WO2021108474A1 - Procédé d'extraction et de purification de conjugués hbed étiquetés ai18f - Google Patents

Procédé d'extraction et de purification de conjugués hbed étiquetés ai18f Download PDF

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WO2021108474A1
WO2021108474A1 PCT/US2020/062127 US2020062127W WO2021108474A1 WO 2021108474 A1 WO2021108474 A1 WO 2021108474A1 US 2020062127 W US2020062127 W US 2020062127W WO 2021108474 A1 WO2021108474 A1 WO 2021108474A1
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solution
radiopharmaceutical
alkanediyl
pbs
targeting moiety
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PCT/US2020/062127
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English (en)
Inventor
Mai LIN
Robert T. TA
Dao LE
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Board Of Regents, The University Of Texas System
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Publication of WO2021108474A1 publication Critical patent/WO2021108474A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds

Definitions

  • the present invention relates generally to the fields of chemistry and biological imaging. More particularly, it concerns methods for preparing purified Al 18 F-labeled HBED conjugates and systems for preparing purified Al 18 F-labeled HBED conjugates.
  • 68 Ga-labeled molecules such as 68 Ga-PSMA-l l is currently one of the most widely used PET agent for imaging both recurrent prostate cancer and relevant metastases.
  • the production and distribution of 68 Ga-PSMA-l 1 are limited to a few daily doses by commercially available 68 Ge/ 68 Ga generators that nominally deliver a modest activity up to 1.85 GBq (50 mCi) when new but decreases over time as a result of radioactive decay. Due to this fact, among other factors, the current production and distribution of 68 Ga-labeled tracers via generators are not meeting the challenges of increasing demands.
  • radiolabeling molecules with 18 F represents an attractive alternative to its 68 Ga-based counterpart.
  • One such alternative is an Al 18 F-labeled HBED- conjugated molecule (PSMA-11).
  • PSMA-11 Al 18 F-labeled HBED- conjugated molecule
  • the present disclosure provides methods for the purification of Al 18 F-labeled HBED conjugates as well as systems for the purification of Al 18 F-labeled HBED conjugates.
  • the present disclosure also provides purified radiopharmaceutical solutions and radiopharmaceutical compositions thereof.
  • the present disclosure provides methods of producing a purified radiopharmaceutical solution comprising: a) contacting a crude radiopharmaceutical solution with a first phosphate-buffered saline (PBS) solution to produce a diluted radiopharmaceutical solution, wherein the crude radiopharmaceutical solution comprises a metal-ion complex of the formula:
  • Li is a covalent bond, -(Xi) n _ , -X 2 _ alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-, wherein: n is 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or — NRa-, wherein:
  • R a is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6>; and Ri is a targeting moiety; and b) contacting the diluted radiopharmaceutical solution with a chromatographic material to produce an adsorbed radiopharmaceutical; and c) eluting the adsorbed radiopharmaceutical with an eluent; to produce the purified radiopharmaceutical solution.
  • the metal-ion complex is of the formula:
  • Li is a covalent bond, -(Xi) n- , -X 2- alkanediyl ( c ⁇ i 2)- C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2)- C(0)-, wherein: n is 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or -NR a- wherein:
  • R a is hydrogen, alkyl ( c ⁇ 6) , or substituted alkyl ( c ⁇ 6 >; and Ri is a targeting moiety.
  • Li is -X 2- alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-. In some embodiments, Li is -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-. In some embodiments, Li is -X 2- pentanediyl-C(0)-. In some embodiments, Xi is -NR a-. In some embodiments, R a is hydrogen.
  • the targeting moiety targets pancreatic cancer cells or neuroendocrine cancer cells. In some embodiments, the targeting moiety targets pancreatic cancer cells, such as -Lys-NHC(0)NH-Glu. In other embodiments, the targeting moiety targets neuroendocrine cancer cells, such as octreotate, octreotide, or Tyr 3 -octreotate. In some embodiments, the metal-ion complex is further defined as:
  • step a is performed prior to step b.
  • the concentration of hydrogen phosphate in the first PBS solution is from about 0.1 mM to about 100 mM. In some embodiments, the concentration of hydrogen phosphate in the first PBS solution is from about 1 mM to about 25 mM. In some embodiments, the concentration of hydrogen phosphate in the first PBS solution is from about 5 mM to about 15 mM. In some embodiments, the concentration of hydrogen phosphate in the first PBS solution is about 10 mM. In some embodiments, the pH of the first PBS solution is from about 6 to about 8. In some embodiments, the pH of the first PBS solution is about 7. In some embodiments, the chromatographic material is contacted with a second PBS solution prior to step b.
  • the concentration of hydrogen phosphate in the second PBS solution is from about 0.1 mM to about 100 mM. In some embodiments, the concentration of hydrogen phosphate in the second PBS solution is from about 1 mM to about 25 mM. In some embodiments, the concentration of hydrogen phosphate in the second PBS solution is from about 5 mM to about 15 mM. In some embodiments, the concentration of hydrogen phosphate in the second PBS solution is about 10 mM.
  • the chromatographic material is a polymeric sorbent.
  • the polymeric sorbent is a reversed-phase polymeric sorbent.
  • the polymeric sorbent is water-wettable.
  • the polymeric sorbent is hydrophilic.
  • the polymeric sorbent comprises a repeat unit, wherein the repeat unit comprises a pyrrolidin-2-one moiety.
  • the polymeric sorbent comprises a substructure of the formula: or a substituted version thereof.
  • the chromatographic material is contained within a cartridge.
  • the eluent comprises a third PBS solution. In some embodiments, the eluent comprises a first organic solvent. In some embodiments, the eluent comprises a first organic solvent and a third PBS solution. In some embodiments, the first organic solvent is ethanol. In some embodiments, the concentration of hydrogen phosphate in the third PBS solution is from about 0.1 mM to about 100 mM. In some embodiments, the concentration of hydrogen phosphate in the third PBS solution is from about 1 mM to about 25 mM. In some embodiments, the concentration of hydrogen phosphate in the third PBS solution is from about 5 mM to about 15 mM.
  • the concentration of hydrogen phosphate in the third PBS solution is about 10 mM.
  • the method further comprises contacting a first solution with a second solution comprising a first aluminum (III) salt to produce the crude radiopharmaceutical solution, wherein the first solution comprises a precursor of the formula: wherein:
  • Li is a covalent bond, -(Xi) n- , -X 2 _ alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-, wherein: n is 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or -NR a- , wherein:
  • R a is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6>;
  • Ri is a targeting moiety.
  • Li is -X 2- alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-. In some embodiments, Li is -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-. In some embodiments, Li is -X 2- pentanediyl-C(0)-. In some embodiments, Xi is -NR a- . In some embodiments, R a is hydrogen. In some embodiments, the targeting moiety targets pancreatic cancer cells or neuroendocrine cancer cells. In some embodiments, the targeting moiety targets pancreatic cancer cells, such as -Lys-NHC(0)NH-Glu. In some embodiments, the targeting moiety targets neuroendocrine cancer cells, such as octreotate, octreotide, or Tyr 3 -octreotate. In some embodiments, the precursor is PSMA-11.
  • the first solution further comprises a second organic solvent. In some embodiments, the second organic solvent is ethanol. In some embodiments, the first solution further comprises an aqueous acetate solution. In some embodiments, the aqueous acetate solution comprises NaOAc. In some embodiments, the pH of the aqueous acetate solution is from about 3 to about 6. In some embodiments, the pH of the aqueous acetate solution is from about 4 to about 5. In some embodiments, the pH of the aqueous acetate solution is about 4.5. In some embodiments, the first aluminum (III) salt comprises 18 F. In some embodiments, the first aluminum (III) salt is A1 18 F 3 .
  • the method further comprises contacting 18 F with a second aluminum (III) salt.
  • the second aluminum (III) salt is AlCb.
  • the second aluminum (III) salt is AICI3 6 H2O.
  • the 18 F is prepared by bombarding 18 0-H20 with a proton in a cyclotron or linear particle accelerator. In some embodiments, the 18 F is prepared by bombarding 18 0-H20 with a proton in a cyclotron.
  • the radiochemical yield of the method is greater than about 5%. In some embodiments, the radiochemical yield of the method is greater than about 20%. In some embodiments, the radiochemical yield of the method is greater than about 30%. In some embodiments, the radiochemical yield of the method is greater than about 40%. In some embodiments, the radiochemical yield of the method is about 42%. In some embodiments, the radiochemical purity of the radiopharmaceutical solution is greater than about 50%. In some embodiments, the radiochemical purity of the purified radiopharmaceutical solution is greater than about 75%. In some embodiments, the radiochemical purity of the purified radiopharmaceutical solution is greater than about 90%. In some embodiments, the radiochemical purity of the purified radiopharmaceutical solution is greater than about 95%. In some embodiments, the radiochemical purity of the purified radiopharmaceutical solution is than about 97%.
  • the present disclosure provides purified radiopharmaceutical solutions prepared according to the methods of the present disclosure.
  • the present disclosure provides radiopharmaceutical compositions comprising: a purified radiopharmaceutical solution of the present disclosure; and an excipient or a pharmaceutically acceptable carrier.
  • the present disclosure provides systems for the production of a purified radiopharmaceutical solution comprising: a) a dilution chamber configured to: receive a crude radiopharmaceutical solution and a PBS solution, wherein the crude radiopharmaceutical solution comprises a metal-ion complex of the formula:
  • L 2 is a chelator of the formula: wherein: Li is a covalent bond, -(Xi) n _ , -X 2 _ alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-, wherein: n is 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or -NRa-, wherein:
  • Ra is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6>;
  • Ri is a targeting moiety; and contact the crude radiopharmaceutical solution with the PBS solution; to produce a diluted radiopharmaceutical solution; and b) a chromatography chamber comprising a chromatographic material, wherein the chromatography chamber is configured to: receive the diluted radiopharmaceutical solution; contact the diluted radiopharmaceutical solution with the chromatographic material to produce an adsorbed radiopharmaceutical; and elute the adsorbed radiopharmaceutical with an eluent; to produce the purified radiopharmaceutical solution; wherein the dilution module and chromatography module are in fluid communication.
  • FIGS. 1A & IB show HPLC traces of purified A1 18 F-PSMA-11 at 0 h (FIG. 1 A) and 4 h (FIG. IB).
  • Activity used 1.5 Ci
  • Activity obtained final product 0.6 Ci
  • precursor amount 50 pg
  • radiochemical yield 40%, non-decay corrected.
  • the methods comprise contacting an obtained crude Al 18 F-labeled HBED conjugate with a first PBS solution to produce a diluted sample and contacting the diluted sample with a chromatographic material to produce the purified A1 18 F-HBED conjugate. Also disclosed herein are radiopharmaceuticals and compositions thereof.
  • Radiopharmaceuticals comprising 68 Ga have found extensive use in imaging, particularly in imaging of recurring prostate cancer and relevant metastases, such as 68 Ga-PSMA-l 1.
  • the production and distribution of 68 Ga-PSMA-l 1 are limited to a few daily doses by commercially available 68 Ge/ 68 Ga generators that nominally deliver a modest activity up to 1.85 GBq (50 mCi) when new but decreases over time.
  • radiopharmaceuticals comprising 68 Ga must be prepared and used very quickly in imaging applications.
  • Radiopharmaceuticals comprising fluorine- 18 may provide enhanced utility as imaging agents.
  • 18 F is a positron-emitting radioisotope that may be produced from a proton beam bombardment of 18 0 in a cyclotron or linear particle accelerator.
  • Compounds, including but not limited to peptides and conjugates thereof, comprising 18 F are a valuable class of radiopharmaceuticals. With a half-life of 109.8 minutes, 18 F provides more time for imaging applications while still being short-lived enough for use in radiotracers. Additionally, with nearly 50 years of experience in the use of 18 F with 18 F-FDG, supply chain distribution has been well established and utilized.
  • Herein are methods for the purification of Al 18 F-labeled HBED conjugates that may be used to image diseases or disorders, such as prostate cancer.
  • the present disclosure is based, in part, on the discovery of a fully defined process of producing purified Al 18 F-labeled HBED conjugates that is amenable to automated systems.
  • the method and systems rapidly and directly provide the purified Al 18 F-labeled HBED conjugates in a solution that may be sufficient for immediate use in imaging applications.
  • the compounds of the present invention are shown, for example, above, in the summary section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein.
  • the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art.
  • Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development A Guide for Organic Chemists (2012), which is incorporated by reference herein.
  • All the compounds of the present disclosure may in some embodiments be used for the imaging, diagnosis, prevention, and/or treatment of one or more diseases or disorders discussed herein or otherwise.
  • one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and/or prodrug may nevertheless also be useful for the imaging, diagnosis, prevention, and/or treatment of one or more diseases or disorders.
  • all the compounds of the present invention are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceutical ingredients (APIs).
  • APIs active pharmaceutical ingredients
  • Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.
  • the compounds of the present invention have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and/or have a better pharmacokinetic profile ( e.g. , higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.
  • the methods and systems of the present invention have the advantage that they may produce the compounds of the present invention in higher radiochemical yield than methods known in the prior art.
  • Compounds of the present invention may contain one or more asymmetrically-substituted carbon or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained.
  • the chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.
  • Chemical formulas used to represent compounds of the present invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.
  • atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms unless the isotope is explicitly depicted, e.g. 18 F.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • pharmaceutical formulations for administration to a patient in need of such treatment, comprise a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and/or drug carriers appropriate to the indicated route of administration.
  • the compounds disclosed herein are formulated in a manner amenable for the treatment of human and/or veterinary patients.
  • formulation comprises admixing or combining one or more of the compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol.
  • the pharmaceutical formulation may be tableted or encapsulated.
  • the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • the pharmaceutical formulations may be subjected to pharmaceutical operations, such as sterilization, and/or may contain drug carriers and/or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.
  • compositions may be administered by a variety of methods, e.g. , by injection (e.g. subcutaneous, intravenous, and intraperitoneal).
  • the compounds disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound.
  • To administer the active compound by other than parenteral administration it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied.
  • the amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
  • active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient.
  • the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal.
  • the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals.
  • the human equivalent dose (HED) in mg/kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw etal, FASEBJ, 22(3):659-661, 2008, which is incorporated herein by reference):
  • HED Animal dose (mg/kg) x (Animal K m /Human K m )
  • K m factors in conversion results in HED values based on body surface area (BSA) rather than only on body mass.
  • BSA body surface area
  • K m values for humans and various animals are well known. For example, the K m for an average 60 kg human (with a BSA of 1.6 m 2 ) is 37, whereas a 20 kg child (BSA 0.8 m 2 ) would have a K m of 25.
  • mice K m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K m of 12 (given a weight of 3 kg and BSA of 0.24).
  • HED dose Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.
  • the actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan.
  • the practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication.
  • the therapeutically effective amount typically will vary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1 mg/kg to about 250 mg/kg, from about 10 mg/kg to about 150 mg/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above).
  • Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day.
  • the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day.
  • the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation.
  • patients may be administered two doses daily at approximately 12-hour intervals.
  • the agent is administered once a day.
  • the agent(s) may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined.
  • the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between.
  • the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the invention provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the patient has eaten or will eat.
  • the symbol “ - ” represents an optional bond, which if present is either single or double.
  • the bond represents a single coordinate bond (i.e., dative bond).
  • the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment.
  • the symbol “ ” means a single bond where the group attached to the thick end of the wedge is “out of the page.”
  • the symbol “ ,,llMI ” means a single bond where the group attached to the thick end of the wedge is “into the page”.
  • the symbol “' LLL ” means a single bond where the geometry around a double bond (e.g., either £ or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
  • variable When a variable is depicted as a “floating group” on a ring system, for example, the group “R” in the formula: then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • the variable When a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula: then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise.
  • Replaceable hydrogens include depicted hydrogens (e.g ., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g, a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed.
  • R may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the subscript letter “y” immediately following the R enclosed in parentheses represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.
  • the minimum number of carbon atoms in the groups “alkyl ( c£ 8 >”, “alkanediyl(c ⁇ 8)”, “heteroaryl(c ⁇ 8)”, and “acyl(c ⁇ 8)” is one
  • the minimum number of carbon atoms in the groups “alkenyl(c ⁇ 8)”, “alkynyl(c ⁇ 8)”, and “heterocycloalkyl(c ⁇ 8)” is two
  • the minimum number of carbon atoms in the group “cycloalkyl ( c ⁇ 8) ” is three
  • the minimum number of carbon atoms in the groups “aryl(c ⁇ 8)” and “arenediyl(c ⁇ 8)” is six.
  • Cn-n' defines both the minimum (n) and maximum number (h') of carbon atoms in the group.
  • alkyl (C 2-io ) designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning.
  • C5 olefin”, “C5-olefm”, “olefm (C 5 ) ”, and “olefines” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms.
  • the group dihexylamino is an example of a di alkyl ami no t e- 12 ) group; however, it is not an example of a dialkylaminOic- 6) group.
  • phenylethyl is an example of an aralkyl c- ) group.
  • any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted.
  • methoxyhexyl which has a total of seven carbon atoms, is an example of a substituted alkyl ( ci- 6).
  • any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.
  • saturated when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below.
  • the term when used to modify an atom, it means that the atom is not part of any double or triple bond.
  • substituted versions of saturated groups one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.
  • saturated when used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.
  • aliphatic signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group.
  • the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicy thesis).
  • Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).
  • aromatic signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4 n +2 electrons in a fully conjugated cyclic p system.
  • An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:
  • Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic p system, two non-limiting examples of which are shown below:
  • alkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen.
  • alkanediyl refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • the groups CY (methylene), -CH 2 CH 2- , -CEhC CEE ⁇ CEh-, and -CH 2 CH 2 CH 2- are non-limiting examples of alkanediyl groups.
  • alkane refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above.
  • aryl refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present.
  • Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C 6 H 4 CH 2 CH 3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g, 4-phenylphenyl).
  • aromaticiyl refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen.
  • arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond.
  • alkyl groups carbon number limitation permitting
  • arene refers to the class of compounds having the formula H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.
  • aralkyl refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above.
  • Non limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
  • the following groups are non-limiting examples of substituted alkyl groups: -CH 2 OH, -CH 2 C1, -CF 3 , -CH 2 CN, -CH 2 C(0)OH, -CH 2 C(0)0CH , -CH 2 C(0)NH 2 , -CH 2 C(0)CH , -CH 2 OCH , -CH 2 0C(0)CH , -CH 2 NH 2 , — CH 2 N(CH 3 ) 2 , and -CH 2 CH 2 C1.
  • haloalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e.
  • -F, -Cl, -Br, or -I such that no other atoms aside from carbon, hydrogen and halogen are present.
  • the group, -CH 2 C1 is a non-limiting example of a haloalkyl.
  • fluoroalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present.
  • the groups -CH 2 F, -CF 3 , and -CH 2 CF 3 are non-limiting examples of fluoroalkyl groups.
  • Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl.
  • -CON(CH 3 ) 2 are non-limiting examples of substituted acyl groups.
  • the groups -NHC(0)OCH 3 and -NHC(0)NHCH 3 are non-limiting examples of substituted amido groups.
  • phosphonate when used without the “substituted” modifier refers to a compound with the formula R-P(0)(OR')(OR"), in which R, R', and R" can be the same or different alkyl, aryl, or aralkyl groups, as those terms are defined above, or R' and R" can be taken together to represent an alkanediyl.
  • R-P(0)(OMe)(OBn) Et-P(0)(OMe)(OBn) and C 5 H II -P(0)(0C 5 H II ) 2 .
  • isotopes of elements e.g. fluorine- 18.
  • Isotopes are designated either with a superscripted mass number prefix or a hyphenated, non-superscripted suffix, e.g. fluorine-18 or 18 F.
  • Isotopes as disclosed herein should not necessarily be taken to refer to the neutral elements but may refer to ions of these isotopes or to complexes thereof.
  • 18 F should be taken to refer to a 18 F species, e.g. 18 F or an 18 F complex, for example an aluminum (III) complex. Such complexes may themselves be neutral or may be electrically charged.
  • an “active ingredient” (AI) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, radiological agent, imaging agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically or radiologically active.
  • excipient is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a radiopharmaceutical, medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.
  • Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.
  • the main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle.
  • Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life.
  • the suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.
  • hydrate when used as a modifier to a compound means that the compound has less than one (e.g ., hemihydrate), one (e.g, monohydrate), or more than one (e.g, dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.
  • the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof.
  • the patient or subject is a primate.
  • Non-limiting examples of human patients are adults, juveniles, infants and fetuses.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient that is involved in carrying, delivering and/or transporting a chemical agent.
  • Carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some carriers may increase the effectiveness of drug delivery to the specific target sites. Some carriers may target specific tissues such as thyroid, brain, gastrointestinal, pancreas, spleen, kidney, neuroendocrine tumors, renal cell carcinoma, lung cancer, breast cancer, prostate cancer, and malignant lymphoma.
  • Non-limiting examples of carriers include: peptides, small molecules, antibodies, or antibody-drug conjugates, or fragments thereof.
  • Further non-limiting examples of carrier molecules include prostate-specific membrane antigen (PSMA), 1,4,7- triazacyclononane-N,N',N''-triacetic acid (NOTA), l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA), di ethylene triamine pentaacetic acid (DTP A), desferrioxamine, DOTA-Tyr(3)-octreotide (DOTATOC), DOTA-Tyr(3)-Tyr(8)- octreotide (DOTATATE), DOTA-l-naphtyl-alanine (DOTANOC), DOTA-benzothienyl-alanine (DOTA-BOC), DOTA-bombesin, DOTA-arginine-glycine-aspartic acid-bomb
  • PCTA-RGD DOTA-albumin, DOTA-human epidermal growth factor, l,4,7-triazacyclononane-l-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid-integrin alpha(IIb)beta(3)-specific cyclic hexapeptide (NOPO-RGDfK), l,4,7-triazacyclononane-l,4-bis(acetic acid)-7-(2-glutaric acid) (NODAGA), NOPO-NaI(3)-octreotide conjugate (NOPO-NOC), l,4,7-triazacyclononane-l,4,7-tris[(2-carboxyethyl)methylenephosphinic acid] (TRAP(RGD)3), or citrate.
  • NOPO-RGDfK N-NaI(3)-octreotide conjugate
  • a “pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug, agent, or preparation) is a composition used to diagnose, image, cure, treat, or prevent disease, which comprises an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (defined above).
  • API active pharmaceutical ingredient
  • an “imaging agent” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
  • radiopharmaceuticals may be imaging agents, such as A1 18 F-PSMA-11.
  • Precursor compounds are those which can be made detectable by incorporating a radionuclide or other radiolabel into the compound or form a complex with radionuclide.
  • Imaging agents may be used to detect cells, organs, regions, or antibodies specifically reactive with the radiopharmaceutical or may be used to detect cells, organs, or regions where the radiopharmaceutical accumulates.
  • the imaging agent comprises is a radionuclide, such as 18 F.
  • a radionuclide such as 18 F.
  • Methods of detecting and/or for quantifying a detectable imaging agent depend on the nature of the imaging agent. Examples of detectors suitable for detecting such detectable labels include, without limitation, x-ray film, radioactivity counters, scintillation counters, spectrophotometers, colorimeters, fluorometers, luminometers, and densitometers. Imaging may be by optical imaging, ultrasound, PET, SPECT, MRI, or phototherapy.
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g ., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • a “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands.
  • “Diastereomers” are stereoisomers of a given compound that are not enantiomers.
  • Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds.
  • a molecule can have multiple stereocenters, giving it many stereoisomers.
  • the total number of hypothetically possible stereoisomers will not exceed 2 n , where n is the number of tetrahedral stereocenters.
  • Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%.
  • enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
  • the phrase “substantially free from other stereoisomers” means that the composition contains ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%, or most preferably ⁇ 1% of another stereoisomer(s).
  • unit dose refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration.
  • unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.
  • activity when used in the context of radiopharmaceutical refers to the number of radioactive transformations per second that occur in a particular radionuclide. Activity may be measure in Curie (Ci) or becquerel (Bq). Methods of detecting and/or quantifying activity are well known in the art. Non-limiting examples of detectors include gamma counters, scintillation detectors, Geiger counters, ion chambers, etc.
  • radiochemical yield refers to the amount of activity in the product expressed as the percentage (%) relative to the starting activity utilized in a process (e.g. synthesis, separation, etc.), wherein both values relate to the same radionuclide. Radiochemical yields disclose herein are non-decay corrected.
  • radiochemical purity refers the fraction of radioactivity of the radionuclide of interest in the desired chemical form to the total radioactivity of that radionuclide present in the preparation. Measurement of RCP may require the use of a method to separate the different labeled chemical species, which may be present in the radiopharmaceutical preparation.
  • Non-limiting methods for determining radiochemical purity include thin-layer chromatography (TLC), liquid chromatography (LC), high-performance liquid chromatography (HPLC), solid-phase extraction (SPE), and gel electrophoresis.
  • PBS phosphate-buffered saline
  • PET positron emission tomography
  • PSMA prostate-specific membrane antigen
  • °C degrees Celsius, h or hr, hours
  • rt room temperature
  • MeOH methanol, EtOH, ethanol
  • /PrOH isopropanol.
  • the methods provided herein for preparing purified Al 18 F-labeled HBED conjugates comprise obtaining the Al 18 F-labeled HBED-conjugate to be purified.
  • the obtained Al 18 F-labeled HBED conjugate to be purified may be prepared from the reaction of A1 18 F 3 with an HBED precursor.
  • the 18 F may be prepared or synthesized using a cyclotron or linear particle accelerator.
  • a cyclotron is understood to be an apparatus in which charged atomic and subatomic particles are accelerated by an alternating electric field while following an outward spiral or circular path in a magnetic field.
  • the 18 F is synthesized via irradiation of 18 0, typically in the form of 18 0-H 2 0, which upon irradiation is converted into 18 F.
  • the present disclosure provides methods of producing a purified radiopharmaceutical comprising: a) contacting a compound with a first phosphate-buffered saline (PBS) solution, wherein the compound is of the formula: wherein:
  • Li is a covalent bond, -(Xi) n _ , -X 2 _ alkanediyl ( c ⁇ i 2) _ C(0)- or substituted
  • n 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or — NRa-, wherein:
  • Ra is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6>; and Ri is a targeting moiety; to produce a diluted solution; and b) contacting the diluted solution with a chromatographic material to produce the purified radiopharmaceutical.
  • the compound of formula (I) is diluted with the first phosphate buffer solution.
  • phosphate-buffered saline may stabilize the Al 18 F-complex and protect against degradation upon chromatographic separation of the compound from impurities.
  • the concentration of hydrogen phosphate in the first PBS solution may be from about 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 50 mM to about 100 mM or any range derivable therein.
  • the concentration of hydrogen phosphate in the first PBS solution is from about 1 mM to about 25 mM or from about 5 mM to about 15 mM. In some embodiments, the concentration of hydrogen phosphate in the first PBS solution is about 10 mM. In some embodiments, the first PBS solution is IX PBS.
  • the diluted solution is contacted with a chromatographic material.
  • chromatographic material One of skill in the art will appreciate that many different types of chromatographic materials may be effective for the separation of the purified radiopharmaceutical from any impurities, including but not limited to solid-phase extraction sorbents.
  • the chromatographic material has a higher affinity for the Al 18 F-complex than it does for one or more impurity associated with the production of the complex.
  • the chromatographic material should have a higher affinity for Al 18 F-complex than for impurities so that the impurities are eluted from the anion-exchange resin while the majority, preferably substantially all, of the Al 18 F-complex is retained on the chromatographic material under an initial set of conditions.
  • the chromatographic material should have an affinity for the Al 18 F-complex that can be modulated so as to allow for the Al 18 F-complex, i.e., the purified radiopharmaceutical, to be eluted from the material under a second set of conditions.
  • Non-limiting examples of chromatographic materials that may be employed in the methods and systems of the present disclosure are solid-phase extraction sorbents and ion-exchange resins, such as anion-exchange resins or cation-exchange resins.
  • a non-limiting example of a chromatographic material useful in the methods and systems of the present disclosure is the Oasis ® HLB sorbent.
  • the chromatographic material is a polymeric sorbent.
  • the sorbent is a reversed-phase polymeric sorbent.
  • the sorbent is water- wettable.
  • the sorbent is hydrophilic.
  • the polymeric sorbent may comprise a repeat unit, wherein the repeat unit comprises a pyrrolidin-2-one moiety. In some embodiments, the polymeric sorbent comprises a substructure of the formula: or a substituted version thereof.
  • the chromatographic material is a hydrophilic, reversed-phase, water- wettable polymeric solid-phase extraction sorbent.
  • the resin should be resistant to radiation.
  • the chromatographic material exists in particulate form, so that a column contains a packed bed of the particulate material.
  • the material may be porous, e.g. microporous, mesoporous, nanoporous etc.
  • a typical resin column may contain from about 0.01 g to about 2 g of resin, e.g. about 0.01, 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1, 1.5, or 2 g.
  • chromatographic material may be contacted with a second phosphate buffer solution prior to contacting the diluted solution comprising the compound to be purified.
  • concentration of hydrogen phosphate in the second PBS solution may be from about 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 50 mM to about 100 mM or any range derivable therein.
  • the concentration of hydrogen phosphate in the second PBS solution is from about 1 mM to about 25 mM or from about 5 mM to about 15 mM. In some embodiments, the concentration of hydrogen phosphate in the second PBS solution is about 10 mM. In some embodiments, the second PBS solution is IX PBS.
  • the Al 18 F-complex may be eluted from the chromatographic material resin by contacting the chromatographic material with an eluent.
  • the eluent comprises a third PBS solution.
  • the eluent comprises a first organic solvent.
  • the eluent comprises both a third PBS solution and a first organic solvent.
  • the first organic solvent is an alcoholic solvent, such as methanol, ethanol, or propanol.
  • the concentration of hydrogen phosphate in the third PBS solution may be from about 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 50 mM to about 100 mM or any range derivable therein.
  • the concentration of hydrogen phosphate in the third PBS solution is from about 1 mM to about 25 mM or from about 5 mM to about 15 mM. In some embodiments, the concentration of hydrogen phosphate in the third PBS solution is about 10 mM. In some embodiments, the third PBS solution is IX PBS.
  • the eluent modulates the affinity of the chromatographic material for the purified radiopharmaceutical, i.e., the Al 18 F-complex. The methods and systems provided herein provide purified radiopharmaceuticals with improved radiopharmaceutical yields.
  • the methods or systems produce the purified radiopharmaceutical having a radiochemical yield of from about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% to to about 100%, or any range derivable therein, such as greater than about 20% or greater than about 30%.
  • the methods or systems provided herein produce the purified radiopharmaceutical having a radiochemical yield of about 40%.
  • the present disclosure also provides systems for the production of a purified radiopharmaceutical.
  • the systems comprise: a) a dilution chamber configured to: receive a compound and a PBS solution; contact the compound with the PBS solution; and produce a diluted sample; wherein the compound is of the formula: wherein:
  • Li is a covalent bond, -(Xi) n _ , -X 2 _ alkanediyl ( c ⁇ i 2) _ C(0)- or substituted -X 2- alkanediyl ( c ⁇ i 2) _ C(0)-, wherein: n is 1-50;
  • Xi is an amino acid residue
  • X2 is -O- or — NRa-, wherein:
  • Ra is hydrogen, alkyl(c ⁇ 6), or substituted alkyl(c ⁇ 6>; and Ri is a targeting moiety; and b) a chromatography chamber comprising a chromatographic material, wherein the chromatography chamber is configured to: receive the diluted sample; contact the diluted sample with the chromatographic material; and produce the purified radiopharmaceutical; wherein the dilution module and chromatography module are in fluid communication.
  • the system may be portable or may be fixed in a specific location.
  • the present disclosure also provides purified radiopharmaceuticals prepared according to the methods of the present disclosure and radiopharmaceutical compositions thereof.
  • Said radiopharmaceuticals and compositions thereof may be used to image, diagnose, treat, and/or prevent a disease or disorder in a patient.
  • the radiopharmaceuticals and compositions thereof disclosed herein may be useful for biological imaging, e.g. PET imaging.
  • Compositions may further comprise an excipient or pharmaceutically acceptable carrier.
  • Compositions may be prepared by the addition of the radiopharmaceutical prepared according to a method of the present disclosure to a carrier molecule or a solution comprising a carrier molecule. Further processing of the composition may be performed prior to administration to a patient. Such processing may include purification, concentration, or dilution.
  • Compositions of the present disclosure may also comprise pharmaceutically acceptable excipients.
  • compositions disclosed herein may be formulated for administration intraarterially, intraarticularly, intracranially, intrapericardially, intraperitoneally, intratumorally, intravenously, intravesicularlly, parenterally, via injection, via local delivery, or via localized perfusion.
  • the compositions may be administered once or more than once.
  • the compositions may be used to image tissue, such as a tumor, e.g. a prostate, pancreatic, lung, or neuroendocrine tumor.
  • the compositions may be used to image a tumor that exhibits elevated levels of PSMA.
  • this disclosure contemplates methods of imaging of target cells, antigens, tissues, or regions using radiopharmaceuticals, such as HBED-conjugates with detectable moieties (e.g., radionuclides).
  • radiopharmaceuticals such as HBED-conjugates with detectable moieties (e.g., radionuclides).
  • the radioactivity can be detected by various methods known in the art, such as positron emission tomography.
  • Positron emission tomography is an imaging technique that produces a three- dimensional image.
  • the system detects pairs of gamma rays emitted indirectly by a positron- emitting radionuclide (tracer).
  • Three-dimensional images of tracer concentration within the area are then constructed by computer analysis.
  • a radioactive tracer isotope is injected into subject, e.g., into blood circulation. Typically there is a waiting period while tracer becomes concentrated in tissues of interest; then the subject is placed in the imaging scanner.
  • the radioisotope undergoes positron emission decay, it emits a positron, an antiparticle of the electron with opposite charge, until it decelerates to a point where it can interact with an electron, producing a pair of (gamma) photons moving in approximately opposite directions. These are detected in the scanning device.
  • the technique depends on simultaneous or coincident detection of the pair of photons moving in approximately opposite direction (the scanner has a built-in slight direction-error tolerance). Photons that do not arrive in pairs (i.e. within a timing-window) are ignored.
  • the radiopharmaceuticals and compositions thereof described herein can be used to screen patients for cancer or can be used to monitor or stage patients diagnosed with cancer.
  • the reaction was permitted to proceed at room temperature for 10 min (start: 10:37; end: 10:47).
  • the crude reaction mixture was diluted with 10 mM PBS (pH 7) (3+20 mL) and slowly passed through a pre-conditioned Oasis cartridge (activity in the waste: 502 mCi; HPLC analysis of the waste: ⁇ 10% was the desired compound).
  • the purified A1 18 F-PSMA-11 was eluted with 3 mL EtOH/PBS (7/3, v/v) into a final product vial containing 20 mL of 10 mM PBS (activity acquired: 569 mCi; radiochemical purity: 97.4%).

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Abstract

Des procédés de production de solutions radiopharmaceutiques purifiées sont divulgués, la solution radiopharmaceutique purifiée comprenant un complexe métal-ion de la formule : AI3 + (L2 - )18F-, où L2- est un chélateur de la formule (I) et dans laquelle les variables sont définies dans la description. La présente invention concerne également des solutions radiopharmaceutiques produites selon les procédés de la présente invention ainsi que des compositions radiopharmaceutiques de celles-ci. La présente invention concerne également des systèmes de production de solutions radiopharmaceutiques purifiées.
PCT/US2020/062127 2019-11-25 2020-11-25 Procédé d'extraction et de purification de conjugués hbed étiquetés ai18f WO2021108474A1 (fr)

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Non-Patent Citations (4)

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