WO2020206503A1 - Conjugates and their use as imaging agents - Google Patents
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- WO2020206503A1 WO2020206503A1 PCT/AU2020/050359 AU2020050359W WO2020206503A1 WO 2020206503 A1 WO2020206503 A1 WO 2020206503A1 AU 2020050359 W AU2020050359 W AU 2020050359W WO 2020206503 A1 WO2020206503 A1 WO 2020206503A1
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
-
- 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
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/66—Arsenic compounds
- C07F9/70—Organo-arsenic compounds
- C07F9/74—Aromatic compounds
- C07F9/78—Aromatic compounds containing amino groups
Definitions
- the present invention broadly relates to a radiolabelled conjugate according to Formula (I) defined herein, and a compound according to Formula (II) defined herein.
- the present invention further relates to the use of such radiolabelled conjugates in imaging of cell death, diagnosis and treatment of conditions associated with cell death, and methods of producing such radiolabelled conjugates.
- Cell death plays an integral role in cell turnover.
- An imbalance of cell death characterised by a marked increase or decrease of cell death relative to cell regeneration, is often associated with disease.
- excessive cell death is characteristic of vascular disorders, neurodegenerative diseases, myelodysplastic syndromes, ischaemia/reperfusion injury, organ transplant rejection, and neoplastic conditions including tumours and cancers, among others.
- cancer results from imbalance between rates of cellular proliferation and survival in a tissue.
- Visualisation of cell death therefore has the potential to be a highly useful tool in the diagnosis and treatment of numerous conditions associated with abnormal levels of cell death, as well as assessment and monitoring cell death, for example during drug development and testing of tissue toxicity of a given substance.
- oncology for example, where successful treatment controls cancer cell growth by inhibiting cellular proliferation and/or promoting cell death, the ability to directly image cell death as a means of assessing response to treatment is highly desirable but not available.
- imaging for assessment of treatment response in oncology indirectly assesses cell death by either a reduction in tumour size (by anatomic techniques such as computerised tomography (CT) and magnetic resonance imaging (MRI)) or by a reduction in metabolic activity (most usually glucose metabolic activity) by positron emission tomography (PET).
- CT computerised tomography
- MRI magnetic resonance imaging
- metabolic activity most usually glucose metabolic activity
- PET positron emission tomography
- these techniques are widely and routinely used in oncology, they indirectly assess cell death, and are thus subject to both false positive and false negative findings.
- these techniques do not assess cell death in real time and typically are not performed until at least a number of weeks after commencement of therapy (e.g. positron emission tomography with 2-fluoro-2-deoxyglucose (FDG PET/CT) is usually not performed until after two cycles of chemotherapy - typically 6 to 8 weeks after commencement of treatment).
- FDG PET/CT 2-fluoro-2-deoxyglucose
- changes in tumour size measured by CT such as using Response Evaluation Criteria in Solid Tumours (RECIST 1.1), are often but not always associated with response to therapy.
- tumour cell death in near real-time would potentially be highly beneficial in clinical and research oncology.
- a particularly advantageous imaging agent would allow rapid serial imaging commensurate with the time course of cell death following, for example, administration of a cancer treatment which causes tumour cell death.
- Such an imaging agent would allow changes in cell death to be visualised on a biologically and clinically relevant timescale. It is thus desirable to provide convenient and sensitive imaging agents which allow non-invasive effective and accurate visualisation of cell death, in a manner and time frame suitable for use in the diagnosis and treatment of disease.
- A is -As(OH) 2 or an arsenoxide equivalent group
- each of Ri, R2 , R3 and R t is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH3, -NHCOCH 2 X or NO, and X is a halogen
- R5 is -NHCH 2 COOH, OH or ORr, wherein Re is a C1-5 straight or branched alkyl group
- Z is a radioisotope with a half-life of less than 4 days, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- each of Ri, R 2 , R 3 and R t are H.
- R 5 is -NHCH2COOH.
- the compound is a compound according to Formula (la)
- A is as defined above, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- Z has a half-life of less than 1 day. In some embodiments, Z has a half-life of less than 4 hours. In some embodiments, Z has a half-life of less than 2 hours. In some embodiments, Z is 68 Ga.
- 68 Ga has a half-life of 68 minutes, meaning it is particularly useful for visualisation of cell death by way of PET; the use of such a short-lives positron emitting radioisotope allows frequent serial and quantitative imaging.
- a particularly preferred compound is a compound according to Formula (I) wherein Z is 68 Ga, Ri- R4 are H, R5 is -NHCH2COOH, and A is As(OH)2.
- the present disclosure provides the compounds according to the first aspect for use as imaging agents, for example for use as imaging agents in positron emission tomography.
- the present disclosure provides the compounds according to the first aspect for use in visualising cell death.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to the first aspect together with a pharmaceutically acceptable carrier, excipient, diluent, vehicle and/or adjuvant.
- the present disclosure provides a compound according to Formula (II)
- A is -As(OH)2 or an arsenoxide equivalent group
- each of Ri, R2 , R3 and Rt is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH3, -NHCOCH2X or NO, and X is a halogen
- R5 is -NHCH2COOH, OH or OR5 , wherein FT, is a C1-5 straight or branched alkyl group; or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- Such compounds are useful in the preparation of the compounds according to the first aspect as described above, and may be converted to compounds of Formula (I) by radiolabelling with a radioisotope.
- each of Ri, R 2 , R3 and R4 are H.
- R5 is -NHCH2COOH.
- the compound according to Formula (II) is a compound according to Formula (Ila)
- A is as defined for Formula (II); or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- the present disclosure provides use of a compound according to the first aspect as an imaging agent.
- the imaging agent may be used in positron emission tomography.
- the imaging agent may be used to visualise cell death.
- the present disclosure provides a compound of the first aspect for use in therapy.
- the compound may be for use in the treatment of a condition associated with changes in cell death and/or treatment of which results in a change in cell death.
- the present disclosure provides a compound of the first aspect for use in in vivo diagnostics.
- the compound may be for use in the diagnosis of a condition associated with changes in cell death and/or treatment of which results in a change in cell death.
- the compound for use according to the fifth or sixth aspect may be for use in the treatment or diagnosis of a neoplastic condition or an autoimmune condition.
- the neoplastic condition may be a tumour.
- the neoplastic condition may be cancer.
- the present disclosure provides a method of diagnosing or treating a condition in a subject wherein the condition is associated with changes in cell death and/or treatment of the condition results in a change in cell death, or visualising cell death in a subject comprising administering an effective amount of a compound according to the first aspect.
- the condition is a neoplastic condition or an autoimmune condition.
- the method may further comprise conducting positron-emission tomography on the subject following administration of a compound according to the first aspect. Multiple positron-emission tomography images may be collected following administration of the compound according to the first aspect. In some embodiments, the collection of multiple images may allow more accurate and quantifiable assessments of cell death to be made, since differences in cell death over a given period may be determined rather than absolute values.
- the compound according to the first aspect may be administered intravenously.
- the neoplastic condition may be a tumour.
- the neoplastic condition may be cancer.
- the present disclosure provides a method of assessing response of a subject to a therapy intended to cause a change in level of cell death, comprising: administering the therapy; administering a compound according to the first aspect; and visualising cell death.
- cell death is visualised by conducting positron emission tomography on the subject.
- the therapy is chemotherapy, radiotherapy, targeted therapy or immunotherapy, or combinations thereof.
- the present disclosure provides a process for preparing a compound according to the first aspect wherein Z is 68 Ga, comprising eluting 68 Ga onto a strong cation exchange column; and eluting the strong cation exchange column into a mixture comprising a compound according to Formula (II) and a buffer, wherein the buffer has a pH of about 4.5.
- Fig. 1 shows the structures of NODAGA-GSAO and 68 Ga-NODAGA-GSAO.
- FIG. 2 is a schematic diagram of a 68 Ga-NODAGA-GSAO radiolabelling system as used in Example 2.
- Fig. 3 is a radiometric HPLC chromatogram of the final product produced in Example 2
- Fig. 4 is a radiometric HPLC chromatogram of the final product produced in Example 2 (the same product as Fig. 4) following reaction with 2,3-Dimercapto-l-propanol (DMP).
- Fig. 5 shows the biodistribution of 68 Ga-NODAGA-GSAO (%ID/g) in healthy male rats at 1 and 2 hours post administration of 68 Ga-NODAGA-GSAO.
- Fig. 6 shows the maximum intensity projection of 68 Ga-NODAGA-GSAO PET CT scans performed a) 1 hour and b) 2 hours following tracer ( 68 Ga-NODAGA-GSAO) administration.
- Fig. 7 shows anterior maximum intensity projections of 68 Ga-NODAGA-GSAO PET at 8 time points following injection in patient 1.
- Fig. 8 shows anterior maximum intensity projections of 68 Ga-NODAGA-GSAO PET at 8 time points following injection in patient 2.
- Fig. 9 shows anterior maximum intensity projections of 68 Ga-NODAGA-GSAO PET at 8 time points following injection in patient 3.
- Fig. 10 shows anterior maximum intensity projections of 68 Ga-NODAGA-GSAO PET at 8 time points following injection in patient 4.
- Fig. 11 shows biodistribution of 68 Ga-NODAGA-GSAO in normal organs of patient 1 over time.
- Fig. 12 shows biodistribution of 68 Ga NODAGA GSAO in selected normal tissues and tumour for patient 1.
- Fig. 13 shows biodistribution of 68 Ga NODAGA GSAO in selected normal tissues and tumour for patient 2.
- Fig. 14 shows biodistribution of 68 Ga NODAGA GSAO in selected normal tissues and tumour for patient 3.
- Fig. 15 shows biodistribution of 68 Ga NODAGA GSAO in selected normal tissues and tumour for patient 4.
- Fig. 16 shows the biodistribution in selected normal tissues (mean SUV ⁇ SD) of 68 Ga NODAGA GSAO in subjects 1-4.
- Fig. 17 shows blood pool activity and uptake of 68 Ga NODAGA GSAO into tumour deposits in subjects 1-4.
- Fig. 18 shows anterior maximum projection intensity images of FDG-PET (Fig. 18A) performed 60 min after administration of 256 MBq of FDG (Fluorodeoxyglucose), and CDI- PET (Fig. 18B) performed 60 min after administration of 205 MBq of CDI (68Ga NODAGA GSAO) in patient 3.
- the tumours were surgically excised, fixed and adjacent sections stained for apoptotic cells (Fig. 18C, brown TU EL stain, a and b) or for morphology by
- a and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
- an element means one element or more than one element.
- subject refers to any mammal, including, but not limited to, livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans. Typically the subject is a human.
- livestock and other farm animals such as cattle, goats, sheep, horses, pigs and chickens
- performance animals such as racehorses
- companion animals such as cats and dogs
- laboratory test animals such as cats and dogs
- the terms “treating”,“treatment”, “treating”, “reduce”,“reducing”, “prevent” “preventing” and “prevention” and the like refer to any and all applications which remedy, or otherwise hinder, retard, or reverse the progression of, an infection or disease or at least one symptom of an infection or disease, including reducing the severity of an infection or disease.
- the terms“treat”, “treating”,“treatment”, do not necessarily imply that a subject is treated until complete elimination of the infection or recovery from a disease.
- the terms“prevent”, “preventing”,“prevention” and the like refer to any and all applications that prevent the establishment of an infection or disease or otherwise delay the onset of an infection or disease.
- the terms "effective amount” and “effective dose” include within their meaning a non-toxic but sufficient amount or dose of a compound to provide the desired effect.
- the exact amount or dose required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular compound being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact“effective amount” or “effective dose”. However, for any given case, an appropriate“effective amount” or “effective dose” may be determined by one of ordinary skill in the art using only routine experimentation.
- arsenoxide equivalent includes dithiol reactive entities, such as As, Ge, Sn and Sb species.
- Arsenoxide equivalents are expected to exhibit identical or substantially identical activity to that of the corresponding arsenoxide.
- bifunctional chelator refers to a chemical moiety which comprises a chelating moiety capable of binding a metal or other ion, for example a radionuclide, as well as a chemically reactive functional group for attachment to a further chemical entity.
- the term “bifunctional chelator” refers to both the relevant chemical compound before chelation with a metal or other ion and/or before reaction at the reactive functional group, as well as once chelated to a metal or other ion and/or attached to a further chemical entity by way of the reactive functional group, the relevant definition being readily apparent from context.
- a bifunctional chelator is suitable for chelating a metal or other ion.
- Ci-Cs-alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and three, one and six or one and twelve carbon atoms, respectively.
- Examples of Ci-Cs-alkyl radicals include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.
- pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Reference to a compound herein shall be understood to include its pharmaceutically acceptable salts unless specified otherwise or otherwise understood from context.
- A is -As(OH)2 or an arsenoxide equivalent group
- each of Ri, R2 , R3 and R t is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH3, -NHCOCH2X or NO, and X is a halogen
- R5 is -NHCH2COOH, OH or OR5 , wherein 5 is a C1-5 straight or branched alkyl group
- Z is a radioisotope with a half-life of less than 4 days
- L is a bif mctional chelator chelating Z; or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- the compound according to Formula (X) is a compound according to Formula (Xa), or pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- Z is 68 Ga.
- L is a bifunctional chelator known to chelate a radioisotope having a half-life of less than 4 days, in particular 68 Ga, at room temperature and with a high affinity.
- each of Ri, R 2, R 3 and R t is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH 3 , -NHCOCH 2 X or NO, and X is a halogen;
- R 5 is -NHCH 2 COOH, OH or OR 5, wherein Re is a C 1-5 straight or branched alkyl group; and Z is a radioisotope with a half-life of less than 4 days, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- each of Ri, R 2 , R 3 and R t are H.
- R 5 is - NHCH 2 COOH.
- the compound is a compound according to Formula (la):
- A is an arsenoxide group As(OH)2.
- the arsenoxide group (- AS(OH)2) can typically be replaced by an arsenoxide equivalent.
- Such compounds are based on 4-(A-(.S'-ghitathionylacctyl)amino)phcnylarscnous acid (GSAO) which has been radiolabelled with a radioisotope using a bifunctional chelator.
- the bifunctional chelator is 2,2'-(7-(l-carboxy-4-((2,5- dioxopyrrolidin- 1 -yl)oxy)-4-oxobutyl)- 1 ,4,7-triazonane- 1 ,4-diyl)diacetic acid (NODAGA), as shown in Formula (I) and Formula (la).
- GSAO undergoes specific uptake into dead and dying cells. Without wishing to be bound by theory, it is thought that GSAO is retained in the cytosol of dying and dead cells via the formation of covalent bonds between the As(III) ion and the thiol groups of proximal cysteine residues.
- GSAO is a trivalent As (III) peptide, which has been found to activate the mitochondrial permeability transition pore.
- GSAO is toxic to proliferating cells and inhibits angiogenesis in vivo ( Don AS, Kisker O, Dilda P et al (2003) A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells.
- Radiolabelled compounds according to the present disclosure are thus useful for imaging cell death in vitro and in vivo.
- radiolabelled conjugates as described herein can be used in diagnosing, treating and monitoring conditions associated with changes in cell death, for example neoplastic disorders or autoimmune disorders, for example tumours or for example cancer.
- Radiolabelled compounds of the present invention provide one or more advantages of being able to be readily synthesised for use in vivo using readily available and affordable materials, showing favourable biodistribution and imaging characteristics and radiation dosimetry, and being a non-invasive means of imaging and measuring cell death.
- Embodiments of the present disclosure enable imaging of treatment response earlier and in circumstances where it was previously not possible (such as very early after commencement of therapy), and would enable image guided personalised treatment, which is currently not possible as existing imaging modalities are insufficiently accurate or rapid.
- Z may be, for example, n C, 64 Cu, 13 N, 15 0, ⁇ A1 18 F ⁇ 2+ , 68 Ga, 89 Zr, 82 Rb or 99m Tc.
- Z has a half-life of less than 1 day, for example less than 12 hours, for example less than 8 hours, for example less than 6 hours, for example less than 4 hours, or for example less than 2 hours.
- the compounds of the present disclosure are suitable for use in Positron Emission Tomography (PET).
- PET Positron Emission Tomography
- Z is 68 Ga.
- 68 Ga has a half-life of 68 minutes, meaning it is particularly useful for visualisation of cell death by way of PET; the use of such a short-lives positron emitting radioisotope allows imaging on a practical and clinically relevant timescale (i.e. long waits are not required following administration for images to be obtained).
- a short half-life permits, in some instances, frequent serial and quantitative imaging. That is, repeated imaging may be conducted, allowing accurate changes in cell death over a time to be recorded, for example before and after administration of a chemotherapeutic agent or other treatment which induces cell death, such as radiotherapy, targeted therapy or immunotherapy or combinations thereof.
- Z is ⁇ A1 18 F ⁇ 2+ .
- Such a radioisotope is particularly advantageous as 18 F is widely available, and has a half-life (109.7 minutes) which is both short enough to be particularly useful in Positron Emission Tomography, as described above, but also long enough to facilitate production and distribution of products containing the radioisotope without substantial decay.
- the compound according to Formula I is 68 Ga- NODAGA-GSAO (i.e. the compound of Formula I wherein Z is 68 Ga, Ri- R t are H, FG is - NHCEhCOOH, and A is As(OH)2).
- 68 Ga- NODAGA-GSAO i.e. the compound of Formula I wherein Z is 68 Ga, Ri- R t are H, FG is - NHCEhCOOH, and A is As(OH)2).
- A is -As(OH) 2 or an arsenoxide equivalent group
- each of Ri, R 2, R 3 and R t is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH 3 , -NHCOCH 2 X or NO, and X is a halogen
- R5 is -NHCH 2 COOH, OH or OR5 , wherein R6 is a C1-5 straight or branched alkyl group
- L is a bifunctional chelator; or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof or derivative thereof.
- the compound according to Formula (Y) is a compound according to Formula (Y a)
- A is -As(OH) 2 or an arsenoxide equivalent group
- each of Ri, R 2, R 3 and R t is independently selected from H, X, OH, NH 2 , CO, SCN, -CH 2 NH, -NHCOCH3, -NHCOCH 2 X or NO, and X is a halogen
- R 5 is -NHCH 2 COOH, OH or OR 5, wherein 5 is a C 1-5 straight or branched alkyl group; or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- Compounds of Formula (Y) are useful in the synthesis of Formula (X).
- compounds according to Formula (II) are useful in the synthesis of compounds according to Formula I, by radiolabelling of the NODAGA group.
- Such a synthesis is represented schematically below in Scheme 1, exemplified by NODAGA-GSAO as the starting material and 68 Ga as the radioisotope.
- each of Ri, R 2 , R3 and R4 are H.
- R5 is -NHCH 2 COOH.
- the compound is a compound according to Formula (Ila)
- A is as defined for Formula (II); or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- A is an arsenoxide group As(OH)2.
- the arsenoxide group (- AS(OH)2) can typically be replaced by an arsenoxide equivalent.
- the present disclosure provides a process for preparing a compound according to Formula (I) comprising mixing a radioisotope having a half-life of less than 4 days with a compound according to Formula (II), wherein the compound of Formula (I) or Formula (II) may be any of those described above In preferred embodiments, the mixing takes place at room temperature, i.e. without heating.
- the present disclosure provides a process for preparing a compound according to Formula (I) wherein Z is 68 Ga, comprising eluting 68 Ga onto a strong cation exchange column; and eluting the strong cation exchange column into a mixture comprising a compound according to Formula (II) and a buffer, wherein the buffer has a pH of about 4.5.
- the mixing is carried out at room temperature, i.e. without heating.
- the compounds according to Formula (I) and Formula (II) are compounds according to Formula (la) and Formula (Ila) respectively.
- the present disclosure further provides a process for preparing a compound according to Formula (X), comprising mixing a radioisotope having a half-life of less than 4 days with a compound according to Formula (Y), wherein the compound of Formula (X) or Formula (Y) may be any of those described above.
- the mixing takes place at room temperature, i.e. without heating.
- the present disclosure provides a process for preparing a compound according to Formula (X) wherein Z is 68 Ga, comprising eluting 68 Ga onto a strong cation exchange column; and eluting the strong cation exchange column into a mixture comprising a compound according to Formula (Y) and a buffer, wherein the buffer has a pH of about 4.5.
- the mixing is carried out at room temperature, i.e. without heating.
- compositions and/or therapeutic formulations that is, compounds of the present disclosure present together with a pharmaceutical acceptable carrier, excipient, diluent and/or vehicle.
- salts of the compounds according to the present disclosure may be used and they include pharmaceutically acceptable salts, although other salts may be used in the preparation of the compound or of the pharmaceutically acceptable salt thereof.
- pharmaceutical acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- suitable pharmaceutically acceptable salts of the compounds of the present disclosure may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methane sulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methane sulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid.
- Representative acid addition salts include acetate, adipate, alginate, ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleat, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitat, pamoate
- alkali or alkaline earth metal salts include sodium, lithium potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- prodrugs will be functional derivatives of the compounds of the present disclosure which are readily converted in vivo to the required (active) compounds of the present disclosure, such as imaging, therapeutic and/or diagnostic agents.
- solvates refer to those forms of the compounds according to the present disclosure which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Crystals of the present compounds may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
- the present disclosure also relates to those forms of the process of preparing compounds according to the present disclosure in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
- the compounds or pharmaceutical compositions can be carried out with dose levels and patterns being selected by the treating physician. Regardless, the compounds or pharmaceutical compositions of the present disclosure should provide a quantity of the compound sufficient to effectively treat or diagnose the patient, or visualise cell death in a subject.
- a compound of the present disclosure may be administered in a dose of, for example, up to 300 pg, for example up to 250 pg, for example up to 200 pg, for example up to 150 pg, for example up to 100 pg, for example up to 50 pg. In some embodiments, the compound of the present disclosure is administered in a dose of less than 50pg, for example 10 to 50 pg.
- the compounds of the present disclosure may be administered alone, it is generally preferable that the compound be administered as a pharmaceutical composition/formulation.
- pharmaceutical formulations of the compounds of the present disclosure may be prepared according to methods which are known to those of ordinary skill in the art and accordingly may include a pharmaceutically acceptable carrier, excipient, diluent, vehicle and/or adjuvant.
- the carriers, excipients, diluents, vehicles and adjuvants must be "acceptable” in terms of being compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
- compositions of the present disclosure comprise a compound according to the present disclosure, as well as one or more further components selected from ascorbic acid, sodium, phosphate, acetate and chloride. In some embodiments, the pharmaceutical compositions comprises all such components. In a preferred form the pharmaceutical composition of a compound of the present disclosure comprises an effective amount of a compound according to the present disclosure, together with the pharmaceutically acceptable carriers, diluents and/or adjuvants as shown in Example 3.
- compositions of the present disclosure may be administered by standard routes.
- non-toxic parenterally acceptable diluents or carriers can include, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1, 2-propylene glycol.
- the present disclosure provides compounds and compositions according to the present disclosure for use in detecting, imaging and/or visualising cell death. Such use may be in therapy, or in vivo diagnostics, or the use may be in an otherwise healthy subject.
- the compounds according to the present disclosure may be used to visualise cell death in a subject by way of positron emission tomography (PET).
- PET positron emission tomography
- the compounds of the present disclosure When administered intravenously, the compounds of the present disclosure will target dying cells and may be visualised by virtue of their radiolabelling, thus providing information on the levels of cell death in different parts of a subject.
- the compounds according to the present disclosure may be used to provide a measure of cell death at a single point in time, i.e. by conducting a single PET scan.
- more than one administration and/or scan may be carried out, before and after a stimulus is applied which induces cell death (for example a chemotherapeutic drug, radiotherapy, targeted therapy or immunotherapy, or a combination thereof), to assess the changes in levels of cell death before and after application of the stimulus.
- a stimulus for example a chemotherapeutic drug, radiotherapy, targeted therapy or immunotherapy, or a combination thereof.
- Such visualisation of cell death may find use, for example, in assessing normal tissue toxicity of a substance, environmental condition or activity, for example an experimental therapy. Such compounds thus find use in research and drug development.
- the compounds may be used to assess cell death in drug screening in animal models of cancer and other conditions.
- the compounds may also be used to assess cell death in human tissues, for example during clinical trials, which is beneficial for patient safety, as well as potentially allowing more rapid dose escalation regimes by providing accurate feedback on the level of cell death given a particular dose. This would allow an individualised risk-adapted approach during trials, which is helpful in all patients, especially patients with altered renal or hepatic function or at the extremes of age.
- the compounds of the present disclosure find particular use in later phase oncology clinical trials, and are potentially useful for understanding overall and temporal treatment response, e.g. drug dosing and duration. For instance, in the event of a relatively modest overall response rate, use of the compounds may allow identification of a responding subpopulation to enable optimisation of future studies. Such use of the compounds may also help in demonstrating to regulatory authorities subpopulations with significant response to increase the likelihood of potential regulatory and reimbursement approval.
- the compounds according to the present disclosure for use in therapy, and for use in in vivo diagnostics for example by PET imaging.
- Use in treatment and in vivo diagnosis may be for any condition associated with changes in levels of cell death, or conditions the treatment of which results in a change in levels of cell death.
- a change in cell death is a change (increase or decrease) relative to the level of cell death expected in the area in question in a healthy subject.
- compounds of the present disclosure may be used in the diagnosis of a neoplastic condition, for example a tumour, for example a solid tumour and/or, for example, cancer.
- a tumour may contain high levels of cell death and thus be visualised by use of the compounds of the present disclosure.
- Compounds of the present disclosure may further be used in the treatment of such conditions, by allowing visualisation of cell death and changes in the levels thereof in response to administration of a therapy, to determine whether or not treatment is successful.
- successful treatment of neoplastic conditions, such as a tumour, or such as cancer following administration of a therapy intended to treat such condition can be determined by visualisation of increased levels of cell death at the site of the neoplastic condition by use of compounds of the present disclosure.
- the compounds of the present disclosure may be used in the diagnosis or treatment of an autoimmune condition, wherein autoimmunity is causing cell death.
- autoimmune conditions include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus (SEE), multiple sclerosis, type 1 diabetes, Crohn's disease, vasculitis and seronegative arthropathies.
- SEE systemic lupus erythematosus
- the compounds according to the present disclosure may be used to diagnose and/or monitor the condition, and assess success of any treatments applied.
- compounds of the present disclosure may be used to tailor or alter the treatment applied, for example the intensity, type or duration of treatment.
- the measure of cell death may indicate that a particular therapy is or is not proving effective; where it is ineffective, an alternative dose, or an alternative treatment may be adopted. Where it is effective, treatment may be continued if required, or reduced/discontinued if required.
- compounds of the present disclosure may be used to visualise cell death in response to an applied treatment, and the treatment dose adjusted accordingly dependent on the level of cell death.
- identification of patients in whom there is little or no tumour cell death following therapy would indicate the need for either an increase in the dose or duration of current treatment (escalation) or a change to more intensive or multimodal therapies in order to maximise the chance of cure or disease control.
- accurately assessing response early on in the course of treatment would allow a reduction in either the duration or intensity of treatment in cancer patients who are responding well in order to avoid treatment related morbidity and mortality (de-escalation) without compromising the chance of cure or disease control.
- An assessment of cell death may cause the adoption of a new therapy, where the measure of cell death following an initial therapeutic approach suggests that the initial approach is not successful.
- the present disclosure further provides methods of treating or diagnosing the above- mentioned conditions, or of visualising cell death, or of monitoring such conditions by administration of a compound described herein.
- the present disclosure further provides use of the compounds described herein in such methods, and use in the manufacture of medicaments for the treatment of such conditions.
- Use of the compounds described herein as imaging agents, for example in PET, and to visualise cell death is also provided herein.
- Use of the compounds of the present disclosure and methods of treatment or diagnosis provided herein, for example of the conditions described above, include administration of an effective amount of a compound described herein to a subject.
- the method may further comprise conducting PET on the subject following administration of the compound described herein, for example immediately after administration of the compound described herein.
- any suitable imaging method other than PET may be used to image the compound described herein.
- PET scans are carried out after a time interval of at least 10 minutes, for example at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, or at least 1 hour following administration of the compound according to the present disclosure.
- multiple PET scans may be carried out at various times following administration.
- the compound of the present disclosure may be administered, and a PET scan may be carried out immediately following administration, as well as at about 30 minutes, about 1 hour, about 2 hours and about 3 hours following administration.
- the method of diagnosis or treatment comprises administration of a species which induces cell death, for example a chemotherapeutic agent, radiotherapy, targeted therapy or immunotherapy, or a combination thereof, in the treatment of a tumour, wherein the compound of the present disclosure may be administered to visualise the effectiveness of the species in inducing cell death.
- a chemotherapeutic agent, radiotherapy, targeted therapy or immunotherapy or combination thereof may be administered to a subject together with, prior to or subsequent to administering a compound of the present disclosure.
- PET scans may be carried out following administration of the compound to visualise the cell death-inducing activity of the chemotherapy, radiotherapy, targeted therapy or immunotherapy, or combination thereof.
- an administered species for example a drug
- Some administered species may take some time before its effects are shown; visualisation of cell death, such as by a PET scan, may therefore take place a longer time after administration of the species, for example 1 day, 3 days, 5 days, 1 week, 2 weeks or a month following administration; in such cases, a compound according to the present disclosure may be administered prior to the scan, in addition to or instead of prior to administration of the drug or other species.
- the present disclosure provides a method of assessing a response of a subject to a therapy intended to cause a change in level of cell death, comprising: administering the therapy; administering a compound according to the present disclosure; and visualising cell death.
- the cell death is visualised by conducting positron emission tomography on the subject.
- the therapy intended to cause a change in level of cell death is chemotherapy, radiotherapy, targeted therapy or immunotherapy, or a combination thereof.
- a compound according to the present disclosure is administered and/or cell death is also visualised prior to administration of the therapy, to allow comparison between the level of cell death before and after administration of the therapy.
- an increase in the level of cell death between the two visualisations may indicate successful therapy.
- low levels of cell death or a decrease in cell death may indicate unsuccessful or sub-optimal therapy.
- a therapy is intended to decrease the level of cell death in a particular part of a subject; in such embodiments, a low level of cell death or decreased level of cell death in the area of interest indicates successful therapy, and a high level of cell death or increased cell death indicates unsuccessful or sub-optimal therapy.
- administration of the compound of the present disclosure and visualisation of cell death may take place, for example, about 1 day, about 2 days, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks and/or about 6 weeks following administration of the therapy.
- administration of the compound of the present disclosure and visualisation of cell death takes place within 7 days of administration of the therapy.
- administration of the compound of the present disclosure and visualisation of cell death takes place at least 4 weeks following administration of the therapy.
- administration of the compound of the present disclosure and visualisation of cell death takes place more than once following administration of the therapy.
- administration of the compound of the present disclosure and visualisation of cell death takes place both within 7 days of and at least 4 weeks following administration of the therapy.
- visualisation of cell death may take place, for example, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour or at least 90 minutes following administration of the compound according to the present disclosure.
- the compound of the present disclosure may be administered, and visualisation may be carried out, for example, immediately following administration, or about 30 minutes, about 1 hour, about 90 minutes, about 2 hours or about 3 hours following administration of the compound according to the present disclosure.
- the present disclosure relates to the above methods, compounds according to the present disclosure for use in such methods, use of compounds of the present disclosure in such methods, and use of compounds according to the present disclosure in the manufacture of a medicament for use in such methods.
- This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.
- GSAO was prepared using the process described in Park D, Don AS Massamiri T et al (2011) Non-invasive imaging of cell death using an Hsp90 ligand. J Am Chem Soc 133:2932-3835; 4-(/V-(bromoacetyl)amino)phenylarsonic acid (BRAA) was synthesized from p-arsanilic and bromoacetyl bromide, and BRAA reduced to 4-(N-(bromoacetyl)amino) phenylarsonous acid (BRAO). BRAO was coupled to glutathione (GSH) to produce GSAO.
- GSH glutathione
- GSAO was resolved from unreacted BRAO and GSH by C18 chromatography.
- step d) The residue resulting from step d) was redissolved in deaerated water (4 mL), filtered (0.45 pm), and purified by reverse phase high-performance liquid chromatography (RP-HPLC). A gradient of 2-20 % mobile phase B (0.2% trifluoroacetic acid (TFA) in acetonitrile) in mobile phase A (0.2% TFA in ultrapure water) was applied from 0 to 25 minutes. NODAGA-GSAO was eluted at 20.6 minutes. The sample was collected by hand and each fraction was instantly purged with nitrogen.
- RP-HPLC reverse phase high-performance liquid chromatography
- HPLC was carried out on a Shimadzu LC-20 series LC system with two LC-20AP pumps, a SIL-10AP autosampler, an SPD-20A UV/VIS detector, and a Shimadzu ShimPack GIS-C18 column (150 x 10.0 mm i.d., 5pm, 4mL/min ') (System A). Shimadzu LabSolutions Software (Ver. 5.73) was used for data acquisition and processing.
- NODAGA-GSAO was dispensed in aliquots of 54 pg per 100 pL water and stored at -20°C.
- NODAGA-GSAO eluted at 19.4 minutes.
- LC-MS was conducted using an Agilent system (Santa Clara, CA, USA) consisting of a 1260 series quartemary pump with an inbuilt degasser, 1200 series autosampler, thermostated column compartment, diode array detector, fraction collector, a 6120 series single -quadrupole mass spectrometer, and an Agilent Zorbax Eclipse XDB-C18 column (150 x 4.6 mm i.d., 5 pm) at 30 °C (System B). The drying gas flow, temperature, and nebulizer were set to 12 L/min, 350°C, and 35 psi respectively.
- Ascorbic acid solution (0.25 M) was obtained by dissolving 44 mg of ascorbic acid in 1 mL water (Water Ultrapur, Merck).
- a sodium acetate buffer (1.5 M CLLCOONa-SLhO, pH4.5) was obtained by dissolving 10.21 g CLbCOONa-SLhO in water (Water Ultrapur, Merck). The pH was adjusted to pH 4.5 with glacial acetic acid and water was added to a total volume of 50 mL
- a sterile, closed radiolabelling system is used for the above procedure, as is preferred for preparation for human use and also for minimization of the risk of radioactive contamination to the operator and environment (Fig. 2). This may also be automated using a radiochemistry synthesis module.
- Radiochemical purity of 68 Ga-NODAGA-GSAO was assessed by HPLC system C at 9-9-60% mobile phase B (acetonitrile) in mobile phase A (0.1% TFA in ultrapure water) over 0-6-10 minutes using radiometric detection.
- the AUC of 68 Ga-NOD AGA-GSAO peak over the sum of all radiometric peaks greater than three times background was used to determine radiochemical purity.
- Absorbance was also measured at 210 and 280 nm; however, the molar quantities were below the limits of reliable absorbance detection and were therefore not used for assessment of purity.
- 68 Ga-NODAGA-GSAO was eluted with a retention time of approximately 3 minutes and 55 seconds., as shown in the radiometric HPLC chromatogram of the final product in Fig. 3: region 1 is corresponds to 68 Ga, region 2 corresponds to oxidation products, and region 3 corresponds to 68 Ga-NOD AGA-GSAO.
- the release criterion used for radiochemical purity of 68 Ga-NOD AGA-GSAO in the final product was >91% ⁇ European Pharmacopeia (2016) 01/2013:2482 Gallium (68Ga) Edotreotide injection correct 8.6. European Pharmacopeia, 9 th edn, pp 1150-1152).
- the DMP- 68 Ga-NODAGA-GSAO peak (with a retention time of approximately 9 minutes and 30 seconds) over the sum of all radiometric peaks greater than three times background should be >91%; as DMP binds with very high affinity to the phenylarsonous moiety of 68 Ga- NODAGA-GSAO this will abolish the usual 68 Ga-NODAGA-GSAO peak with a retention time of approximately 3 minutes and 55 seconds and result in a new peak with a retention time of approximately 9 minutes and 30 seconds.
- This provides specific information about the radiochemical purity of the active GSAO and is able to distinguish between 68 Ga- NODAGA-GSAO and other products, such as oxidized degradation products of GSAO.
- Radiometric HPLC chromatogram obtained is shown in Fig. 4: region 1 corresponds to unchelated 68 Ga, region 2 corresponds to oxidation products, and region 3 corresponds to DMP- 68 Ga-NODAGA-GSAO.
- composition was prepared containing ingredients in the amounts listed in Table 1 below.
- Biodistribution was expressed as %ID/g and %ID/organ.
- %retained activity was the sum total of all activity in all individually harvested organs as well as the activity in the remaining carcass as a percentage of the injected dose.
- % recovered activity was the sum total of all activity in all individually harvested organs as well as the activity in the remaining carcass and excreted activity in the impervious matting as a percentage of the injected dose.
- the rats weighed an average of 170g (range 120 - 229g, standard deviation 32.2g).
- the average injected activity was 27.3MBq (range 18.9 - 38.6MBq, standard deviation 7.4MBq).
- the mean uptake time was 62.6 (range 60 - 65) minutes and for the 2 hour biodistribution group the mean uptake time was 122.2 (range 120 - 126) minutes.
- Fig. 5 shows the organ biodistribution of 68 Ga-NODAGA-GSAO (%ID/g) in healthy male rats at 1 and 2 hours post administration of 68 Ga-NODAGA-GSAO.
- the highest concentration of 68 Ga-NODAGA-GSAO is in the kidneys, and the organs with the greatest uptake of 68 Ga-NODAGA-GSAO are the kidneys, liver and small bowel.
- the high renal and hepatic uptake is consistent with renal excretion and hepatic metabolism while the small bowel uptake is likely to reflect uptake within dead and dying small bowel epithelial cells.
- FIG. 6 shows the maximum intensity projections of 68 Ga-NODAGA- GSAO PET CT scans performed a) 1 hour and b) 2 hours following tracer ( 68 Ga-NODAGA- GSAO) administration.
- the images performed one hour after tracer administration demonstrate a high concentration of tracer in the kidneys (arrows i) in Fig. 6 a) and b)), with lower levels of uptake in the liver (arrows ii)).
- Fig. 6 shows the maximum intensity projections of 68 Ga-NODAGA- GSAO PET CT scans performed a) 1 hour and b) 2 hours following tracer ( 68 Ga-NODAGA- GSAO) administration.
- the images performed one hour after tracer administration demonstrate a high concentration of tracer in the kidneys (arrows i) in Fig. 6 a) and b)), with lower levels of uptake in the liver (arrows
- the biodistribution data derived above was used to estimate human radiation dosimetry using the methods described by Stabin for a standard adult male ( Stabin and Siegel 2003).
- the %ID/g for a given standard male organ was extrapolated from the rat biodistribution data using the following equation:
- 68 Ga-NODAGA-GSAO has advantageous imaging characteristics, with relatively little interference from physiologic renal and hepatic activity.
- the rapid clearance suggests that imaging between 1 and 2 hours post injection is feasible and thus well suited to using 68 Ga (clinically for 68 Ga- based somatostatin receptor expression imaging, imaging is performed at 45-90 minutes following injection).
- 68 Ga-NODAGA-GSAO PET/CT images Fig. 6
- Fig. 6 is the visualisation of uptake within small and large bowel and also in the physes of the long bones, which may represent uptake in areas of high rates of physiologic cell death.
- the estimated human radiation dosimetry is favourable, with an estimated total body effective dose of 0.021mSv/MBq which, assuming a standard injected dose of 150MBq, would deliver a total dose whole body effective dose of 3.2mSv.
- the dose limiting organ is the urinary bladder wall with a dose of 0.32mSv/MBq.
- the biodistribution data demonstrates prompt intravascular distribution of 68 Ga-NODAGA-GSAO with rapid initial clearance, followed by a second slower phase of clearance from the blood pool. There is rapid renal uptake and excretion.
- %ID % injected dose excreted in urine by 2 hours averaged 30% (range 19 - 38%) and by 3 hours averaged 48% (range 21 - 71%).
- Fig. 7 shows anterior maximum intensity projections of 68 Ga- NODAGA-GSAO PET at 8 time points; anterior maximum projection of the FDG PET is shown underneath for comparison. The location of the tumour is arrowed at each time point. Low levels of tracer uptake are seen in the remaining organs which gradually declines over time (apart from the testis and large bowel). No hepatobiliary excretion is evident. There is almost absent activity within the brain, suggesting that it does not cross the blood brain barrier to any extent. Imaging finding from patients 2-4 are similarly shown in Fig. 8 (patient 2) Fig. 9 (patient 3), Fig. 10 (patient 4).
- Fig. 11 shows biodistribution of 68 Ga-NODAGA-GSAO in normal organs over time in patient 1.
- Most of the organs demonstrate an early peak followed by a gradual decline, similar to the second phase of blood clearance, except for the large bowel and testes which demonstrate an initial increase in concentration up to approximately 40 minutes following administration and then a slow decline. This may be due to higher physiologic rates of cell death in these two organs. Note that the urinary bladder wall was evaluated separately.
- Figures 12-15 show biodistribution of 68 Ga NODAGA GSAO in selected normal tissues and tumour for patients 1-4 respectively. Note that Tumour 2 is only applicable in patients 3 and 4, so is blank in Figures 12 and 13.
- Figure 16 shows the biodistribution in selected normal tissues (mean SUV ⁇ SD) of subjects 1-4.
- the whole-body effective dose was estimated by drawing representative spherical volumes of interest within the organs, estimating the %ID/g for each organ and then calculating the %ID/organ using the organ weights from a standard adult phantom.
- the effective whole-body dose from 68 Ga NODAGA GSAO for subjects 1-4 ranged from 2.16 x 10 2 to 3.38 x 10 2 mSv/MBq, giving an estimated effective whole-body dose ranging from 13.5 - 15.9 mSv for the protocol used in the first in human study.
- Detailed organ dosimetry for 68 Ga NODAGA GSAO is shown for the four subjects (tables 5 - 8). In all cases, the urinary bladder was the dose limiting organ.
- CTs computed tomography
- PET/CT scans x-ray computed tomography
- the estimated whole-body dose from the one (1) low dose CT and two (2) ultra-low dose CTs was 9.2mSv.
- Table 3 shows the estimate for radiation dosimetry for subject 1.
- the overall estimated radiation dose to subject 1 was 14.5mSv.
- Table 4 shows the estimate for radiation dosimetry for subject 2.
- the overall estimated radiation dose to subject 1 was 13.9 mSv.
- Table 5 shows the estimate for radiation dosimetry for subject 3.
- the overall estimated radiation dose to subject 1 was 13.5 mSv.
- Table 6 shows the estimate for radiation dosimetry for subject 4.
- the overall estimated radiation dose to subject 1 was 15.9 mSv.
- Fig. 17 shows blood pool activity and uptake of 68 Ga NODAGA GSAO into tumour deposits in subjects 1-4 (note: in patients 3 and 4, there are two tumour deposits, and these have been analysed separately). Whilst blood pool and clearance are reproducible, tumour uptake and clearance vary by tumour type.
- tumour uptake was variable depending on tumour histology, with high levels of uptake seen in squamous cell carcinoma of the oesophagus (SUVmean 3.8) and metastatic cutaneous squamous cell carcinoma (SUVmean 4.1) and lower uptake seen in metastatic ovarian carcinoma (SUVmean 1.9) and breast carcinoma (SUVmean 1.8). Note that in subjects 3 and 4 there were two tumour deposits and these have been analysed separately. It is not unexpected that different tumour histology will have differing rates of de novo cell death.
- tumour cell death was performed on two tumour deposits in patient 3 (one with high uptake of 68 Ga NODAGA GSAO SUVmean 4.1 in the right axilla and the other with low uptake of 68 Ga NODAGA GSAO SUVmean 2.7 in the right upper anterior cervical triangle) (Figure 18).
- Dissected tumours were fixed in formalin, embedded in paraffin and 4 pm thick sections were cut. Adjacent sections were stained for apoptotic cells using TUNEL (Abeam, Cat#206386) or morphology using haematoxylin and eosin. For TUNEL staining, sections were deparaffinized in xylene, rehydrated in decreasing concentrations of ethanol and permeabilized with Proteinase K for 20 min at room temperature. The endogenous peroxidase activity was quenched with 3% H2O2 for 5 min.
- Apoptotic cells were labelled with biotinylated terminal deoxynucleotidyl transferase at 37 °C in a humidified chamber for 2 h followed by a 30 min incubation with streptavidin-HRP conjugate.
- HRP-positive cells were developed using diaminobenzidine and sections counterstained with methyl green (Sigma). Whole sections were imaged using PowerMosaic scanning at lOx magnification on a Leica DM6000D microscope.
- FIG. 18 shows anterior maximum projection intensity images of FDG-PET (Fig. 18A) performed 60 min after administration of 256 MBq of FDG (Fluorodeoxyglucose), and CDI-PET (Fig. 18B) performed 60 min after administration of 205 MBq of CDI ( 68 Ga NODAGA GSAO) in a 66 year old male with metastatic cutaneous squamous cell carcinoma ( patient 3).
- the FDG-PET demonstrates two intensely metabolically active nodal metastases, one in the right axilla and the other in the right upper anterior cervical triangle. These are thought to represent synchronous nodal metastases from two different cutaneous squamous cell carcinomas (previously resected).
- the tumours were surgically excised, fixed and adjacent sections stained for apoptotic cells (Fig. 18C, brown TUNEL stain, a and b) or for morphology by haematoxylin and eosin (Fig. 18C, c and d). Arrows in the TUNEL staining point to areas of extensive apoptosis.
- tumours with high uptake have uptake up to 2 fold greater than blood pool, and the uptake is greater than uptake in all other organs except for the renal tract which is the route of excretion.
- This high level of uptake within some tumours combined with the low level of activity within normal tissues and organs demonstrates the potential for use of 68 Ga NODAGA GSAO as an effective imaging agent.
- the effective whole- body dose from 68Ga NODAGA GSAO ranged from 2.16 x 10-2 to 3.38 x 10-2 mSv/MBq, giving an estimated effective whole-body dose ranging from 4.3 - 6.8mSv for ad administered activity of 200 MBq.
- This is comparable to many other diagnostic radiopharmaceuticals used for PET/CT and SPECT/CT as well as for effective whole-body dose from other radiologic procedures such as x-ray computed tomography (CT).
- CT x-ray computed tomography
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022077068A1 (en) * | 2020-10-14 | 2022-04-21 | Centenary Institute Of Cancer Medicine And Cell Biology | Therapeutic radiolabelled conjugates and their use in therapy |
WO2023060317A1 (en) * | 2021-10-14 | 2023-04-20 | Centenary Institute Of Cancer Medicine And Cell Biology | Processes for preparing radiolabelled conjugates |
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JP2022529335A (en) | 2022-06-21 |
CA3136647A1 (en) | 2020-10-15 |
AU2020256682A1 (en) | 2021-11-04 |
WO2020206503A9 (en) | 2021-05-06 |
US20240009330A1 (en) | 2024-01-11 |
US20220152229A1 (en) | 2022-05-19 |
EP3953338A4 (en) | 2023-06-07 |
CN114206844A (en) | 2022-03-18 |
EP3953338A1 (en) | 2022-02-16 |
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