# US 8,771,646 B2 · Nicotinic acid and picolinic acid derived near-infrared fluorophores > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,771,646 B2 - Document ID: US8771646B2 - Status: Granted - Kind: B2 - Application number: 13/828,648 - Filed: 2013-03-14 - Published: 2013-10-17 - Granted: 2014-07-08 - Earliest claimed: 2005-09-02 - Assignees: VisEn Medical, Inc. - Applicants: VisEn Medical, Inc. - Inventors: Milind Rajopadhye; Narasimhachari Narayanan; Jeffrey D. Peterson - Web page: https://patentgrep.com/patent/US8771646B2 ## CPC - A61K 49/0032: {Methine dyes, e.g. cyanine dyes} - A61K 49/0021: {the fluorescent group being a small organic molecule} - C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 401/14: containing three or more hetero rings - C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms - C09B 23/0008: {substituted on the polymethine chain} - C09B 23/083: {five >CH- groups} - 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) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C09B: ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES {, e.g. PIGMENTS}; MORDANTS; LAKES (fermentation or enzyme using processes to synthesise a desired chemical compound C12P) ## Abstract This invention relates to new fluorescent chemical entities, including fluorescent molecules that comprise a carboxyl or carbonyl functionalized pyridine moiety. This invention also relates to the corresponding reactive versions of such molecules. This invention also relates to the corresponding conjugates with moieties such as peptides, proteins, various biomolecules, carbocyclic and heterocyclic compounds, sugars, and their uses thereof. ## Claims ### Claim 1 A method of in vivo optical imaging, the method comprising: (a) administering to a subject a biocompatible fluorescent molecule comprising one or more biomolecules covalently linked to a fluorescent compound represented by formula (2): or a salt thereof, wherein: X is independently selected from the group consisting of C(CH2Y1)(CH2Y2), O, S, and Se; Y1 and Y2 are independently selected from the group consisting of H, C1-C20 aliphatic group and a C1-C20 aliphatic group wherein one or more methylene groups are replaced by O, S, or NH; W represents a benzo-condensed ring or a naphtho-condensed ring; R1 is selected from the group consisting of H, (CH2)xCH3, (CH2)nSO3− and (CH2)nSO3H, wherein x is an integer selected from 0 to 6 and n is an integer selected from 2 to 6; R4 is selected from the group consisting of H, (CH2)xCH3, (CH2)nSO3− and (CH2)nSO3H, wherein x is an integer selected from 0 to 6 and n is an integer selected from 2 to 6; R2 and R3 are independently selected from the group consisting of H, carboxylate, carboxylic acid, carboxylic ester, amine, amide, sulfonamide, hydroxyl, alkoxyl, a sulphonic acid moiety and a sulphonate moiety; Q is a heteroaryl ring substituted with —CO2H, —C(O)-halide, —C(O)O-benzotriazolyl, —C(O)O—N-succinimidyl, —C(O)O-tetrafluorophenyl, —C(O)O-pentafluorophenyl, —C(O)O-imidazolyl, or —C(O)O-p-nitrophenyl; or Q is selected from the group consisting of Q is a 6-membered heteroaryl ring substituted with —C(═O)R**, wherein R** is a saturated straight-chain hydrocarbon, a branched hydrocarbon, or a cyclic hydrocarbon; or Q is a carboxyl or carbonyl substituted 6-membered heteroaryl ring selected from the group consisting of pyridine, pyrimidone, pyrazine and pyridazine; and wherein the biomolecule is chemically linked to the fluorescent compound via reaction with Q thereby producing the biocompatible fluorescent molecule; (b) allowing time for the biocompatible fluorescent molecule to distribute within the subject or to contact or interact with a biological target within the subject; (c) illuminating the subject with light of a wavelength absorbable by the biocompatible fluorescent molecule; and (d) detecting the optical signal emitted by the biocompatible fluorescent molecule. ### Claim 2 (depends on 1) The method of claim 1, wherein the signal emitted by the biocompatible fluorescent molecule is used to construct an image. ### Claim 3 (depends on 2) The method of claim 2, wherein steps (a)-(d) are repeated at predetermined intervals thereby allowing for evaluation of the emitted signals of the biocompatible fluorescent molecule in the subject over time. ### Claim 4 (depends on 3) The method of claim 3, wherein the subject is an animal or human. ### Claim 5 (depends on 4) The method of claim 4, wherein in step (a) two or more biocompatible fluorescent molecules whose signal properties are distinguishable are administered to a subject. ### Claim 6 (depends on 5) The method of claim 5, wherein the illuminating and detecting steps are performed using an endoscope, catheter, tomographic system, hand-held optical imaging system, surgical goggles, or intra-operative microscope. ### Claim 7 (depends on 6) The method of claim 6, wherein the presence, absence, or level of signal emitted by the biocompatible fluorescent molecule is indicative of a disease state. ### Claim 8 (depends on 7) The method of claim 7, wherein the method is used to detect and monitor disease. ### Claim 9 (depends on 8) The method of claim 8, wherein the disease is selected from the group consisting of cancer, cardiovascular diseases, neurodegenerative diseases, immunologic diseases, autoimmune diseases, respiratory diseases, metabolic diseases, inherited diseases, infectious diseases, bone diseases, and environmental diseases. ### Claim 10 (depends on 1, 9) The method of claim 9, wherein prior to step (a) the fluorescent compound of claim 1 is mixed with cells to label the cells and the resulting labeled cells are administered to the subject in step (a). ### Claim 11 (depends on 10) The method of claim 10, wherein the signal emitted by the biocompatible fluorescent molecule is used for monitoring trafficking and localization of cells or evaluation a cell therapy. ### Claim 12 (depends on 1) The method of claim 1, wherein the fluorescent compound has an absorption maxima and an emission maxima between about 500 nm and about 900 nm. ### Claim 13 (depends on 12) The method of claim 12, wherein the fluorescent compound has an absorption maxima and an emission maxima between about 600 nm and 800 nm. ### Claim 14 (depends on 1) The method of claim 1, wherein the biocompatible fluorescent molecule becomes activated upon interaction with the biological target. ### Claim 15 (depends on 1) The method of claim 1, wherein the biocompatible fluorescent molecule has a high binding affinity to the biological target. ### Claim 16 (depends on 1) The method of claim 1, wherein the biomolecule is a cell. ### Claim 17 (depends on 1) The method of claim 1, wherein R1 is selected from the group consisting of (CH2)xCH3, (CH2)nSO3− and (CH2)nSO3H, wherein x is an integer selected from 0 to 6 and n is an integer selected from 2 to 6. ### Claim 18 (depends on 1) The method of claim 1, wherein Q is selected from the group consisting of carboxyl substituted pyridine, pyrimidone, pyrazine, and pyridazine. ### Claim 19 (depends on 1) The method of claim 1, wherein Q is carboxyl substituted pyridine. ### Claim 20 (depends on 1) The method of claim 1, wherein Q is selected from the group consisting of isonicotinic acid, nicotinic acid and picolinic acid. ### Claim 21 (depends on 1) The method of claim 1, wherein Q is represented by a structural formula selected from the group consisting of: ### Claim 22 (depends on 1) The method of claim 1, wherein at least one of the moieties R1 to R3 is, or contains a sulphonic acid moiety or a sulphonate moiety. ### Claim 23 (depends on 1) The method of claim 1, wherein R1 and R4 are independently —H, (CH2)nSO3− or (CH2)nSO3H. ### Claim 24 (depends on 1) The method of claim 1, wherein the fluorescent compound of formula (2) is: ### Claim 25 (depends on 1) The method of claim 1, wherein the fluorescent compound of formula (2) is: ### Claim 26 (depends on 1) The method of claim 1, wherein Q is represented by a structural formula selected from the group consisting of: ### Claim 27 (depends on 1) The method of claim 1, wherein in step (a) said administration is topical administration.