 99.64%, ≥ 99.63%, ≥ 99.62%, ≥ 99.61%, ≥ 99.60%, ≥ 99.59%, ≥ 99.58%, ≥ 99.57%, ≥ 99.56%, ≥ 99.55%, ≥ 99.54%, ≥ 99.53%, ≥ 99.52%, ≥ 99.51%, ≥ 99.50%, ≥ 99.49%, ≥ 99.48%, ≥ 99.47%, ≥ 99.46%, ≥ 99.45%, ≥ 99.44%, ≥ 99.43%, ≥ 99.42%, ≥ 99.41%, ≥ 99.40%, ≥ 99.39%, ≥ 99.38%, ≥ 99.37%, ≥ 99.36%, ≥ 99.35%, ≥ 99.34%, ≥ 99.33%, ≥ 99.32%, ≥ 99.31%, ≥ 99.30%, ≥ 99.29%, ≥ 99.28%, ≥ 99.27%, ≥ 99.26%, ≥ 99.25%, ≥ 99.24%, ≥ 99.23%, ≥ 99.22%, ≥ 99.21%, ≥ 99.20%, ≥ 99.19%, ≥ 99.18%, ≥ 99.17%, ≥ 99.16%, ≥ 99.15%, ≥ 99.14%, ≥ 99.13%, ≥ 99.12%, ≥ 99.11%, ≥ 99.10%, ≥ 99.09%, ≥ 99.08%, ≥ 99.07%, ≥ 99.06%, ≥ 99.05%, ≥ 99.04%, ≥ 99.03%, ≥ 99.02%, ≥ 140 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 99.01%, ≥ 99.00%, ≥ 98.99%, ≥ 98.98%, ≥ 98.97%, ≥ 98.96%, ≥ 98.95%, ≥ 98.94%, ≥ 98.93%, ≥ 98.92%, ≥ 98.91%, ≥ 98.90%, ≥ 98.89%, ≥ 98.88%, ≥ 98.87%, ≥ 98.86%, ≥ 98.85%, ≥ 98.84%, ≥ 98.83%, ≥ 98.82%, ≥ 98.81%, ≥ 98.80%, ≥ 98.79%, ≥ 98.78%, ≥ 98.77%, ≥ 98.76%, ≥ 98.75%, ≥ 98.74%, ≥ 98.73%, ≥ 98.72%, ≥ 98.71%, ≥ 98.70%, ≥ 98.69%, ≥ 98.68%, ≥ 98.67%, ≥ 98.66%, ≥ 98.65%, ≥ 98.64%, ≥ 98.63%, ≥ 98.62%, ≥ 98.61%, ≥ 98.60%, ≥ 98.59%, ≥ 98.58%, ≥ 98.57%, ≥ 98.56%, ≥ 98.55%, ≥ 98.54%, ≥ 98.53%, ≥ 98.52%, ≥ 98.51%, ≥ 98.50%, ≥ 98.49%, ≥ 98.48%, ≥ 98.47%, ≥ 98.46%, ≥ 98.45%, ≥ 98.44%, ≥ 98.43%, ≥ 98.42%, ≥ 98.41%, ≥ 98.40%, ≥ 98.39%, ≥ 98.38%, ≥ 98.37%, ≥ 98.36%, ≥ 98.35%, ≥ 98.34%, ≥ 98.33%, ≥ 98.32%, ≥ 98.31%, ≥ 98.30%, ≥ 98.29%, ≥ 98.28%, ≥ 98.27%, ≥ 98.26%, ≥ 98.25%, ≥ 98.24%, ≥ 98.23%, ≥ 98.22%, ≥ 98.21%, ≥ 98.20%, ≥ 98.19%, ≥ 98.18%, ≥ 98.17%, ≥ 98.16%, ≥ 98.15%, ≥ 98.14%, ≥ 98.13%, ≥ 98.12%, ≥ 98.11%, ≥ 98.10%, ≥ 98.09%, ≥ 98.08%, ≥ 98.07%, ≥ 98.06%, ≥ 98.05%, ≥ 98.04%, ≥ 98.03%, ≥ 98.02%, ≥ 98.01%, ≥ 98.00%, ≥ 97.99%, ≥ 97.98%, ≥ 97.97%, ≥ 97.96%, ≥ 97.95%, ≥ 97.94%, ≥ 97.93%, ≥ 97.92%, ≥ 97.91%, ≥ 97.90%, ≥ 97.89%, ≥ 97.88%, ≥ 97.87%, ≥ 97.86%, ≥ 97.85%, ≥ 97.84%, ≥ 97.83%, ≥ 97.82%, ≥ 97.81%, ≥ 97.80%, ≥ 97.79%, ≥ 97.78%, ≥ 97.77%, ≥ 97.76%, ≥ 97.75%, ≥ 97.74%, ≥ 97.73%, ≥ 97.72%, ≥ 97.71%, ≥ 97.70%, ≥ 97.69%, ≥ 97.68%, ≥ 97.67%, ≥ 97.66%, ≥ 97.65%, ≥ 97.64%, ≥ 97.63%, ≥ 97.62%, ≥ 97.61%, ≥ 97.60%, ≥ 97.59%, ≥ 97.58%, ≥ 97.57%, ≥ 97.56%, ≥ 97.55%, ≥ 97.54%, ≥ 97.53%, ≥ 97.52%, ≥ 97.51%, ≥ 97.50%, ≥ 97.49%, ≥ 97.48%, ≥ 97.47%, ≥ 97.46%, ≥ 97.45%, ≥ 97.44%, ≥ 97.43%, ≥ 97.42%, ≥ 97.41%, ≥ 97.40%, ≥ 97.39%, ≥ 97.38%, ≥ 97.37%, ≥ 97.36%, ≥ 97.35%, ≥ 97.34%, ≥ 97.33%, ≥ 97.32%, ≥ 97.31%, ≥ 97.30%, ≥ 97.29%, ≥ 97.28%, ≥ 97.27%, ≥ 97.26%, ≥ 97.25%, ≥ 97.24%, ≥ 97.23%, ≥ 97.22%, ≥ 97.21%, ≥ 97.20%, ≥ 97.19%, ≥ 97.18%, ≥ 97.17%, ≥ 97.16%, ≥ 97.15%, ≥ 97.14%, ≥ 97.13%, ≥ 97.12%, ≥ 97.11%, ≥ 97.10%, ≥ 97.09%, ≥ 97.08%, ≥ 97.07%, ≥ 97.06%, ≥ 97.05%, ≥ 97.04%, ≥ 97.03%, ≥ 97.02%, ≥ 97.01%, or ≥ 97%. 5.6.5. Long Lived Radionuclidic impurities

[0480] In certain embodiments of a method of producing high-purity radionuclides as provided herein, comprising the step of isolating a desired radionuclide the method further comprises the step of purifying a radionuclide salt solution to decrease amounts of chemical impurities. In certain of these embodiments, purifying includes anion / cation exchange chromatography. In certain embodiments, purifying comprises alkyl phosphate resin chromatography. In certain 141 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO embodiments, purifying comprises weak cation exchange chromatography. In certain embodiments, purifying comprises decreasing the specific activity (e.g., in Bq / g) of certain radionuclides below a certain threshold.

[0481] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a56Co specific activity of ≤ 1500 Bq / g, ≤ 1450 Bq / g, ≤ 1400 Bq / g, ≤ 1350 Bq / g, ≤ 1300 Bq / g, ≤ 1250 Bq / g, ≤ 1200 Bq / g, ≤ 1150 Bq / g, ≤ 1100 Bq / g, ≤ 1050 Bq / g, ≤ 1000 Bq / g, ≤ 950 Bq / g, ≤ 900 Bq / g, ≤ 850 Bq / g, ≤ 800 Bq / g, ≤ 750 Bq / g, ≤ 700 Bq / g, ≤ 650 Bq / g, ≤ 600 Bq / g, ≤ 550 Bq / g, ≤ 500 Bq / g, ≤ 450 Bq / g, ≤ 400 Bq / g, ≤ 350 Bq / g, ≤ 300 Bq / g, ≤ 250 Bq / g, ≤ 200 Bq / g, ≤ 150 Bq / g, ≤ 100 Bq / g, or ≤ 50 Bq / g.

[0482] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by a57Co specific activity of ≤ 100 Bq / g, ≤ 95 Bq / g, ≤ 90 Bq / g, ≤ 85 Bq / g, ≤ 80 Bq / g, ≤ 75 Bq / g, ≤ 70 Bq / g, ≤ 65 Bq / g, ≤ 60 Bq / g, ≤ 55 Bq / g, ≤ 50 Bq / g, ≤ 45 Bq / g, ≤ 40 Bq / g, ≤ 35 Bq / g, ≤ 30 Bq / g, ≤ 25 Bq / g, ≤ 20 Bq / g, ≤ 15 Bq / g, ≤ 10 Bq / g, ≤ 5 Bq / g, ≤ 4.6 Bq / g, ≤ 4.5 Bq / g, ≤ 4.4 Bq / g, ≤ 4.3 Bq / g, ≤ 4.2 Bq / g, ≤ 4.1 Bq / g, ≤ 4 Bq / g, ≤ 3.9 Bq / g, ≤ 3.8 Bq / g, ≤ 3.7 Bq / g, ≤ 3.6 Bq / g, ≤ 3.5 Bq / g, ≤ 3.4 Bq / g, ≤ 3.3 Bq / g, ≤ 3.2 Bq / g, ≤ 3.1 Bq / g, ≤ 3 Bq / g, ≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0483] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by a58Co specific activity of ≤ 1500 Bq / g, ≤ 1450 Bq / g, ≤ 1400 Bq / g, ≤ 1350 Bq / g, ≤ 1300 Bq / g, ≤ 1250 Bq / g, ≤ 1200 Bq / g, ≤ 1150 Bq / g, ≤ 1100 Bq / g, ≤ 1050 Bq / g, ≤ 1000 Bq / g, ≤ 950 Bq / g, ≤ 900 Bq / g, ≤ 850 Bq / g, ≤ 800 Bq / g, ≤ 750 Bq / g, ≤ 700 Bq / g, ≤ 650 Bq / g, ≤ 600 Bq / g, ≤ 575 Bq / g, ≤ 550 Bq / g, ≤ 525 Bq / g, ≤ 500 Bq / g, ≤ 475 Bq / g, ≤ 450 Bq / g, ≤ 425 Bq / g, ≤ 400 Bq / g, ≤ 375 Bq / g, ≤ 350 Bq / g, ≤ 325 Bq / g, ≤ 300 Bq / g, ≤ 275 Bq / g, ≤ 250 Bq / g, ≤ 225 Bq / g, ≤ 200 Bq / g, ≤ 175 Bq / g, ≤ 150 Bq / g, ≤ 125 Bq / g, ≤ 100 Bq / g, ≤ 75 Bq / g, ≤ 50 Bq / g, or ≤ 25 Bq / g.

[0484] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a60Co specific activity of ≤ 15 Bq / g,≤ 14 Bq / g,≤ 13 Bq / g,≤ 12 Bq / g,≤ 11 142 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO Bq / g,≤ 10 Bq / g,≤ 9 Bq / g,≤ 8 Bq / g,≤ 7 Bq / g,≤ 6 Bq / g,≤ 5 Bq / g,≤ 4 Bq / g,≤ 3 Bq / g,≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0485] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by a108mAg specific activity of ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, ≤ 0.1 Bq / g.

[0486] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by a110mAg specific activity of ≤ 5 Bq / g, ≤ 4.9 Bq / g, ≤ 4.8 Bq / g, ≤ 4.7 Bq / g, ≤ 4.6 Bq / g, ≤ 4.5 Bq / g, ≤ 4.4 Bq / g, ≤ 4.3 Bq / g, ≤ 4.2 Bq / g, ≤ 4.1 Bq / g, ≤ 4 Bq / g, ≤ 3.9 Bq / g, ≤ 3.8 Bq / g, ≤ 3.7 Bq / g, ≤ 3.6 Bq / g, ≤ 3.5 Bq / g, ≤ 3.4 Bq / g, ≤ 3.3 Bq / g, ≤ 3.2 Bq / g, ≤ 3.1 Bq / g, ≤ 3 Bq / g, ≤ 2.9 Bq / g, ≤ 2.8 Bq / g, ≤ 2.7 Bq / g, ≤ 2.6 Bq / g, ≤ 2.5 Bq / g, ≤ 2.4 Bq / g, ≤ 2.3 Bq / g, ≤ 2.2 Bq / g, ≤ 2.1 Bq / g, ≤ 2 Bq / g, ≤ 1.9 Bq / g, ≤ 1.8 Bq / g, ≤ 1.7 Bq / g, ≤ 1.6 Bq / g, ≤ 1.5 Bq / g, ≤ 1.4 Bq / g, ≤ 1.3 Bq / g, ≤ 1.2 Bq / g, ≤ 1.1 Bq / g, ≤ 1 Bq / g, ≤ 0.9 Bq / g, ≤ 0.8 Bq / g, ≤ 0.7 Bq / g, ≤ 0.6 Bq / g, ≤ 0.5 Bq / g, ≤ 0.4 Bq / g, ≤ 0.3 Bq / g, ≤ 0.2 Bq / g, or ≤ 0.1 Bq / g.

[0487] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a109Cd specific activity of ≤ 15 Bq / g, ≤ 14 Bq / g, ≤ 13 Bq / g, ≤ 12 Bq / g, ≤ 11 Bq / g, ≤ 10 Bq / g, ≤ 9 Bq / g, ≤ 8 Bq / g, ≤ 7 Bq / g, ≤ 6 Bq / g, ≤ 5 Bq / g, ≤ 4 Bq / g, ≤ 3 Bq / g, ≤ 2 Bq / g, or ≤ 1 Bq / g. 5.6.6. Radiochemical identity

[0488] In certain embodiments, the presence and / or quantity of61Cu is characterized by γ- photons. In certain embodiments,61Cu is characterized by γ-photons with energy peak at: 511 ± 20 keV. In certain embodiments,61Cu is characterized by γ-photons with energy peak at: 511 ± 20 keV and 283 keV ± 20 keV. In certain embodiments,61Cu is characterized by γ-photons with energy peak at: 511 ± 20 keV, 283 keV ± 20 keV, and 656 keV ± 20 keV. In certain embodiments,61Cu is characterized by γ-photons with energy peak at: 511 ± 20 keV (eventually sum peak at 1022 keV ± 20 keV), 283 keV ± 20 keV and 656 keV ± 20 keV. 143 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.6.7. Chemical purity

[0489] In certain embodiments,61Cu can be characterized by other chemical impurities. In certain embodiments, non-radioactive (cold) elements are present in a [61Cu]CuCl2solution. In certain embodiments, cold elements are present and quantified by ICP-MS (inductively coupled plasma mass spectrometry). In some embodiments,61Cu is a transmutation product provided by methods described in the present disclosure. In some embodiments, transmutation of a target metal (e.g.,natNi,60Ni, or61Ni) provides61Cu in varying levels of radiochemical purity. 5.6.7.1 Aluminum

[0490] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising aluminum (e.g., non-radioactive)in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.6.7.2 Cobalt

[0491] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising cobalt (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.6.7.3 Copper

[0492] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising copper (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 144 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO 5.6.7.4 Iron

[0493] In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising iron (e.g., non-radioactive) in an amount ≤ 3 ng / MBq, ≤ 2.9 ng / MBq, ≤ 2.8 ng / MBq, ≤ 2.7 ng / MBq, ≤ 2.6 ng / MBq, ≤ 2.5 ng / MBq, ≤ 2.4 ng / MBq, ≤ 2.3 ng / MBq, ≤ 2.2 ng / MBq, ≤ 2.1 ng / MBq, ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.6.7.5 Lead

[0494] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by comprising lead (e.g., non-radioactive) in an amount ≤ 2 ng / MBq, ≤ 1.9 ng / MBq, ≤ 1.8 ng / MBq, ≤ 1.7 ng / MBq, ≤ 1.6 ng / MBq, ≤ 1.5 ng / MBq, ≤ 1.4 ng / MBq, ≤ 1.3 ng / MBq, ≤ 1.2 ng / MBq, ≤ 1.1 ng / MBq, ≤ 1 ng / MBq, ≤ 0.9 ng / MBq, ≤ 0.8 ng / MBq, ≤ 0.7 ng / MBq, ≤ 0.6 ng / MBq, ≤ 0.5 ng / MBq, ≤ 0.4 ng / MBq, ≤ 0.3 ng / MBq, ≤ 0.2 ng / MBq, or ≤ 0.1 ng / MBq. 5.6.7.6 Nickel

[0495] In certain embodiments, a composition comprising [61Cu]CuCl2as provided herein is characterized by comprising nickel (e.g., non-radioactive) in an amount ≤ 4.5 ng / MBq, ≤ 4.4 ng / MBq, ≤ 4.3 ng / MBq, ≤ 4.2 ng / MBq, ≤ 4.1 ng / MBq, ≤ 4 ng / MBq, ≤ 3.9 ng / MBq, ≤ 3.8 ng / MBq, ≤ 3.7 ng / MBq, ≤ 3.6 ng / MBq, ≤ 3.5 ng / MBq, ≤ 3.4 ng / MBq, ≤ 3.3 ng / MBq, ≤ 3.2 ng / MBq, ≤ 3.1 ng / MBq, ≤ 3 ng / MBq, ≤ 2.9 ng / MBq, ≤ 2.8 ng / MBq, ≤ 2.7 ng / MBq, ≤ 2.6 ng / MBq, ≤ 2.5 ng / MBq, ≤ 2.4 ng / MBq, ≤ 2.3 ...

Claims

Attorney Ref: NCL-008WO WHAT IS CLAIMED IS:

1. A cassette for purifying a metal radionuclide, comprising: a manifold comprising an inlet, an outlet and a fluid pathway therein; a fluid pressure source fluidically coupled to the inlet, wherein the pressure source provides a fluid pressure to the fluid pathway; a plurality of valves fluidically coupled to the manifold; a fluidic inlet fluidically coupled to the fluid pathway through a first valve of the plurality of valves, wherein a fluid flows from the fluidic inlet into the fluid pathway through the first valve in a first flow direction caused by the fluid pressure within the fluid pathway; an ion exchanger system fluidically coupled to the fluid pathway through a second valve of the plurality of valves and comprising an ion exchanger column, wherein the fluid from the fluid pathway flows into the ion exchanger system to form a purified solution that flows into the fluid pathway at a third valve of the plurality of valves in the first flow direction; and a vessel fluidically coupled to the fluid pathway through a fourth valve of the plurality of valves, wherein the purified solution flows from the fluid pathway into the vessel through the fourth valve in a second flow direction.

2. The cassette of claim 1, wherein the pressure source comprises an inert gas.

3. The cassette of claim 1, wherein the fluid flows in the first direction at a rate of about 1 mL / min to about 2 mL / min.

4. The cassette of claim 1, wherein the fluidic inlet is fluidically connected to a dissolution vessel.

5. The cassette of claim 4, wherein dissolution occurs within the dissolution vessel simultaneously as a conditioning process occurs in the ion exchanger system.

6. The cassette of claim 1, wherein the ion exchanger system comprises: a second ion exchanger column coupled to a fifth valve of the plurality of valves and containing a second purifying solution.

7. The cassette of claim 6, wherein the fluid flows into the ion exchanger column through the third valve to form a first purified solution, wherein the first purified solution then flows into the second ion exchanger column through the fifth valve to form a second purified solution, 176 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO wherein the second purified solution then flows into the fluid pathway via the fifth valve in the first flow direction.

8. The cassette of claim 1, further comprising a computing device electromechanically connected to an actuator of the plurality of valves, wherein the computing device is configured to transition any of the plurality of valves from a first flow orientation to a second flow orientation through activation of the actuator.

9. The cassette of claim 8, wherein the computing device is configured to operate one or more of the plurality of valves in a time interval.

10. The cassette of claim 9, wherein the time interval is about 10 seconds to about 40 seconds.

11. The cassette of claim 1, wherein the first, second, third, and fourth valves are operated in a sequence.

12. The cassette of claim 11, wherein the sequence comprises a timed actuation process.

13. The cassette of claim 1, wherein the fourth valve is fluidically isolated from an adjacent valve positioned between the fourth valve and the outlet of the manifold.

14. The cassette of claim 1, wherein the second flow direction is perpendicular to the first flow direction.

15. A system for purifying a metal radionuclide and preparing a radiopharmaceutical composition comprising a purified metal radionuclide, comprising: a cassette, comprising: a manifold comprising an inlet, an outlet and a fluid pathway therein; a fluid pressure source fluidically coupled to the inlet, wherein the pressure source provides a fluid pressure to the fluid pathway; a plurality of valves fluidically coupled to the manifold; a fluidic inlet fluidically coupled to the fluid pathway through a first valve of the plurality of valves, wherein a fluid flows from the fluidic inlet into the fluid pathway through the first valve in a first flow direction caused by the fluid pressure within the fluid pathway; an ion exchanger system fluidically coupled to the fluid pathway through a second valve of the plurality of valves, wherein the ion exchanger system receives the fluid from the fluid pathway and forms a purified solution that flows into the fluid pathway at a third valve of the plurality of valves in the first flow direction; and 177 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO a vessel fluidically coupled to the fluid pathway through a fourth valve of the plurality of valves, wherein the purified solution flows from the fluid pathway into the vessel through the fourth valve in a second flow direction; and a second vessel fluidically coupled to the fluid pathway through a fifth valve and containing at least a precursor compound, wherein, during an off state of the fluid pressure source, the purified solution flows from the fluid pathway in a third flow direction opposite the first flow direction into the second vessel through the fifth valve to mix with the at least a precursor compound, thereby forming a radiopharmaceutical composition comprising a purified metal radionuclide.

16. The system of claim 15, wherein the fifth valve is positioned between the inlet of the manifold and the first valve.

17. The system of claim 15, wherein the first, second, third, and fourth valves are operated in a sequence.

18. The system of claim 17, wherein the sequence comprises a timed actuation process.

19. A method of purifying a metal radionuclide using a cassette, comprising: providing a fluid pressure from a fluid pressure source to a fluid pathway of a manifold at an inlet of the manifold; receiving, a fluid from a fluidic inlet at a first port of a first valve of a plurality of valves coupled to the; directing the fluid through a second port of the first valve into the fluid pathway in a first flow direction caused by the fluid pressure within the fluid pathway; flowing the fluid from the fluid pathway into an ion exchanger system via a first port of a third valve, wherein the fluid mixes with anion exchanger column of the ion exchanger system to form a purified solution; directing the purified solution into the fluid pathway via a second port of the third valve in the first flow direction; and directing the purified solution into a vessel through a first port of a fourth valve in a second flow direction perpendicular to the first flow direction, wherein the purified solution has an activity concentration of about 1 GBq / mL to about 5 GBq / ml.

20. The method of claim 19, further comprising, during an off state of the fluid pressure source, flowing the purified solution out of the vessel through the fifth valve into the fluid pathway 178 39973 / 58004 / FW / 18108752.1Attorney Ref: NCL-008WO through and into a second vessel containing at least a precursor compound through a sixth valve of the plurality of valves in a third flow direction opposite the first flow direction, thereby forming a radiopharmaceutical composition comprising a purified metal radionuclide.

21. The method of claim 19, wherein the fluidic inlet is fluidically connected to a dissolution vessel.

22. The method of claim 21, further comprising performing dissolution within the dissolution vessel and conditioning of the ion exchanger system simultaneously.

23. The method of claim 19, wherein the purified solution has a radioactivity at least about 50% of a starting radioactivity of the fluid. 179 39973 / 58004 / FW / 18108752.1

Images