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WO2016149188A1 - Agents thérapeutiques et d'imagerie visant psma à chélation nota et marquage par le68ga - Google Patents

Agents thérapeutiques et d'imagerie visant psma à chélation nota et marquage par le68ga Download PDF

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Publication number
WO2016149188A1
WO2016149188A1 PCT/US2016/022309 US2016022309W WO2016149188A1 WO 2016149188 A1 WO2016149188 A1 WO 2016149188A1 US 2016022309 W US2016022309 W US 2016022309W WO 2016149188 A1 WO2016149188 A1 WO 2016149188A1
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Prior art keywords
psma
group
imaging
tumor
alkyl
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English (en)
Inventor
Martin G. Pomper
Ronnie MEASE
Sangeeta Ray
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Johns Hopkins University
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Johns Hopkins University
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Priority to US15/557,854 priority Critical patent/US10717750B2/en
Publication of WO2016149188A1 publication Critical patent/WO2016149188A1/fr
Anticipated expiration legal-status Critical
Priority to US16/934,414 priority patent/US20210040126A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • PSMA transmembrane glycoprotein prostate-specific membrane antigen
  • PSMA is found in benign, as well as in malignant prostate tissue (Murphy et al, (1995) Prostate 26, 164-8; Murphy et al, (1998) Urology 51, 89-97; Murphy et al, (1998) J Urol 160, 2396-401). However, expression of PSMA is greatest in prostate adenocarcinoma, particularly in castration-resistant disease (Sweat et al. (1998) Urology 52, 637-40; Silver et al. (1997) Clin Cancer Res 3, 81-5).
  • PSMA is also present in the neovasculature of solid tumors including kidney, lung (Wang et al. (2015) PLoS ONE 10.), stomach, colon, and breast (Haffner et al. (2009) Hum Pathol 40, 1754-61 ; Haffner et al (2012) Mod Pathol 25, 1079-85; Baccala et al. (2007) Urology 70, 385-90).
  • Expression of PSMA is associated with the neovascular endothelium in non-prostate tumors (Chang et al. (1999) Mol Urol 3, 313-320; Chang et al. (1999) Clin Cancer Res 5, 2674-81).
  • PSMA-targeted agents to image patients with prostate cancer using positron emission tomography have been reported by several groups (Cho et al. (2012) J NuclMed 53, 1883-91; Afshar-Oromieh et al. (2012) Eur J Nucl Med Mol Imaging 39, 1085-6; Afshar-Oromieh et al. (2013) Eur JNuclMed Mol Imaging 40, 1629-30; Afshar-Oromieh et al. (2014) Eur J Nucl Med Mol Imaging 41, 887-97; Afshar- Oromieh et al. (2015) Eur. J. NuclMed. Mol. Imaging 42, 197-209; Eiber et al.
  • the radiometal 68 Ga can be produced on-site with a generator, followed by simple synthesis of the radiotracer (Fani et al. (2008) Contrast media & molecular imaging 3, 67-77).
  • 68 Ga-l a radiotracer that employed the DOTA-mono-amide chelator with conjugation to H 2 N-Lys-(CH 2 )3-Lys-urea-Glu for targeting to PSMA (FIG. 1) has been previously reported (Banerjee et al. (2010) J Med Chem 53, 5333-41). That chelator has been chosen to make it possible to complex imaging radiometals, such as 68 Ga, 86 Y, 20 Pb, as well as therapeutic radiometal nuclides, such as 177 Lu, 90 Y, 212 Pb or 225 Ac, within the same scaffold.
  • 68 Ga-based agents have demonstrated excellent clinical results for detection of prostate cancer, namely, 68 Ga-DKFZ-PSMA-l l (Glu-urea-Lys-(Ahx)- HBED-CC) and EuK-Sub-kff- 68 Ga-DOTAGA ( 68 Ga-PSMA I&T) (Herrmann et al. (2015) Journal of Nuclear Medicine; Eder et al. (2012) Bioconjug Chem 23, 688-97; Weineisen et al. (2015) JNuclMed; Weineisen et al. (2014) EJNMMI Res 4, 63).
  • the presently disclosed subject matter provides a compound
  • Z is tetrazole or CO2Q;
  • Q is H or a protecting group;
  • X and Y are each independently O or S;
  • a is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • each Ri is independently H or C1-C4 alkyl;
  • each R 2 is independently H or -COOR 3 , wherein each R 3 is independently H or a Ci-
  • the metal (M) is selected from the group consisting of Tc-94m, Tc-99m, In-I l l, Ga-67, Ga-68, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, Gd-152, or Dy-166.
  • the metal (M) is Ga-68. In still more particular aspects, the compound of Formula (I) is Ga-SRV168.
  • the presently disclosed subject matter provides a method for imaging one or more prostate-specific membrane antigen (PSMA) tumors or cells, the method comprising contacting the one or more tumor or cells, with an effective amount of a compound of Formula (I) and making an image, the compound of Formula (I) comprising:
  • Z is tetrazole or CO2Q;
  • Q is H or a protecting group;
  • X and Y are each independently O or S;
  • a is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • each Ri is independently H or C1-C4 alkyl;
  • each R2 is independently H or -COOR3, wherein each R3 is independently H or a Ci- Ce alkyl
  • the presently disclosed subject matter provides a method for treating or preventing a disease or condition associated with one or more PSMA expressing tumors or cells, the method comprising administering to a subject in need of treatment thereof, at least one compound of Formula (I), in an amount effective to treat or prevent the disease or condition.
  • the presently disclosed subj ect matter provides a kit comprising a compound of Formula (I).
  • FIG. 1 shows chemical structures of representative radiotracers used for the presently disclosed studies
  • FIG. 3 A, FIG. 3B, FIG. 3C, and FIG. 3D show the comparison of PSMA+ PC3 PIP tumor-to-PSMA- PC3 flu tumor (A); PSMA+ PC3 PIP-to-kidney (B);
  • PSMA+ PC3 PIP-to-salivary gland C
  • PSMA+ PC3 PIP-to-blood D
  • FIG. 4 shows the X H NMR spectrum of Ga-2 in DMSO at room temperature
  • FIG. 5A, FIG. 5B, FIG. 5C, FIG. 5D, and FIG. 5E show preparative HPLC chromatograms of 68 Ga-l (A), 68 Ga-2 (B, C) and 68 Ga-DKFZ-PSMA-l l (D, E) for radio-HPLC (A,B,D) and UV (C, E) peaks; and
  • FIG. 6 shows whole-body PET-CT imaging at 1 h post injection for the radiotracers, 68 Ga-l, 68 Ga-2 and 68 Ga-DKFZ-PSMA-l l using NOD-SCID male mice bearing both PSMA+ PC3 PIP (right) and PSMA- flu (left) tumor xenografts within the upper flanks; PSMA+ PC3 tumor uptake for 68 Ga-2 was further blocked by injecting ZJ43 (50 mg/kg), 30 min prior to injection of the radiotracer.
  • Prostate-specific membrane antigen is an increasingly important target for imaging and therapy of prostate cancer.
  • a variety of high affinity radiohalogenated, urea-based PSMA inhibitors that selectively image prostate tumors in experimental models has been previously synthesized.
  • Chelated radiometal-linker- urea conjugates also have been synthesized. These compounds also selectively image prostate tumors in experimental models.
  • 68 Ga-Labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET).
  • PET positron emission tomography
  • the DOTA ligand was selected because it can chelate both imaging and therapeutic nuclides.
  • the growing number of clinical trials employing 68 Ga-based, PSMA-targeted PET has encouraged the investigation of structural elements that could promote the least off-target uptake of this class of radiotracers.
  • the presently disclosed subject matter provides, in some embodiments, a head-to-head, preclinical comparison of radiometal-chelate-linker- urea based PSMA binding imaging agents, wherein the chelating agents are DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) and NOTA (1,4,7- triazacyclononane-l,4,7-trisacetic acid), with a known imaging agent, DKFZ-PSMA- 11, when radiolabeled with 68 Ga.
  • DOTA l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid
  • NOTA 1,4,7- triazacyclononane-l,4,7-trisacetic acid
  • 68 Ga-l which is disclosed in WO 2010108125 A2 20100923
  • the new radiotracer 68 Ga-2 were compared with 68 Ga- DKFZ-PSMA-11, which is currently in clinical trial in Europe. Structures of the representative agents are shown in FIG. 1.
  • Z is tetrazole or CO2Q;
  • Q is H or a protecting group;
  • X and Y are each independently O or S;
  • a is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • each Ri is independently H or C1-C4 alkyl;
  • each R 2 is independently H or -COOR 3 , wherein each R 3 is independently H or a Ci-
  • Formula (I) does not include compounds disclosed in WO 2009/002529 and WO 2010/108125.
  • the metal (M) is selected from the group consisting of Tc-94m, Tc-99m, In-11 1, Ga-67, Ga-68, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, Gd-152, or Dy-166.
  • the metal (M) is Ga-68.
  • the compound of Formula (I) is 68 Ga- SRV168.
  • the presently disclosed subject matter provides a method for imaging one or more prostate-specific membrane antigen (PSMA) tumors or cells, the method comprising contacting to the one or more tumors or cells, with an effective amount of a compound of Formula (I) and making an image, the compound of Formula (I) comprising:
  • Z is tetrazole or CO2Q;
  • Q is H or a protecting group;
  • X and Y are each independently O or S;
  • a is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • each Ri is independently H or C1-C4 alkyl;
  • each R 2 is independently H or -COOR 3 , wherein each R 3 is independently H or a Ci- e
  • Formula (I) does not include compounds disclosed in WO 2009/002529 and WO 2010/108125.
  • Contacting means any action which results in at least one compound comprising the imaging agent of the presently disclosed subject matter physically contacting at least one PSMA-expressing tumor or cell. Contacting can include exposing the cell(s) or tumor(s) to the compound in an amount sufficient to result in contact of at least one compound with at least one cell or tumor.
  • the method can be practiced in vitro or ex vivo by introducing, and preferably mixing, the compound and cell(s) or tumor(s) in a controlled environment, such as a culture dish or tube.
  • the method can be practiced in vivo, in which case contacting means exposing at least one cell or tumor in a subject to at least one compound of the presently disclosed subject matter, such as administering the compound to a subject via any suitable route.
  • contacting may comprise introducing, exposing, and the like, the compound at a site distant to the cells to be contacted, and allowing the bodily functions of the subject, or natural (e.g., diffusion) or man-induced (e.g., swirling) movements of fluids to result in contact of the compound and cell(s) or tumor(s).
  • natural e.g., diffusion
  • man-induced e.g., swirling
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the presently disclosed methods include radioactive metal capable of emitting radiation suitable for detection with PET or SPECT.
  • the radioactive metal suitable for imaging (M) is selected from the group consisting of Tc-94m, Tc-99m, In-I l l, Ga-67, Ga-68, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, Gd-152, or Dy-166.
  • the radioactive metal suitable for imaging (M) is Ga-68.
  • the compound of Formula (I) is 68 Ga-2.
  • the imaging comprises positron emission tomography (PET). In other embodiments, the imaging comprises single-photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the one or more PSMA-expressing tumors or cells is selected from the group consisting of: a prostate tumor or cell, a metastasized prostate tumor or cell, a lung tumor or cell, a renal tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a stomach tumor or cell, and combinations thereof.
  • the one or more PSMA-expressing tumors or cells is a prostate tumor or cell.
  • the one or more PSMA-expressing tumors or cells is in vitro, in vivo or ex-vivo.
  • the one or more PSMA- expressing tumors, cells organs, or tissues is present in a subject.
  • a subject treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject.”
  • a "subject" can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal (non-human) subject for medical, veterinary purposes, or developmental purposes.
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like.
  • mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; cap
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a "subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the terms “subject” and “patient” are used interchangeably herein.
  • a detectably effective amount of the imaging agent of the presently disclosed methods is administered to a subject.
  • a detectably effective amount is defined as an amount sufficient to yield an acceptable image using equipment which is available for clinical use.
  • a detectably effective amount of the imaging agent may be administered in more than one injection.
  • the detectably effective amount of the imaging agent can vary according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual, the dosimetry, and instrument and film- related factors. Optimization of such factors is well within the level of skill in the art.
  • the compound of formula (I) comprising the radioactive metal suitable for imaging substantially localizes to the tumor or cell within about 60 minutes of administration. It is preferable that the compounds of the presently disclosed subj ect matter are excreted from tissues of the body quickly.
  • the presently disclosed methods comprise clearance of the compound comprising the imaging agent from the tumor or cell in the subject. In some other embodiment, the imaging agent is cleared more rapidly from a subject's kidneys than from a tumor in the subject.
  • the presently disclosed subject matter provides a method for treating or preventing a disease or condition associated with one or more PSMA expressing tumors or cells, the method comprising administering to a subject in need of treatment thereof, at least one compound of Formula (I), in an amount effective to treat or prevent the disease or condition, the compound of formula (I) comprising:
  • Z is tetrazole or CO2Q;
  • Q is H or a protecting group;
  • X and Y are each independently O or S;
  • a is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • each Ri is independently H or C1-C4 alkyl;
  • each R 2 is independently H or -COOR 3 , wherein each R 3 is independently H or a Ci- e
  • Formula (I) does not include compounds disclosed in WO 2009/002529 and WO 2010/108125.
  • the term "treating" can include reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
  • the "effective amount" of an active agent refers to the amount necessary to elicit the desired biological response.
  • the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like.
  • the term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound of Formula (I) and at least one other active agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state.
  • the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other).
  • the single dosage form may include additional active agents for the treatment of the disease state.
  • the disease or condition is a prostate cancer, renal cancer, head cancer, neck cancer, head and neck cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, esophageal cancer, stomach cancer, leukemia/lymphoma, uterine cancer, skin cancer, endocrine cancer, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, adenomas, and tumor neovasculature.
  • the disease or condition is prostate cancer. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the cancer or the tumor neovasculature.
  • a “cancer” in a subject refers to the presence of cells possessing
  • cancer cells will be in the form of a tumor; such cells may exist locally within a subject, or circulate in the blood stream as independent cells, for example, leukemic cells.
  • a cancer can include, but is not limited to, renal cancer, head cancer, neck cancer, head and neck cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, esophageal cancer, stomach cancer, leukemia/lymphoma, uterine cancer, skin cancer, endocrine cancer, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, and adenomas.
  • the disease or condition is prostate cancer.
  • a detectably effective amount of the therapeutic agent of the presently disclosed methods is administered to a subject.
  • the presently disclosed subject matter provides a kit comprising a compound of Formula (I).
  • Formula (I) does not include compounds disclosed in WO 2009/002529 and WO 2010/108125.
  • the kit provides packaged pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention.
  • the packaged pharmaceutical composition will comprise the reaction precursors necessary to generate the compound of the invention upon combination with a radio labeled precursor.
  • Other packaged pharmaceutical compositions provided by the present invention further comprise indicia comprising at least one of: instructions for preparing compounds according to the invention from supplied precursors, instructions for using the composition to image cells or tissues expressing PSMA, or instructions for using the composition to image glutamatergic neurotransmission in a patient suffering from a stress-related disorder, or instructions for using the composition to image prostate cancer.
  • the present disclosure provides a pharmaceutical composition including one compounds of Formula (I) alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient.
  • pharmaceutical compositions include the pharmaceutically acceptable salts of the compounds described above.
  • Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another.
  • bases include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another.
  • acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
  • Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • the compounds of the disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.
  • the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound(s), and the preference and experience of the attending physician.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium
  • CMC carboxymethyl-cellulose
  • PVP polyvinylpyrrolidone
  • polyvinylpyrrolidone agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye- stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • R groups such as groups R 1; R 2 , and the like, or variables, such as "m” and "n"
  • R groups such as groups R 1; R 2 , and the like, or variables, such as "m” and "n"
  • Ri and R 2 can be substituted alkyls, or Ri can be hydrogen and R 2 can be a substituted alkyl, and the like.
  • a when used in reference to a group of substituents herein, mean at least one.
  • a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R substituent the group may be referred to as "R-substituted.”
  • R- substituted the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • R or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein.
  • certain representative “R” groups as set forth above are defined below.
  • a "substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein:
  • hydrocarbon refers to any chemical group comprising hydrogen and carbon.
  • the hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions.
  • the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, poly cyclic, or heterocyclic.
  • Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, ⁇ -propyl, isopropyl, cyclopropyl, allyl, vinyl, w-butyl, fert-butyl, ethynyl, cyclohexyl, and the like.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon group, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent groups, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons).
  • alkyl refers to Ci-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., "straight-chain"), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, « -propyl, isopropyl, w-butyl, isobutyl, seobutyl, fert-butyl, w-pentyl, seopentyl, isopentyl, neopentyl, w-hexyl, seohexyl, w-heptyl, w-octyl, «-decyl, n- undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C 1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Higher alkyl refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • alkyl refers, in particular, to C 1-8 straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to C 1-8 branched-chain alkyls.
  • Alkyl groups can optionally be substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different.
  • alkyl group substituent includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl”), or aryl.
  • substituted alkyl includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH 2 -CH 2 -0-CH 3 , -CH 2 -CH 2 -NH-CH 3 ,
  • -CH CH-N(CH 3 )- CH 3 , 0-CH 3 , -0-CH 2 -CH 3 , and -CN.
  • up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)NR', -NR'R", -OR', -SR, -S(0)R, and/or -S(0 2 )R' .
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • Cyclic and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the cycloalkyl group can be optionally partially unsaturated.
  • the cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene.
  • cyclic alkyl chain There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group.
  • Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl.
  • Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like.
  • cycloalkylalkyl refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkyl group, also as defined above.
  • alkyl group also as defined above.
  • examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • cycloheteroalkyl or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10- member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and optionally can include one or more double bonds.
  • N nitrogen
  • O oxygen
  • S sulfur
  • P phosphorus
  • Si silicon
  • the cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings.
  • Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • heterocylic refers to a non-aromatic 5-, 6-, or 7- membered ring or a poly cyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7- membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quatemized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • 1 -(1,2,5,6- tetrahydropyridyl) examples include, but are not limited to, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • cycloalkylene and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl.”
  • alkenyl refers to a monovalent group derived from a Ci-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule.
  • Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1- methyl-2-buten-l-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.
  • cycloalkenyl refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • alkynyl refers to a monovalent group derived from a straight or branched C 1-2 o hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.
  • alkylene by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • alkylene groups include methylene (-CH 2 -); ethylene (-CH 2 -CH 2 -); propylene (-(CH 2 ) 3 -);
  • each of q and r is independently an integer from 0 to about 20, e.g., 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-0-CH 2 -0-); and
  • An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure.
  • a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkylene by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)OR'- represents both -C(0)OR'- and -R'OC(O)-.
  • aryl means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 - naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,
  • arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl and heteroarylalkyl are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
  • heteroalkyl where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. "3 to 7 membered"), the term “member” refers to a carbon or heteroatom.
  • a ring structure for example, but not limited to a 3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • the presence or absence of the R group and number of R groups is determined by the value of the variable "n," which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution.
  • n is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available
  • a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
  • heterocycloalkyl aryl
  • heteroaryl aryl
  • phosphonate and “sulfonate” as well as their divalent derivatives
  • divalent derivatives are meant to include both substituted and unsubstituted forms of the indicated group.
  • Optional substituents for each type of group are provided below.
  • R', R", R'" and R" each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R is meant to include, but not be limited to, 1- pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and - CH 2 CF 3 ) and acyl (e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and - CH 2 CF 3
  • acyl e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like.
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'- (C"R"') d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • R, R', R" and R' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • acyl specifically includes arylacyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2- phenylacetyl group.
  • acyl groups include acetyl and benzoyl.
  • alkoxyl or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C 1-2 o inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, w-butoxyl, seobutoxyl, fert-butoxyl, and ⁇ -pentoxyl, neopentoxyl, w-hexoxyl, and the like.
  • alkoxy alkyl refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • Alkyl refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl.
  • exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • Alkyloxyl refers to an aralkyl-O- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxyl group is benzyloxyl, i.e.,
  • An aralkyloxyl group can optionally be substituted.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and fert-butyloxycarbonyl.
  • aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • acyloxyl refers to an acyl-O- group wherein acyl is as previously described.
  • amino refers to the -NH 2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • amino refers to the -NH 2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • acylamino and alkylamino refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • aminoalkyl refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • alkylamino refers to a group having the structure -NHR' wherein R' is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR'R", wherein R' and R" are each independently selected from the group consisting of alkyl groups.
  • trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R", and R'" are each independently selected from the group consisting of alkyl groups. Additionally, R', R", and/or R'" taken together may optionally be -(CH 2 ) k - where k is an integer from 2 to 6.
  • Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.
  • the amino group is -NR'R", wherein R and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom.
  • thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, w-butylthio, and the like.
  • Acylamino refers to an acyl-NH- group wherein acyl is as previously described.
  • Aroylamino refers to an aroyl-NH- group wherein aroyl is as previously described.
  • Carboxyl refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
  • halo refers to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobut l, 3-bromopropyl, and the like.
  • hydroxyalkyl refers to an alkyl group substituted with an -OH group.
  • mercapto refers to the -SH group.
  • oxo as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.
  • nitro refers to the -NO 2 group.
  • thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
  • thiohy droxyl or thiol refers to a group of the formula
  • sulfide refers to compound having a group of the formula -SR.
  • sulfone refers to compound having a sulfonyl group -S(0 2 )R.
  • sulfoxide refers to a compound having a sulfinyl group -S(0)R
  • ureido refers to a urea group of the formula -NH— CO— NH 2 .
  • Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms.
  • Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 1 C- or I4 C- enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure may exist as salts.
  • the present disclosure includes such salts.
  • Examples of applicable salt forms include
  • salts may be prepared by methods known to those skilled in art.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange.
  • acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
  • dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • the term "about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1 %, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • 68 Ga-Labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET).
  • PSMA prostate-specific membrane antigen
  • PET positron emission tomography
  • the presently disclosed subject matter compares the pharmacokinetics of three PSMA-targeted radiotracers: 68 Ga-l, using DOTA-monoamide as the chelating agent; 68 Ga-2, containing the macrocyclic chelating agent / SCN-Bn-NOTA, and 68 Ga-DKFZ-PSMA-l l, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC.
  • the PSMA- targeting scaffold for all three agents utilizes a similar Glu-Lys-urea-linker construct.
  • Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT).
  • PET/CT PET/computed tomography
  • 68 Ga-2 demonstrated the highest PSMA+ PC3 PIP tumor uptake, at 42.2 ⁇ 6.7 percentage injected dose per gram (%ID/g) of tissue at 1 h post- injection, and the fastest rate of clearance from all tissues.
  • 68 Ga-l and 68 Ga-DKFZ- PSMA-11 displayed similar uptake and retention patterns in PSMA+ PC3 PIP tumors up to 3 h post-injection.
  • Ga-DKFZ-PSMA-l 1 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection.
  • 68 Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging.
  • the biodistribution profile of Ga-1 indicates promise for future therapeutic radionuclides that could employ a similar combination of chelator and targeting scaffold.
  • Triethylsilane (Et 3 SiH), diisopropylethylamine (DIEA) and triethylamine (TEA) were purchased from Sigma- Aldrich (St. Louis, MO). All other chemicals were purchased from Thermo Fisher Scientific (Pittsburgh, PA) unless otherwise specified.
  • HPLC purification of stable compounds was performed using a Phenomenex Ci 8 Luna 10 x 250 mm 2 column and elution with water (0.1% TFA) (A) and CH 3 CN (0.1 % TFA) (B) on a Waters 600E Delta LC system with a Waters 486 variable wavelength UV/Vis detector, both controlled by Empower software (Waters Corporation, Milford, MA).
  • HPLC purifications of 68 Ga-l, 68 Ga-2 and 68 Ga-DKFZ- PSMA-11 were performed on a Varian Prostar System (Palo Alto, CA), equipped with a Varian ProStar 325 UV-Vis variable wavelength detector and a Bioscan Flow- count in-line Radioactivity detector (Washington DC), all controlled by Galaxie software (Varian Inc., Walnut Creek, CA).
  • radiotracers were purified using a Varian microsob-MV 100-5 C 8 25x4.6 mm column with a flow rate 1 mL/min with water (0.1% TFA) (A) and CH 3 CN (0.1% TFA) (B) as the eluting solvents.
  • various HPLC methods were applied to separate excess ligand from the radiolabeled compound.
  • 68 Ga-l an isocratic solution of 80% A and 20% B was used.
  • 68 Ga-2 and 68 Ga-DKFZ-PSMA-l an isocratic solution of 85% water and 15% B was employed.
  • Retention times of the radiolabeled compound and unlabeled free ligands are listed in Table 1.
  • the radiochemical yield and purity of the radiotracers were further checked by withdrawing 1 aliquots of the radiolabeled solution and were analyzed by radio-TLC on RP-18 thin layer plates using 5/1 saline/methanol as the mobile phase.
  • the specific radioactivity was calculated as the radioactivity eluting at the retention time of product during the preparative HPLC purification divided by the mass corresponding to the area under the curve of the UV absorption.
  • Ga(III)Cl 3 was obtained in a total volume of 400 ⁇ , eluted in 2.4/97.6 0.05 N HCl/acetone. The Ga(III) in HCl/acetone was used immediately for the
  • PSMA Inhibition Assay The PSMA inhibitory activity of 1, 2 and DKFZ- PSMA-11 and the corresponding natural Ga-labeled analogs Ga-1 and Ga-2 were determined using a fluorescence-based assay according to a previously reported procedure (Banerjee et al. (2011) Angewandte Chemie 50, 9167-70) (Table 1).
  • NAAG N-acetylaspartylglutamate
  • Inhibition curves were determined using semi-log plots and IC 50 values were determined at the concentration at which enzyme activity was inhibited by 50 %. Enzyme inhibitory constants C3 ⁇ 4 values) were generated using the Cheng-Prusoff conversion (Cheng et al. (1973) Biochemical pharmacology 22, 3099-108). Assays were performed in triplicate. Data analysis was performed using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California).
  • PSMA-positive (+) PC3 PIP or are devoid of target [PSMA-negative (-) PC3 flu]. They were generously provided by Dr. Warren Heston (Cleveland Clinic). Cells were grown in RPMI 1640 medium (Coming Cellgro, Manassas, VA) containing 10 % fetal bovine serum (FBS) (Sigma- Aldrich, St. Louis, MO) and 1 % penicillin- streptomycin (Corning Cellgro, Manassas, VA). PSMA+ PC3 PIP cells were grown in the presence of 20 ⁇ g/mL of puromycin to maintain PSMA expression. All cell cultures were maintained in an atmosphere containing 5 % carbon dioxide (CO2), at 37.0 °C in a humidified incubator.
  • CO2 carbon dioxide
  • SCID mice Johns Hopkins Immune Compromised Animal Core mice (Johns Hopkins Immune Compromised Animal Core) were implanted subcutaneously (sc) with PSMA+ PC3 PIP and PSMA- PC3 flu cells (1 x 10 6 in 100 of HBSS (Corning Cellgro, Manassas, VA) at the forward right and left flanks, respectively. Mice were imaged or used in biodistribution assays when the xenografts reached 5 to 7 mm in diameter.
  • a mouse was subcutaneously administered a blocking dose of the known PSMA inhibitor ZJ43 (Olszewski et al. (2004) Journal of neurochemistry 89, 876-85) (50 mg/kg) at 30 min before the injection of 68 Ga-2, and another mouse was injected with 68 Ga-2 alone.
  • a CT scan was acquired after each PET scan in 512 projections using a 50 keV beam for anatomic co-registration. PET emission data were corrected for decay and dead time and were reconstructed using the 3-dimensional ordered-subsets expectation maximization algorithm. Data were displayed and analyzed using AMIDE software (http://sourceforge.net/amide).
  • mice were sacrificed by cervical dislocation and the blood was immediately collected by cardiac puncture.
  • the heart, lungs, liver, stomach, pancreas, spleen, fat, kidney, muscle, small and large intestines, urinary bladder, PSMA+ PC3 PIP and PSMA- PC3 flu tumors were collected.
  • tissue radioactivity was measured with an automated gamma counter (1282 Compugamma CS, Pharmacia/ LKBNuclear, Inc., Mt. Waverly, Vic. Australia).
  • the percentage of injected dose per gram of tissue was calculated by comparison with samples of a standard dilution of the initial dose. All measurements were corrected for decay.
  • Data Analysis Data are expressed as mean ⁇ standard deviation (SD). Prism software (GraphPAD, San Diego, California) was used to determine statistical significance. Statistical significance was calculated using a two-tailed Student's t test. A -value ⁇ 0.05 was considered significant.
  • DKFZ- PSMA-11 chelated with HBED-CC is reported to provide a uni-negative, hexadentate chelation (N 2 O 4 ) to Ga(III), with two carboxylates and two phenolates (L'Eplattenier et al. (1967) Journal of the American Chemical Society 89; Zoller et al. (1992) Journal of Nuclear Medicine 33, 1366-1372; Eder et al. (2008) European Journal of Nuclear Medicine and Molecular Imaging 35, 1878-1886). All three radiotracers were synthesized in high radiochemical yield (about 95-99 %) and purity (> 98 %), with specific radioactivity >168 GBq/ ⁇ (4.05 mCi/ ⁇ ).
  • Precursor ligands and the corresponding stable metal-labeled compounds demonstrated high binding affinity to PSMA, with ⁇ values ranging from 0.03 to 0.81 nM (Table 1).
  • the known, high-affinity PSMA inhibitor ZJ43 (Olszewski et al. (2004) Journal of neurochemistry 89, 876-85) was used as a reference ligand and exhibited a i of 0.31 nM (Table 1).
  • DKFZ-PSMA-11 displayed the highest PSMA- binding affinity from the compounds tested in this comparative study, ten-fold higher than either of Ga-1 and Ga-2.
  • DKFZ-PSMA-11 is the most lipophilic in the series, although after complexation with gallium (III), the agent Ga-DKFZ-PSMA-11, is the most hydrophilic in the series.
  • the order of hydrophilicity is Ga-DKFZ-PSMA-ll> Ga-2> Ga-SR2.
  • Tables 2, 3 and 4 show the pharmacokinetics in selected organs for 68 Ga-l, 68 Ga-2 and 68 Ga-DKFZ-PSMA-l 1, respectively. All compounds exhibited clear PSMA-dependent binding in PSMA+ PC3 PIP tumor xenografts.
  • the tumor uptake for 68 Ga-l was 19.46 ⁇ 1.81 % ID/g at 1 h, highest at 2 h (24.75 ⁇ 1.05 % ID/g) and remained high at 3h post-injection (19.46 ⁇ 5.12 % ID/g) (Table 2).
  • PSMA+ PC3 PIP-to-PSMA- PC3 flu tumor uptake ratios were 83.60 ⁇ 3.59 at 1 h and 148.75 ⁇ 16.43 at 2 h.
  • the distribution within normal organs and tissues was also favorable, with low blood and normal tissue uptake and rapid clearance.
  • the highest non-specific accumulation of radioactivity was observed in the kidneys, where uptake was expectedly high and peaked at 26.45 ⁇ 6.85 %ID/g at 1 h and decreased to 11.88 ⁇ 0.99 %ID/g by 2 h and remained roughly the same at 3 h post-injection.
  • Table 3 shows the organ-related %ID/g of uptake for Ga-2.
  • Ga-2 showed the highest PSMA-dependent tumor uptake with 42.18 ⁇ 6.66 %ID/g at 1 h post- injection. Tumor uptake remained high, with faster clearance from 1 h to 2 h.
  • the PSMA+ PC3 PIP-to-PSMA- PC3 flu tumor ratios were 109.82 ⁇ 21.61 at 1 h, 232.14 ⁇ 25.99 at 2 h and 182.27 ⁇ 14.59 at 3 h.
  • Renal uptake for 68 Ga-2 was highest at 1 h, 106.37 ⁇ 23.29 %ID/g, much higher than that seen for 68 Ga-l and showed faster renal clearance, which decreased to 34.73 ⁇ 5.74 %ID/g by 2 h post-injection.
  • non-target organs such as blood, heart, liver, spleen, stomach, pancreas, showed lower uptake ( ⁇ 1 %ID/g at 1 h, except for spleen) and faster clearance than for 68 Ga- 1
  • Table 4 lists the organ-related %ID/g of uptake for b8 Ga-DKFZ-PSMA-l 1. Unlike 68 Ga-l, 68 Ga-DKFZ-PSMA-l 1 showed the highest PSMA-dependent tumor uptake with 26.86 ⁇ 5.59 % ID/g at 3 h post-injection. Tumor uptake was nearly comparable from 1 to 3 h post-injection.
  • the PSMA+ PC3 PIP-to-PSMA- PC3 flu ratios were 46.62 ⁇ 7.57 % ID/g at 1 h, 57.68 ⁇ 27.10 % ID/g at 2 h and 110.57 ⁇ 21.27 % ID/g at 3 h post-injection.
  • FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D summarize several comparative tissue uptake properties of the three agents.
  • PSMA+ PC3 PIP tumor uptake of 68 Ga-2 was significantly higher than 68 Ga-l at 1 h post-injection (P ⁇ 0.004) (FIG. 2A).
  • PSMA+ PIP tumor uptake between 68 Ga-l and 68 Ga-DKFZ-PSMA-l 1 or between 68 Ga-2 and 68 Ga-DKFZ-PSMA-l 1 (P ⁇ 0.09).
  • renal uptake of 68 Ga-l was significantly lower than 68 Ga-2 (P ⁇ 0.006) and 68 Ga-DKFZ-PSMA- 11 (P ⁇ 0.001 ) at 1 h, although there was no significant difference between 68 Ga-2 and 68 Ga-DKFZ-PSMA-l 1.
  • renal uptake of both 68 Ga-l and 68 Ga-2 were significantly lower than for 68 Ga-DKFZ-PSMA-l l (P ⁇ 0.003) and renal uptake of 68 Ga-l was still significantly lower than 68 Ga-2 (P ⁇ 0.005).
  • renal uptake of both 68 Ga-l and 68 Ga-2 were significantly lower than for 68 Ga-DKFZ-PSMA- 11.
  • FIG. 2C reveals that 68 Ga-DKFZ-PSMA-l 1 demonstrated significantly higher salivary gland uptake up to 3 h after injection compared to 68 Ga-l and 68 Ga-2 (P ⁇ 0.001).
  • Figure 2D shows higher spleen uptake for 68 Ga-DKFZ-PSMA-l 1 compared to either 68 Ga-l or 68 Ga-2 (P ⁇ 0.04) at all time -points. Between 68 Ga-l and 68 Ga-2, the former showed significantly lower spleen (P ⁇ 0.03) uptake at 1 h and 2 h post- injection compared to the latter. Selected PSMA+ PC3 PIP tumor-to-background for the three agents at 1-3 h post-injection are shown in FIG. 3 A, FIG. 3B, FIG. 3C, and FIG. 3D.
  • PSMA+ PC3 PIP tumor-to- salivary gland ( ⁇ 0.002) and PSMA+ PC3 PIP tumor-to-kidney ratios proved significantly higher for 68 Ga-l and 68 Ga-2 than for 68 Ga-DKFZ-PSMA-l 1 (P ⁇ 0.04).
  • PSMA+ PC3 PIP tumor-to-PSMA- PC3 flu tumor ratios were also significantly higher for 68 Ga-l and 68 Ga-2 compared to 68 Ga-DKFZ-PSMA-l 1 at 1 h post-injection (P ⁇ 0.02).
  • the data show that PSMA+ PC3 PIP tumor-to-blood ratios were highest for 68 Ga-2 at all three time points.
  • Small Animal PET-CT Imaging Whole body PET-CT images were studied for 68 Ga-l, 68 Ga-2 and 68 Ga-DKFZ-PSMA-l 1 in intact male NOD/SCID mice (FIG. 6) bearing both PSMA+ PC3 PIP and PSMA- PC3 flu xenografts in opposite, upper flanks. Irrespective of charge and lipophilicity, all radiotracers enabled visualization of PSMA+ PC3 PIP tumor and kidneys (FIG. 6). As anticipated from the
  • Such optimization is geared toward high tumor uptake with minimal off-target, namely, renal and salivary gland, uptake at times convenient for imaging and endoradiotherapy. High salivary gland uptake in particular has proved to be a concern.
  • 68 Ga-l (Banerjee et al.
  • the commercially available p- isothiocyanatobenzyl derivative of NOTA has been used in 68 Ga-2 for its mild radiolabeling conditions in the hope of creating a 68 Ga-based agent with improved pharmacokinetics that could be generated simply, as in a kit-like preparation.
  • the key parameter of non-specific tissue uptake depends on the overall physicochemical properties of the radiolabeled agent, including the metabolic stability of the metal- chelate complex, charge and lipophilicity.
  • Both the chelating agent and the linker employed to attach the radionuclide to the targeting agent are important in establishing those physicochemical features - particularly for compounds ⁇ 1,500 Da.
  • certain 99m Tc-oxo cores with different combinations of NxSy-based chelating agents demonstrated high retention in kidney and spleen for more than 6 h (Ray Banerjee et al. (2013j J Med Chem 56, 6108-21). Such agents displayed high PSMA+ tumor retention.
  • 99m Tc(CO)3- based agents showed much faster clearance from most normal tissues including kidneys, although, these agents showed slightly higher gastrointestinal uptake at initial time-points ( ⁇ 2 h) (Banerjee et al. (2013) J. Med. Chem. (submitted). High kidney uptake and retention for NOTA-chelated 64 Cu-labeled PSMA-inhibitor were observed, compared to the CB-TE2A-conjugated 64 Cu-labeled agent (Banerjee et al. (2014) J Med Chem 57, 2657-69) although both chelating agents are known to form a copper complex with comparable stability (Dumont et al.
  • Afshar-Oromieh et al PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2013, 40, 969-70.

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Abstract

La présente invention concerne des agents PET/SPECT visant PSMA utilisés pour l'imagerie de cancer réagissant positivement à PSMA et ou de la néovasculature de tumeurs, et un agent radiothérapeutique pour le traitement de cancer réagissant positivement à PSMA ou de la néovasculature de tumeurs. Des procédés d'imagerie de tumeurs exprimant PSMA, ou des cellules et des kits sont également décrits.
PCT/US2016/022309 2009-03-19 2016-03-14 Agents thérapeutiques et d'imagerie visant psma à chélation nota et marquage par le68ga Ceased WO2016149188A1 (fr)

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US12263234B2 (en) 2019-01-23 2025-04-01 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-PD-L1 diabodies and the use thereof
CN112190722A (zh) * 2020-10-30 2021-01-08 南方医科大学南方医院 一种靶向前列腺特异性膜抗原的化合物及其应用
CN113372285A (zh) * 2021-05-28 2021-09-10 西南医科大学附属医院 前列腺特异性膜抗原抑制剂、其放射性核素标记物及制法和应用
WO2023097329A1 (fr) * 2021-11-29 2023-06-01 Point Biopharma, Inc. Méthodes de traitement radiopharmaceutique et utilisation

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