Saccharide sensing molecules having enhanced fluorescent properties

• US 6,673,625 B2
• Filed: 03/30/2001
• Issued: 01/06/2004
• Est. Priority Date: 09/15/1999
• Status: Expired due to Term

• Current Assignee: Lawrence Livermore National Security LLC (Government of the United States of America), Minimed, Inc. (Medtronic Plc)
• Original Assignee: Minimed, Inc. (Medtronic Plc), Regents of the University of California (University of California)
• Inventors: Cary, Douglas R., Tran, Joe Anh, Satcher, Joe H. Jr., Lane, Stephen M., Darrow, Christopher B.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Cole, Monique T.
• Application Number:
  US09/823,522
• Publication Number:
  US 20020010279A1
• Time in Patent Office: 1,012 Days
• Field of Search: 252/700, 436/94, 436/95, 422/82.07, 546/1, 546/13, 546/15, 546/16, 546/17, 546/26, 546/79, 546/101, 546/285, 546/290, 546/296, 546/298, 546/299
• US Class Current: 436/94
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C09B 19/00 Oxazine dyes
• CPC Class Codes: C09B 57/08 Naphthalimide dyes; Phthalimide dyes
• CPC Class Codes: C09B 57/10 Metal complexes of organic compounds not being dyes in uncomplexed form
• CPC Class Codes: G01N 33/52 Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements immunological elements G01N33/54386; involving labelled immunochemicals G01N33/58; for haemoglobin or occult blood G01N33/72
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]
• CPC Class Codes: Y10T 436/144444 Glucose

Abstract

The present invention provides formulae for fluorescent compounds that have a number of properties which make them uniquely suited for use in sensors of analytes such as saccharides. The advantageous fluorescent properties include favorable excitation wavelengths, emission wavelengths, fluorescence lifetimes, and photostability. Additional advantageous properties include enhanced aqueous solubility, as well as temperature and pH sensitivity. The compound comprises an aryl or a substituted phenyl botonic acid that acts as a substrate recognition component, a fluorescence switch component, and a fluorophore. Fluorescent compounds are described that are excited at wavelengths greater than 400 nm and emit at wavelengths greater than 450 nm, which is advantageous for optical transmission through skin. The fluorophore is typically selected from transition metal-ligand complexes and thiazine, oxazine, oxazone, or oxazine-one as well as anthracene compounds. The fluorescent compound can be immobilized in a glucose permeable biocompatible polymer matrix that is implantable below the skin.

Claims

1. A fluorescent compound that emits a signal that can be correlated to an analyte concentration, wherein the compound has the general formula:

wherein R¹ is selected from the group consisting of hydrogen, lower aliphatic and aromatic groups;

wherein L¹ and L² are optional linking groups having from zero to five contiguous atoms selected from the group consisting of nitrogen, carbon, oxygen, sulfur, and phosphorus, and the sum of the contiguous atoms contained in both linking groups is 2 or more;

wherein Z¹ and Z² are heteroatoms selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus; and

wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are optional groups selected from the group consisting of hydrogen, lower aliphatic and aromatic groups and groups that form covalent bonds to a polymer matrix.

2. The fluorescent compound as recited in claim 1, wherein the fluorophore emits at a wavelength greater than about 450 nm.

3. The fluorescent compound as recited in claim 1, wherein the fluorophore emits at a wavelength greater than about 500 nm.

4. The fluorescent compound as recited in claim 1, wherein the excitation wavelength for the fluorophore is greater than about 400 nm.

5. The fluorescent compound as recited in claim 1, wherein the excitation wavelength for the fluorophore is greater than about 425 nm.

6. The fluorescent compound as recited in claim 1, wherein Z is nitrogen.

7. The fluorescent compound as recited in claim 1, wherein the fluorophore and Z are selected to satisfy the following equation such that Δ

G, the free energy for electron transfer, is less than about 3.0 kcal mol<sup>−

1</sup>;

8. The fluorescent compound as recited in claim 1, wherein the fluorescent compound emits a signal that is correlated with the concentration of glucose.