WO2022240817A1 - Procédés de visualisation de transporteurs de dopamine - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 110
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 title claims abstract description 29
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 title claims abstract description 29
- 238000002603 single-photon emission computed tomography Methods 0.000 claims abstract description 418
- GTQLIPQFXVKRKJ-HYRAKNMCSA-N methyl (1s,3s,4s,5r)-3-(4-fluorophenyl)-8-[(e)-3-iodanylprop-2-enyl]-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C\C=C\[123I])[C@H]2C(=O)OC)=CC=C(F)C=C1 GTQLIPQFXVKRKJ-HYRAKNMCSA-N 0.000 claims abstract description 155
- 238000001990 intravenous administration Methods 0.000 claims abstract description 30
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
Definitions
- the invention relates to nuclear medicine; in particular, dosing of radiopharmaceutical imaging agents for diagnosing dopaminergic disorders.
- Dosing patients with radiopharmaceutical imaging agents or tracers for tomographic brain imaging can be challenging. If an administered tracer dose is too high for a given patient, for example, a patient may receive more radioactivity than necessary. Conversely, if the dose is too low, the resulting imaging quality and analysis may be compromised.
- the invention provides methods method of dopamine transporter (DaT) visualization in the brain of a subject, methods of identifying a subject as having a Parkinsonian syndrome or dementia with Lewy bodies (e.g., distinguishing a dementia with Lewy bodies from other dementias, such as Alzheimer’s disease), methods of assessing the amount of [ 123 I]altropane that is bound to DaT in the subject’s striatum (e.g., in the subject’s head), uses of [ 123 I]altropane in the manufacture of a composition for use in methods described herein, uses of [ 123 I]altropane in methods described herein, and radiopharmaceutical compositions for use in methods described herein.
- DaT dopamine transporter
- the method comprises: intravenously administering the subject with a dose comprising about 1.5 to about 3 mCi of [ 123 I]altropane; determining a first number of single photon emission computed tomography (SPECT) counts per minute from the head within about 10 to about 20 minutes following the administration; and if the first number of SPECT counts per minute is about 5 thousand counts per minute (“cpm”) or more from the subject’s striatum or about 20 thousand cpm or more from the subject’s head, collecting counts for a period of about 30 minutes to obtain a final SPECT image; and if the first number of SPECT cpm is less than about 5 thousand cpm from the subject’s striatum, intravenously administering the subject with a second dose comprising about 2 to about 3 mCi of [ 123 I]altropane, and collecting counts for a period of about 30 minutes to obtain a final SPECT image or determining a second number of SPECT cpm from the head between about
- the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 10 thousand cpm or more from the subject’s striatum. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 15 thousand cpm or more from the subject’s striatum. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 20 thousand cpm or more from the subject’s striatum.
- the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 20 thousand cpm or more from the subject’s head. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 25 thousand cpm or more from the subject’s head. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 30 thousand cpm or more from the subject’s head.
- the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 35 thousand cpm or more from the subject’s head. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 40 thousand cpm or more from the subject’s head. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 60 thousand cpm or more from the subject’s head.
- the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 60 thousand cpm or more from the subject’s head. In some embodiments, the step of collecting counts for a period of about 30 minutes to obtain a final SPECT image follows the determining step providing the number of SPECT cpm of about 80 thousand cpm or more from the subject’s head.
- the collection of counts for the final SPECT image is completed within from about 30 minutes to about 45 minutes from the first administration of [ 123 I]altropane.
- the method comprises: intravenously administering the subject with a first dose comprising about 1.5 to about 3 mCi of [ 123 I]altropane; obtaining a first number of SPECT counts from the head within about 5 to about 20 minutes (e.g., about 10 to about 20 minutes) following the administration; and if the first number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; and if the first number of SPECT counts is insufficient to generate a final SPECT image, intravenously administering the subject with a second dose comprising about 2 to about 3.5 mCi of [ 123 I]altropane, and obtaining the final SPECT image or obtaining a second number of SPECT counts from the head; if the second number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; or if the second number of SPECT counts is insufficient to generate a final SPECT image, intravenously
- the method comprises: intravenously administering the subject with a first dose comprising about 1.5 to about 3 mCi of [ 123 I]altropane; obtaining a first number of SPECT counts from the head within about 5 to about 20 minutes (e.g., about 10 to about 20 minutes) following the administration; if the first number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; and if the first number of SPECT counts is insufficient to generate a final SPECT image, intravenously administering the subject with a second dose comprising about 2 to about 3.5 mCi of [ 123 I]altropane, and obtaining the final SPECT image or obtaining a second number of SPECT counts from the head; if the second number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; or if the second number of SPECT counts is insufficient to generate a final SPECT image, intravenously administer
- the method comprises: intravenously administering the subject with a first dose comprising about 1.5 to about 3 mCi of [ 123 I]altropane; obtaining a first number of SPECT counts from the head within about 5 to about 20 minutes (e.g., about 10 to about 20 minutes) following the administration; if the first number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; and if the first number of SPECT counts is insufficient to generate a final SPECT image, intravenously administering the subject with a second dose comprising about 2 to about 3.5 mCi of [ 123 I]altropane, and obtaining the final SPECT image or obtaining a second number of SPECT counts from the head; if the second number of SPECT counts is sufficient to generate a final SPECT image, obtaining the final SPECT image; or if the second number of SPECT counts is insufficient to generate a final SPECT image, intravenously administer
- the abnormal SPECT image shows asymmetric DaT binding.
- the asymmetric DaT binding is indicated by the absence or reduction of the count intensity in the region of the putamen of one hemisphere relative to the other.
- the abnormal SPECT image shows that DaT binding is absent in the putamen of both hemispheres and confined to the caudate nuclei. In some embodiments, the abnormal SPECT image shows that DaT binding is absent in the putamen of both hemispheres and greatly reduced in one or both caudate nuclei. In some embodiments, the SPECT image is normal. In some embodiments, in trans axial images, normal images are characterized by two symmetric comma- or crescent-shaped focal regions of activity mirrored about the median plane.
- only one dose of [ 123 I]altropane is administered.
- the second dose is required and comprises about 2 to about 3.5 mCi of [ 123 I]altropane.
- the second dose is about 1.5 mCi of [ 123 I]altropane.
- the third dose comprises about 1 to about 3 mCi of [ 123 I]altropane. In some embodiments, the third dose is about 1.5 mCi of [ 123 I]altropane.
- the final SPECT image is based on counts collected over about 60 minutes or less from the start of the final SPECT image acquisition. In some embodiments, the final SPECT image is based on counts collected over about 45 minutes or less from the start of the final SPECT image acquisition. In some embodiments, the final SPECT image is based on counts collected over about 30 minutes or less from the start of the final SPECT image acquisition.
- the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 4 minutes to about 20 minutes after intravenously administering the first dose of [ 123 I]altropane. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 4 minutes to about 15 minutes after intravenously administering the first dose of [ 123 I]altropane. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 5 minutes to about 20 minutes after intravenously administering the first dose of [ 123 I]altropane. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 10 minutes to about 20 minutes after intravenously administering the first dose of [ 123 I]altropane.
- the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 15 minutes. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 10 minutes. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 0.5 to about 10 minutes. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 1 to about 5 minutes. In some embodiments, the first number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 1 to about 2 minutes.
- the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 4 minutes to about 20 minutes after intravenously administering the second dose of [ 123 I]altropane. In some embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 4 minutes to about 15 minutes after intravenously administering the second dose of [ 123 I]altropane. In some embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 5 minutes to about 20 minutes after intravenously administering the second dose of [ 123 I]altropane. In some embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head starting at about 10 minutes to about 20 minutes after intravenously administering the second dose of [ 123 I]altropane.
- the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 15 minutes. In some embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 10 minutes. In some preferred embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 0.5 to about 10 minutes. In some more preferred embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 1 to about 5 minutes. In some yet more preferred embodiments, the second number of SPECT counts is determined by acquiring SPECT counts from the subject’s head over a period of about 1 to about 2 minutes.
- the method comprises: intravenously administering a first dose comprising about 1 to about 3 mCi of [ 123 I]altropane to the subject, and, if the first dose is insufficient to generate a final SPECT image, identifying a dose [ 123 I]altropane sufficient to generate the final SPECT image by uptitration in one or two administrations in increments of about 1 to about 3.5 mCi of [ 123 I]altropane over a period of about 60 minutes or less from the first dose administration until sufficient counts have been registered by a SPECT camera to indicate that the final SPECT image is obtainable, and obtaining the final SPECT image; or if the first dose is sufficient to generate a final SPECT image, obtaining the final SPECT image.
- the first dose is about 1.5 mCi of [ 123 I]altropane.
- the uptitration is in one or two administrations in increments of about 1 to about 2 mCi of [ 123 I]altropane.
- final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 5 thousand cpm or more from the subject’s striatum. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 10 thousand cpm or more from the subject’s striatum.
- the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 15 thousand cpm or more from the subject’s striatum. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 20 thousand cpm or more from the subject’s striatum.
- the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 20 thousand or more cpm from the subject’s head. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 25 thousand or more cpm from the subject’s head.
- the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 30 thousand or more cpm from the subject’s head. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 35 thousand or more cpm from the subject’s head. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 40 thousand or more cpm from the subject’s head. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 60 thousand or more cpm from the subject’s head. In some embodiments, the final SPECT image is obtained following the obtaining step providing the number of SPECT cpm of about 80 thousand or more cpm from the subject’s head.
- the time period between any two consecutive intravenous administrations of [ 123 I]altropane is about 5 to about 30 minutes (e.g., about 15 to about 30 minutes).
- the total dose of [ 123 I]altropane administered during a SPECT session is 8 mCi or less. In some embodiments, the total dose of [ 123 I]altropane administered during a SPECT session is 5 mCi or less.
- the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.5 million or more counts. In some embodiments, the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.5 million to about 1.3 million or more counts. In some embodiments, the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.5 million to about 1.5 million or more counts. In some embodiments, the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.5 million to about 2 million or more counts.
- the number of counts sufficient to generate the final SPECT image indicates that the last administered dose of [ 123 I]altropane is sufficient to generate the final SPECT image of the subject’s striatum.
- the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.2 million or more counts from the subject’s striatum.
- the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.3 million or more counts from the subject’s striatum.
- the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.4 million or more counts from the subject’s striatum.
- the final SPECT image is obtained following the determining/obtaining step providing the number of SPECT counts of about 0.2 million to about 0.5 million or more counts from the subject’s striatum.
- each intravenous administration comprises a flush.
- the SPECT session starting at the first dose administration to the completion of the final SPECT image acquisition is 90 minutes or less.
- the subject is suspected of having a Parkinsonian syndrome.
- the final SPECT image distinguishes essential tremor from a Parkinsonian syndrome.
- the Parkinsonian syndrome is idiopathic Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy.
- the subject is suspected of having Lewy Body dementia.
- the subject is suspected of having Alzheimer’s disease.
- the final SPECT image distinguishes Lewy Body dementia from Alzheimer’s disease.
- each SPECT image is acquired using a gamma camera fitted with high-resolution collimators and set to a photopeak of 159 keV with a ⁇ 10% energy window.
- angular sampling is 120 views over 360 degrees.
- each intravenous administration lasts 15-60 sec.
- the use is a use of [ 123 I]altropane in the manufacture of a composition for use in any method described herein.
- the use is a use of [ 123 I]altropane in any method described herein.
- the radiopharmaceutical composition comprising [ 123 I]altropane is for use of in any method described herein.
- the invention provides methods of dopamine transporter (DaT) visualization in the brain of a subject (e.g., a subject suspected of suffering from Parkinson’s disease or dementia with Lewy bodies, who typically have lost DaT, or Alzheimer’s disease patients, who typically have not lost DaT).
- the methods typically include the step of intravenous administration to the subject of a first dose of [ 123 I]altropane (e.g., 1 to 5 mCi of [ 123 I]altropane) and the step of acquiring SPECT counts from the subject’s head (e.g., obtaining a first number of SPECT counts from the subject’s head).
- a final SPECT image is a SPECT image of the subject’s head.
- the final SPECT image typically includes the subject’s striatum.
- a final SPECT image may require, e.g., about 0.2 million or more (e.g., about 0.3 million or more or about 0.4 million or more) counts from a striatum.
- a final SPECT image may require, e.g., about 0.2 to about 0.5 million or more (e.g., about 0.2 to about 0.35 million or more, about 0.25 to about 0.4 million or more, or about 0.3 to about 0.4 million or more) counts from a striatum.
- a final SPECT image may require, e.g., about 0.5 million counts or more, e.g., about 0.5 to about 2.0 million or more (e.g., about 0.5 to about 1.3 million or more, about 1 to about 1.3 million or more, or about 1 to about 1.5 million or more) counts from the brain or head of the subject.
- the number of counts may be that which is needed for a final SPECT image to be obtained within about 90 minutes from the last intravenous administration of [ 123 I]altropane (e.g., within about 45 minutes from the last intravenous administration of [ 123 I]altropane).
- the number of counts may be that which is needed for a final SPECT image to be obtained within about 60 minutes from the start of the final SPECT image acquisition using a SPECT camera (e.g., within about 45 minutes from the start of the final SPECT image acquisition using a SPECT camera, or within about 30 minutes from the start of the final SPECT image acquisition using a SPECT camera).
- acquisition of about 5 X 10 3 or more e.g., about l x 10 4 or more, about 1.5 X 10 4 or more, or about 2 X 10 4 or more
- cpm from a striatum on average indicates that the administered dose of [ 123 I]altropane is sufficient to provide the requisite counts for a final SPECT image to be obtained.
- acquisition of about 2 X 10 4 or more indicates that the administered dose of [ 123 I]altropane is sufficient to provide the requisite counts for a final SPECT image to be obtained.
- [ 123 I]altropane is a compound of the following structure:
- [ 123 I]Altropane may be provided, e.g., as a sterile, pyrogen-free radiopharmaceutical for intravenous administration ⁇
- [ 123 I]altropane may be supplied as a clear and colorless solution, e.g., in vials.
- Each milliliter of the [ 123 I]altropane solution may contain, e.g., 9-16 ng of [ 123 I]altropane.
- the [ 123 I]altropane solution may include, e.g., 0.1-2.5 mCi/mL (preferably, 0.5-2.0 mCi/mL) of iodine-123 (e.g., 35.5-42.92 MBq (0.96-1.16 mCi) of iodine-123) as [ 123 I]altropane at calibration time.
- the [ 123 I]altropane solution may also include sodium chloride to control osmolarity of the [ 123 I]altropane solution.
- the [ 123 I]altropane solution may contain saline solution (e.g., isotonic solution) for injection (e.g., 0.98 ml, of sodium chloride solution (0.9% w/v) for injection per 1 mL of the [ 123 I]altropane solution).
- the [ 123 I]altropane solution may be isotonic (e.g., having osmolarity of about 0.3 Osm).
- the [ 123 I]altropane solution may be buffered, e.g., the pH of the [ 123 I]altropane solution may be 2.5-7.0 (e.g., 2.5- 3.5).
- the buffer used in the [ 123 I]altropane solution may be, e.g., an acetate buffer (e.g., 0.01M-0.1M, e.g., 0.056M).
- the components used to prepare the acetate buffer in the [ 123 I]altropane solution may be, e.g., 0.6-6 mg/mL (e.g., 3.34 mg/mL) acetic acid and 0.008-0.1 mg/mL (e.g., 0.051 mg/mL) sodium hydroxide.
- the [ 123 I]altropane solution may contain ethanol (e.g., 0.001-0.1 mL ethanol / 1 mL of the [ 123 I]altropane solution; e.g., 0.009-0.018 mL ethanol / 1 mL of the [ 123 I]altropane solution).
- the [ 123 I]altropane solution may contain sterile water for injection (e.g., 0.0002-0.1 mL sterile water for injection / 1 mL of the [ 123 I]altropane solution; e.g., 0.002-0.011 mL sterile water for injection / 1 mL of the [ 123 I]altropane solution).
- Iodine 123 is a cyclotron-produced radionuclide that decays to 123 Te by electron capture and has a physical half-life of 13 2 hours.
- the photon that is useful for detection and imaging studies may be, as shown sin Table 1.
- [ 123 I]Altropane may be useful for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected Parkinsonian syndromes (PS). In these patients, [ 123 I]altropane may be used to help differentiate essential tremor from tremor due to PS (idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy).
- PS Parkinsonian syndromes
- [ 123 I]Altropane may also be useful for early diagnosis of presynaptic Parkinsonian syndromes; differentiation of presynaptic Parkinsonian syndromes from parkinsonism without presynaptic dopaminergic loss, such as drug-induced parkinsonism or psychogenic parkinsonism; and differentiation of dementia with Lewy bodies from other dementias, e.g., Alzheimer’s disease.
- [ 123 I]Altropane may be useful as an adjunct to other diagnostic evaluations.
- [ 123 I]Altropane may be administered, e.g., as a slow intravenous administration (administered over a period of not less than, e.g., 15 to 20 seconds; e.g., administered over a period of 15 to 60 seconds) via an arm vein (e.g., for left ventricular output).
- Single-use vials containing the [ 123 I]altropane solution e.g., 0.1-2.5 mCi/mL solution; preferably, 0.5-2.0 mCi/mL solution; the solution providing, e.g., 1, 1.5, 2, 2.5, or 3 mCi dose).
- 5 mCi in 2.5 mL of the sterile solution of [ 123 I]altropane for intravenous administration (2 mCi/mL at calibration time) may be provided.
- [ 123 I]altropane (e.g., 1 mCi, 1.5 mCi, 2 mCi, 2.5 mCi, 3 mCi, 3.5 mCi, 4 mCi, or 4.5 mCi; preferably, 1.5-3 mCi or 2-3 mCi) is administered intravenously to the subject as a first dose.
- the first dose may be the only dose, e.g., if the first dose is found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s brain. Sufficiency of the first dose may be determined from a first number of SPECT counts.
- the first number of SPECT counts may be determined by acquiring SPECT counts from the subject’s head starting at about 4 to about 20 minutes (e.g., at about 4 to about 15 minutes, at about 4 to about 10 minutes, at about 10 to about 20 minutes, at about 10 to about 15 minutes, at about 15 to about 20 minutes, or at about 10 to about 15 minutes; e.g., at about 10 minutes, at about 15 minutes, at about 20 minutes) after administration of the first dose of [ 123 I]altropane.
- the first number of SPECT counts may be determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 15 minutes (e.g., about 5 minutes to about 10 minutes or about 10 minutes to about 15 minutes; e.g., about 5 minutes, about 10 minutes, or about 15 minutes). If the first dose is found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s brain, then no additional doses of [ 123 I]altropane are administered. If the first dose is found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s head, the final SPECT image is obtained.
- the final SPECT image may be acquired (e.g., starting immediately, or starting at about 1 to about 10 minutes, e.g., at about 5 minutes to about 10 minutes) after the completion of the first number of SPECT counts acquisition.
- the final SPECT image may be acquired (e.g., starting within about 10 minutes, e.g., at about 1 to about 10 minutes or at about 5 minutes to about 10 minutes) after the determination that the administered dose is sufficient to generate a final SPECT image.
- a second dose of [ 123 I]altropane (e.g., 1 mCi, 2 mCi, 3 mCi, or 4 mCi; preferably, 2- 3.5 mCi) may be administered.
- the sum of the first and second doses is preferably, e.g., 5 mCi or less of [ 123 I]altropane.
- the second dose may be found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s brain. Sufficiency of the second dose may be determined from a second number of SPECT counts.
- the second number of SPECT counts may be determined by acquiring SPECT counts from the subject’s head starting at about 4 to about 20 minutes (e.g., at about 4 to about 15 minutes, at about 4 to about 10 minutes, at about 10 to about 20 minutes, at about 10 to about 15 minutes, at about 15 to about 20 minutes, or at about 10 to about 15 minutes; e.g., at about 10 minutes, at about 15 minutes, at about 20 minutes) after administration of the second dose of [ 123 I]altropane.
- the second number of SPECT counts may be determined by acquiring SPECT counts from the subject’s head over a period of about 5 to about 15 minutes (e.g., about 5 minutes to about 10 minutes or about 10 minutes to about 15 minutes; e.g., about 5 minutes, about 10 minutes, or about 15 minutes). If the second dose is found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s brain, then no additional doses of [ 123 I]altropane are administered. If the second dose is found to provide a number of SPECT counts sufficient to obtain a final SPECT image of the subject’s head, the final SPECT image is obtained.
- the final SPECT image may be acquired (e.g., starting immediately, or starting at about 1 to about 10 minutes, e.g., at about 5 minutes to about 10 minutes) after the completion of the second number of SPECT counts acquisition.
- the final SPECT image may be acquired (e.g., starting within about 10 minutes, e.g., at about 1 to about 10 minutes or at about 5 minutes to about 10 minutes) after the determination that the administered dose is sufficient to generate a final SPECT image.
- the final SPECT image may be acquired without determining the second number of SPECT counts; instead, the final SPECT image may be acquired starting at about 4 to about 20 minutes (e.g., at about 4 to about 15 minutes, at about 4 to about 10 minutes, at about 10 to about 20 minutes, at about 10 to about 15 minutes, at about 15 to about 20 minutes, or at about 10 to about 15 minutes; e.g., at about 10 minutes, at about 15 minutes, at about 20 minutes) after administration of the second dose of [ 123 I]altropane.
- the final SPECT image may be acquired without determining the second number of SPECT counts; instead, the final SPECT image may be acquired starting at about 4 to about 20 minutes (e.g., at about 4 to about 15 minutes, at about 4 to about 10 minutes, at about 10 to about 20 minutes, at about 10 to about 15 minutes, at about 15 to about 20 minutes, or at about 10 to about 15 minutes; e.g., at about 10 minutes, at about 15 minutes, at about 20 minutes) after administration of
- each intravenous administration involves a flush (e.g., to wash out any [ 123 I]altropane remaining in the catheter/needle) and as such an administration has not been completed until the flush has been performed.
- a flush e.g., to wash out any [ 123 I]altropane remaining in the catheter/needle
- the timing of such intravenous administration includes the injection/infusion of the [ 123 I]altropane solution and the following flush.
- the timing after an intravenous administration including a flush is calculated from the completion of the flush.
- the timing of such intravenous administration includes the injection/infusion of the [ 123 I]altropane solution.
- the timing after an intravenous administration not including a flush is calculated from the completion of the injection/infusion of the [ 123 I]altropane solution.
- [ 123 I]altropane is administered while the patient is positioned in the SPECT camera, or is exposed to any other suitable photon counting device.
- Emitted photons in the case of SPECT, are typically counted at about 4 to about 20 minutes (e.g., at about 4 to about 15 minutes, at about 4 to about 10 minutes, at about 10 to about 20 minutes, at about 10 to about 15 minutes, at about 15 to about 20 minutes, or at about 10 to about 15 minutes; e.g., at about 10 minutes, at about 15 minutes, at about 20 minutes) after administration.
- the counting may start after [ 123 I]altropane is substantially bound to the DaT in dopaminergic neurons in the brain, from which they would then emit photons which are collected by the camera. If the number of counts after the first administration can provide a final SPECT image, the final SPECT image is then acquired. If the number of counts after the first administration is insufficient to provide a final SPECT image, a second dose of [ 123 I]altropane may be administered. In the unlikely event that counts after the second administration are still below the level needed to provide a final SPECT image, additional doses may be administered in appropriate time increments until the desired number of counts is achieved.
- the number, pattern, and/or density of counts of the image acquired from the patient can also be measured and compared with the number, pattern, and/or density of counts of the image obtained from an age- matched control subject which is not afflicted with a dopaminergic disorder.
- the patient may be deemed to be afflicted with a dopaminergic disorder if the counts, density, and/or pattern of counts acquired is less than that acquired from the control subject.
- Methods described herein thus may provide each patient with an individualized imaging procedure taking into account the pharmacokinetic parameters of the patient.
- the uptitration method described herein is different from the methods used under dosing schemes, which are not individualized, and during which a full radioactivity dose (e.g., 5 mCi) is administered in one intravenous bolus.
- a full radioactivity dose e.g., 5 mCi
- SPECT imaging may commence, e.g., immediately following [ 123 I]altropane administration (or within about 30, within about 20, within about 15, within about 10, or within about 5 minutes of the completion of the [ 123 I]altropane administration). Images are acquired using a gamma camera fitted with high-resolution collimators and set to a photopeak of 159 keV with a ⁇ 10% energy window. Angular sampling is preferably not less than 120 views over 360 degrees. Position the subject supine with the head on an off-the-table headrest, a flexible head restraint such as a strip of tape across the chin or forehead may be used to help avoid movement, and set a circular orbit for the detector heads with the radius as small as possible (typically 11 to 15 cm). Optimal images are typically obtained with matrix size and zoom factors selected to give a pixel size of 3.5 to 4.5 mm. Collect a minimum of 1.5 million counts for optimal images.
- a final SPECT image may require, e.g., about 0.2 million or more (e.g., about 0.3 million or more or about 0.4 million or more) counts from a striatum.
- a final SPECT image may require, e.g., about 0.2-0.5 million or more (e.g., about 0.2-0.35 million or more, about 0.25-0.4 million or more, or about 0.3-0.4 million or more) counts from a striatum.
- a final SPECT image may require, e.g., about 0.5 million or more counts, e.g., about 0.5 to about 2.0 million or more (e.g., about 0.5 to about 1.3 million or more, about 1 to about 1.3 million or more, or about 1 to about 1.5 million or more) counts from the brain or head of the subject.
- the number of counts may be that which is needed for a final SPECT image to be obtained within about 90 minutes from the intravenous administration of [ 123 I]altropane (e.g., within about 45 minutes from the last intravenous administration of [ 123 I]altropane).
- the number of counts may be that which is needed for a final SPECT image to be obtained within about 60 minutes from the start of the final SPECT image acquisition using a SPECT camera (e.g., within about 45 minutes from the start of the final SPECT image acquisition using a SPECT camera, or within about 30 minutes from the start of the final SPECT image acquisition using a SPECT camera).
- acquisition of about 5 X 10 3 or more (e.g., about l x 10 4 or more or about 2 X 10 4 or more) cpm from a striatum on average indicates that the administered dose of [ 123 I]altropane is sufficient to provide the requisite counts for a final SPECT image to be obtained.
- acquisition of about 2 X 10 4 or more indicates that the administered dose of [ 123 I]altropane is sufficient to provide the requisite counts for a final SPECT image to be obtained.
- [ 123 I]Altropane images may be interpreted visually, based upon the appearance of the striata.
- Reconstructed pixel size for example, should be between 3.5 and 4.5 mm with slices 1 pixel thick.
- Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel to the anterior commissure-posterior commissure (AC-PC) line. Determination of whether an image is normal or abnormal is typically made, for example, by assessing the extent (as indicated by shape) and intensity of the striatal signal. Image interpretation usually does not involve integration of the striatal image appearance with clinical signs and/or symptoms.
- a clinical study is conducted that assesses the diagnostic information on dopamine binding in the striatum which is read from SPECT images using [ 123 I]altropane, which is representative of a tracer with fast distribution and high receptor affinity for dopaminergic neurons in the brain.
- the study is conducted in patients with early and late Parkinson’s Disease (PD) and in healthy volunteers (HV).
- Subjects appropriate for each of three cohorts are selected as follows. Late PD subjects have a Modified Hoehn and Yahr score of between 3 and 5 during an “ON state”. An even spread of late-stage PD patients within this range is evaluated. Early PD subjects have a Modified Hoehn and Yahr score of between 1 and 2.5 during an “ON state”. An even spread of early parkinsonism patients within this range is evaluated.
- the inclusion/exclusion and cohort criteria are designed to ensure that study subjects are stratified, as reliably as clinically possible, into early- or late PD patients or are healthy. Subjects > 40 years of age as available are included in the study, as the occurrence of PD in patients less than 40 years of age is unusual. The inability to lie supine for 1 hour excludes subjects who are unsuited for SPECT scanning procedures.
- [ 123 I]altropane is made according to known methods, with no carrier added.
- the chemical mass of drug substance in a 3 mCi to 5 mCi (111 to 185 MBq) dose is not more than 16 ng.
- the radioactive isotope of the drug substance, [ 123 I] emits a 159 keV gamma ray which is readily detected by suitable SPECT cameras.
- the radioisotope has a half-life of 13.2 hours.
- the molecular formula is C18H21FINO2.
- the anhydrous molar mass is 425 g/mol.
- the final product is formulated as a sterile solution for intravenous injection. It is provided in a formulation suitable for human IV administration containing excipients previously approved by the FDA for other intravenously delivered products.
- the drug substance is provided in a clear, colorless, sterile solution containing a predetermined amount of radioactivity (ranging from 1 mCi to 5 mCi) at the timepoint of patient injection.
- Trial participants are administered [ 123 I]altropane in solution under the direct supervision of a nuclear medicine physician or designee.
- a nuclear medicine physician or designee For administration of [ 123 I]altropane in solution, access into a large vein (e.g., antecubital vein) is established using a suitable intravenous (IV) catheter that does not contain silicone.
- IV intravenous
- each study participant While being placed in the SPECT camera, with the camera in “on” mode, i.e., collecting emitted photons from the subject’s ROI (head), each study participant receives an initial single IV injection of [ 123 I]altropane in a solution with a total radioactive dose amounting to about 3 mCi.
- [ 123 I]altropane in solution is administered manually via slow IV injection, followed by, for example, a 2-10 mL saline flush.
- the exact radioactive dose administered is determined by calculating the difference between the radioactivity in the syringe and delivery system immediately before and after injection. After the dose is delivered, the syringe is filled with a volume of saline equal to the administered dose volume and the syringe is recounted under the same conditions as used to determine the dose; separately, the delivery system is placed in a suitably sized plastic container and counted in the dose calibrator using the same parameters as used for the dose. Measured radioactivity values and times of measurement are documented in the source documents and recorded in the electronic case report form (eCRF), as well as the total injected volume.
- eCRF electronic case report form
- 0.5 million or more counts e.g., about 0.5 to about 2.0 million or more (e.g., about 0.5 to about 1.3 million or more, about lto about 1.3 million or more, or about 1 to about 1.5 million or more) counts produce an image of sufficient quality, e.g., to distinguish subjects having Parkinson’s Disease from, for example, those subjects with an essential tremor disorder.
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Abstract
Sont divulgués des procédés de visualisation du transporteur de dopamine (DaT) dans le cerveau d'un sujet (par exemple, un sujet suspecté d'être atteint de la maladie de Parkinson, de la démence à corps de Lewy, ou de la maladie d'Alzheimer). Les procédés comprennent typiquement l'étape d'administration intraveineuse au sujet d'une première dose de [123I]altropane et l'étape d'acquisition de comptages de tomographie d'émission monophotonique (TEMP) à partir du cerveau du sujet (par exemple, l'obtention d'un premier nombre de comptages TEMP du cerveau du sujet). Si le premier nombre de comptages TEMP est inférieur au nombre indiquant qu'une image TEMP finale peut être obtenue au sein d'une session TEMP, alors le sujet est soumis à une augmentation de dose à l'aide d'une ou de plusieurs administrations intraveineuses de [123I]altropane par incréments de, par exemple 0,5-3 mCi de [123I]altropane, jusqu'à ce que le nombre de comptages TEMP acquis indique qu'une image TEMP finale peut être obtenue.
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