US 2014/0369933 A1 · FLUORINE-18 LABELED HYDROGEN ION PROBES

Abstract

Fluorine-containing molecules include fluorine-18 labeled hydrogen ion indicator molecules and methods of making and using the same. Fluorine atoms incorporated into the indicator molecules provides novel structural modifications to the precursor molecules, shifting the absorbance maxima relative to their non-fluorinated precursor/cogeners. These molecules are useful for non-invasive in vivo measurement of blood volume, blood flow and pH in biological objects. Compounds are functionalized by a radioisotopically enriched fluorine-18 label and indicator molecule with structure derived from triarylmethane derived indicators, such as phenol red, cresol red, cresol purple, thymol blue, bromophenol red, naphthol blue, phenolphthalein, cresolphthalein, thymolphthalein, naphtholphthalein, gentian violet (methyl violet 10B), methyl violet 2B, methyl violet 6B, leucomalachite green (malachite green), brilliant green, pararosaniline, fuchsines, or salts thereof. During its radioactive decay, fluorine-18 produces high-energy positrons, which can be detected by positron emission tomography (PET) or single photon emission computer tomography (SPECT).

Claims28

Dependent claims

A compound having a structure of Formula I, II, III, or IV, or a salt thereof:

wherein
X1 and X2 are independently, at each occurrence, hydrogen or fluorine;
R1, R2, R3, and R4, are independently, at each occurrence, hydrogen, optionally substituted C1-6 alkyl;
optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 alkenyl;
optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroaryl, or halo;
X3 and X4 are independently, at each occurrence, hydrogen, fluorine, bromine, chlorine, iodine, optionally substituted C1-6 alkyl;
optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 alkenyl;
optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, or optionally substituted heteroaryl;
provided at least one of X1, X2, X3, and X4 is fluorine;
wherein
where present, the fluorine is either present at its natural abundance of isotopes at each occurrence or is statistically enriched in the radioisotope 18F above its natural isotopic abundance relative to the 19F isotope at each occurrence.

8 more elements

A method of preparing a compound of Formula I, II, III, or IV, or a salt thereof,

wherein
X1 and X2 are independently, at each occurrence, hydrogen or fluorine;
R1, R2, R3, and R4, are independently, at each occurrence, hydrogen, optionally substituted C1-6 alkyl;
optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 alkenyl;
optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroaryl, or halo;
X3 and X4 are independently, at each occurrence, hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted C1-6 alkyl;
optionally substituted C3-6 cycloalkyl, optionally substituted C2-6 alkenyl;
optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, or optionally substituted heteroaryl;
and
provided at least one of X1, X2, X3, and X4 is fluorine;
said method comprising reacting a precursor of Formula V, VI, VII, or VIII or a salt thereof, as appropriate, with fluorine gas in a solvent:
wherein R1, R2, R3, and R4 have the same meanings as provided for the compounds;
and wherein either:
(a) the fluorine gas and at least one fluorine atom per compound molecule is statistically present at their natural isotopic abundance;
or
(b) the fluorine gas is radiolabeled to be enriched in 18F above its natural isotopic abundance relative to the 19F isotope and the at least one fluorine atom per compound molecule is enriched in 18F above its natural isotopic abundance relative to the 19F isotope.

13 more elements

Dependencies are inferred from the claim text.

Fluorine-18 labeled hydrogen ion probes

Life of this patent

Fluorine-18 labeled hydrogen ion probes

Life of this patent

Abstract

Claims28