Voltage sensitive dyes
Inventors
Bardon, Kevin M. • Minns, Richard A. • Selfridge, Scott D. • Takiff, Larry • ADAMS, TIMOTHY
Assignees
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Publication Number
US-11332484-B2
Publication Date
2022-05-17
Expiration Date
Abstract
Voltage sensitive dyes comprising boron and related compositions and methods are provided. In some embodiments, a voltage sensitive dye comprises an electron acceptor comprising boron. The electron acceptor may be attached (e.g., covalently) to at least one electron donating group and at least one polar group. For instance, the electron acceptor may comprise optionally substituted boron dipyrromethene (e.g., optionally substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene). The point of attachment and chemical nature of the electron donating group(s) and polar group(s) may be selected to impart beneficial properties to the voltage sensitive dye. For instance, the voltage sensitive dye may have an extended difference in the dipole moment between the ground and electronic states due at least in part to the position of the electron donating group(s). The voltage sensitive dyes, described herein, may have high specificity, high signal to noise ratio, fast responsivity, high voltage sensitivity, high photostability, and/or high brightness.
Core Innovation
The invention relates to a composition of matter comprising a compound of Formula I or a salt thereof. The chemical structure is defined by substituent selections including R1, R2, R3, R4, Ring A, R5, X, and the electron donating group expressed as —(R6)n—R7, with n being 1-5. A key structural constraint is that at least one of R1 and R2 is an electron donating group, and X is charged or has a log(P) of less than or equal to about 0.
The disclosure describes boron-containing voltage sensitive dyes for measuring membrane potential using compounds that include a boron electron acceptor covalently attached to electron donating groups and to a polar or charged group. The boron electron acceptor is identified as a boron dipyrromethene motif, including 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, within a dye architecture defined by structural formulas and substituent rules.
The disclosure further explains that tuning the dye properties is achieved by controlling the placement of electron donating groups so as to affect dipole moment change, and by placing the polar group to support cell-membrane orientation, with the polar group positioned toward an outside region and the boron acceptor oriented within a membrane. The document states performance attributes including high specificity, high signal-to-noise, fast responsivity, high voltage sensitivity, high photostability, high brightness, and fluorescent yield greater than or equal to 0.1.
Claims Coverage
The provided claim set includes independent claim coverage for a Formula I composition of matter and a separate selected-compound claim. The main inventive coverage combines the boron dye architecture with substituent constraints and a polar or charged group X, and includes a fluorescent yield threshold in a dependent claim.
Formula I composition with electron donating substituent requirement
A composition of matter comprising a compound of Formula I or a salt thereof, wherein R1 and R2 are independently hydrogen, optionally substituted alkyl, or an electron donating group, provided that at least one of R1 and R2 is an electron donating group; each R3 is independently hydrogen or optionally substituted alkyl; each R4 is hydrogen or optionally substituted alkyl; Ring A is optionally substituted arylene or optionally substituted heteroarylene; and the electron donating group is —(R6)n—R7 with n being 1-5.
Charged or low log(P) moiety selection
X is charged or has a log(P) of less than or equal to about 0, within the composition of matter comprising the compound of Formula I or a salt thereof.
Electron donating group architecture with N(R3)2 or thiol
The electron donating group is —(R6)n—R7, where each R6 is independently optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted arylene, or optionally substituted heteroarylene; R7 is —N(R3)2 or optionally substituted thiol; and each R3 is independently C1-12 alkyl, provided that at least one R3 is C2-12 alkyl.
Fluorescent yield minimum threshold
A composition of matter as in claim 1 having a fluorescent yield greater than or equal to 0.1.
Selected compound group or salt
A compound selected from the group consisting of a specified group, or a salt thereof.
Overall, the claim coverage centers on Formula I compositions defined by required electron donating substitution at R1 and R2, a polar or charged group X constrained by charge or logP less than or equal to about 0, and an electron donating group segment expressed as —(R6)n—R7 with n in the range 1-5, plus a separate selected-compound claim.
Stated Advantages
High specificity.
High signal-to-noise.
Fast responsivity.
High voltage sensitivity.
High photostability.
High brightness.
Fluorescent yield greater than or equal to 0.1.
Documented Applications
Measuring membrane potential in connection with exposing a cell membrane to the dye and correlating absorbance or emission wavelengths with membrane potential magnitude.
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