# US 11,109,819 B2 · System and method for quantitatively mapping mitochondrial membrane potential > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,109,819 B2 - Document ID: US11109819B2 - Status: Granted - Kind: B2 - Application number: 16/092,650 - Filed: 2017-04-10 - Published: 2019-05-02 - Granted: 2021-09-07 - Earliest claimed: 2016-04-11 - Assignees: The General Hospital Corporation - Applicants: The General Hospital Corporation - Inventors: Nathaniel M. Alpert; Georges El Fakhri; Nicola Guehl; Marc Normandin - Web page: https://patentgrep.com/patent/US11109819B2 ## CPC - A61B 6/037: {Emission tomography} - A61B 5/0035: {adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography} - A61B 6/4417: {related to combined acquisition of different diagnostic modalities} - A61B 6/486: {involving generating temporal series of image data} - A61B 6/503: {for diagnosis of the heart} - A61B 6/504: {for diagnosis of blood vessels, e.g. by angiography} - A61B 6/5217: {extracting a diagnostic or physiological parameter from medical diagnostic data} - A61B 6/5235: {combining images from the same or different ionising radiation imaging techniques, e.g. PET and CT} - A61B 6/5247: {combining images from an ionising-radiation diagnostic technique and a non-ionising radiation diagnostic technique, e.g. X-ray and ultrasound} - A61K 51/04: Organic compounds - A61K 51/0474: {complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group} - G01N 33/5079: {Mitochondria} - G16H 50/30: for calculating health indices; for individual health risk assessment - A61B 6/12: Arrangements for detecting or locating foreign bodies - G01R 33/481: {MR combined with positron emission tomography [PET] or single photon emission computed tomography [SPECT]} - A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA - G01R: MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES (indicating correct tuning of resonant circuits H03J3/12) ## Abstract A system, and method, for quantitatively mapping of mitochondrial membrane potential of a tissue in a subject is provided. In some aspects, the provided method includes administering to the subject a detectably effective amount of a tracer as an emission tomography imaging agent; acquiring, using an emission tomography system, emission tomography data associated with the tissue; analyzing the emission tomography data to determine a concentration distribution of the tracer within the tissue; correlating the concentration distribution of the tracer with the membrane potential of the tissue; determining, using the correlating step, a membrane potential distribution of the tissue; and generating a report indicating the membrane potential distribution of the tissue. ## Claims ### Claim 1 A method for quantitatively mapping mitochondrial membrane potential of an in vivo tissue in a subject, the method comprising: a) administering to the subject a detectably effective amount of 18F-tetraphenylphosphonium (18F-TPP+) as an emission tomography imaging agent; b) acquiring, using an emission tomography system, emission tomography data associated with the tissue; c) analyzing the emission tomography data to determine a concentration distribution of 18F-TPP+ within the tissue; d) correlating the concentration distribution of 18F-TPP+ with the mitochondrial membrane potential of the tissue, comprising the steps of: i) modeling a total volume of distribution of a plurality of spaces across the mitochondrial membrane and a cell membrane in an image voxel in relation with volume fractions of the plurality of spaces, and electrical potentials across the mitochondrial membrane and the cell membrane; and ii) acquiring, using a medical imaging system, anatomical imaging data and using the anatomical imaging data to determine volume fractions of the plurality of spaces associated with the tissue; e) determining, based on the correlation at step d), a membrane potential distribution of the tissue; and f) generating a report indicating the membrane potential distribution of the tissue. ### Claim 2 (depends on 1) The method of claim 1, wherein the plurality of spaces includes an extracellular space and an intracellular space separated by a mitochondrial membrane wherein the extracellular space includes a plasma membrane and the intracellular space includes a mitochondrial space and a cytosolic space. ### Claim 3 A method for quantitatively mapping membrane potential of a tissue in a subject, the method comprising: a) administering to the subject a detectably effective amount of a radioactive tracer; b) acquiring, using an emission tomography system, emission tomography data associated with the tissue; c) analyzing the emission tomography data to determine a concentration distribution of the radioactive tracer within the tissue; d) correlating, using a model, the concentration distribution of the radioactive tracer with the membrane potential of the tissue; e) determining, based on the correlation at step d), a membrane potential distribution of the tissue; and f) generating a report indicating the membrane potential distribution of the tissue. ### Claim 4 (depends on 3) The method of claim 3, wherein step (b) begins at least one of: before the administration of the tracer and continues for a first duration of time; after the administration of the tracer; or about 100 minutes after the administration of the tracer. ### Claim 5 (depends on 3) The method of claim 3, wherein the tracer is 18F-tetraphenylphosphonium (18F-TPP+). ### Claim 6 (depends on 3) The method of claim 3, wherein the tissue is associated with at least one of a heart, skeletal muscle, liver, kidney, or tumor. ### Claim 7 (depends on 3) The method of claim 3, wherein the membrane potential is a mitochondrial membrane potential. ### Claim 8 (depends on 3) The method of claim 3, wherein the method further comprises generating the model by: reconstructing the emission tomography data into at least one emission tomography image; defining each image voxel in the at least one emission tomography image to include an extracellular space component and an intracellular space component separated by a mitochondrial membrane component; defining the extracellular space component to include a cell membrane component; defining the intracellular space component to include a mitochondrial space component and a cytosolic space component; and relating the electrical potential across the mitochondrial membrane with a total volume of distribution in each image voxel and the electrical potential across the extracellular space volume. ### Claim 9 (depends on 8) The method of claim 8, further comprising acquiring, using a medical imaging system, anatomical imaging data and using the anatomical imaging data to determine a volume distribution of different spaces associated with the tissue. ### Claim 10 (depends on 8) The method of claim 8, wherein the model includes: Vd=(1−ƒECV)(ƒmito·e −β(αΨm+αΨc)+(1−ƒmito)·e−βαΨc)+ƒECV, wherein Vd represents the total volume of distribution of the tracer in the imaging voxel; ƒECV represents a volume fraction of the extracellular space; ƒmito represents a volume fraction of the mitochondrial space; αΨm and αΨc represent the electrical potential across the mitochondrial and cell membranes, respectively. ### Claim 11 (depends on 8) The method of claim 8, wherein the method further comprises: measuring the volume fraction of the extracellular space ƒECV. ### Claim 12 (depends on 8) The method of claim 8, wherein the method further comprises the steps of: estimating the volume fraction of the mitochondrial space; and estimating the electrical potential across the cell membrane. ### Claim 13 A method for identifying a disease condition of a subject, the method comprising: i) administering to the subject a detectably effective amount of a tracer; ii) acquiring, using an emission tomography imaging system, emission tomography data and analyzing the emission tomography data to determine a concentration distribution of the tracer of a tissue of the subject; iii) correlating the concentration distribution of the tracer with a membrane potential of the subject's tissue; iv) processing the emission tomography data to generate a quantitative map of the membrane potential distribution of the subject's tissue; and v) generating a report indicative of the disease condition of the subject. ### Claim 14 (depends on 13) The method of claim 13, wherein step (ii) begins at least one of: before the administration of the tracer and continues for a first duration of time; after the administration of the tracer; or about 100 minutes after the administration of the tracer. ### Claim 15 (depends on 13) The method of claim 13, wherein the tracer is a lipophilic cation. ### Claim 16 (depends on 15) The method of claim 15, wherein lipophilic cation is 18F-tetraphenylphosphonium (18F-TPP+) at concentrations across membranes of the tissue in thermodynamic equilibrium. ### Claim 17 (depends on 13) The method of claim 13, further comprising correlating the concentration distribution of the tracer with a membrane potential of the subject's tissue by using an equation of Vd=(1−ƒECV)(ƒmito·e −β(αΨm+αΨc)+(1−ƒmito)·e−βαΨc)+ƒECV, wherein Vd represents the total volume of distribution of the tracer in the imaging voxel; ƒECV represents a volume fraction of the extracellular space; ƒmito represents a volume fraction of the mitochondrial space; αΨm and αΨc represent the electrical potential in mV across the mitochondrial and cell membranes, respectively. ### Claim 18 (depends on 17) The method of claim 17, further comprising measuring the volume fraction of the extracellular space using imaging data acquired using at least one of a magnetic resonance imaging (MRI) system or a computed X-ray tomography (CT) system. ### Claim 19 (depends on 13) The method of claim 13, wherein the tissue is at least one of heart, skeletal muscle, liver, kidney, or tumor. ### Claim 20 A system for quantitatively mapping membrane potential of a tissue in a subject, the system comprising: an emission imaging system configured to acquire emission data from the subject following an administration of a tracer; and a processor configured to: 1) access the emission data associated with the tissue; 2) analyze the emission data to determine a concentration distribution of the tracer of the tissue of the subject; 3) correlate the concentration distribution of the tracer with a membrane potential of the subject's tissue; and 4) generate, using the correlation, a quantitative map of the membrane potential distribution of the subject's tissue.