Small molecule imaging of fungi by positron emission tomography scanning

Inventors

WILLIAMSON, Peter R. • Kiesewetter, Dale O. • PANEPINTO, John • Qiu, Jin

Assignees

Research Foundation of the State University of New York • US Department of Health and Human Services

Abstract

Disclosed herein are isotopically labeled calcofluor derivatives and uses of such to detect fungi, such as filamentous fungi, including Aspergillus species, such as by positron emission tomography (PET) scanning. In some examples, the disclosed compounds have a formula ofwherein R1 is an amine, a hydroxyl group, a sulfide, a carboxylic acid, an amide, an alkyl, or aryl; R2 is —NHC(O)—R3—L or —C(O)NH—R3—L, wherein R3 is an aryl or an aliphatic group (such as alkyl); each R4 independently may be selected from halogen, aliphatic (such as alkyl), aryl, amine, hydroxyl, haloalkyl, carboxylic acid, amide, aralkyl, cyano, ester, thiol, thioether, or alkoxy; each R5 independently may be selected from hydrogen, aralkyl, alkyl, or aryl, with any one of the aralkyl, alkyl, or aryl groups optionally being substituted with any one of the substituents provided for R4; each n independently is 1, 2, 3, 4, or 5; and L is 18F or a chelator capable of chelating a radiolabel (such as chelators for [18F]AlF, 64Cu, 68Ga),1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-triacetic acid (NOTA).

Core Innovation

The invention disclosed herein relates to radioactive, isotopically-labeled calcofluor derivatives and their use to detect fungi, including filamentous fungi such as Aspergillus species, via positron emission tomography (PET) scanning. The compounds have a general formula where substituents R1, R2, R3, R4, R5, n, and L define chemical groups, with L being 18F or a chelator capable of binding radiolabels suitable for PET imaging. These compounds selectively bind to chitin in fungal cell walls, enabling noninvasive detection of fungal infections.

The background highlights that Aspergillus, typically harmless, can be lethal in immunosuppressed patients with high mortality rates. Current diagnostic methods such as CT scans, bronchoscopies, and biopsies are invasive with suboptimal yield, while noninvasive imaging detects nodules but fails to specifically identify fungal infections, often confusing them with cancer or other infections. Thus, there exists a need for a noninvasive diagnostic test specific for fungal infections.

To address this need, the invention provides synthesis of calcofluor derivatives labeled with radioactive isotopes like 18F, which retain specificity for fungi and enable PET imaging. The disclosed synthetic methods are rapid and efficient, crucial due to the short half-life of 18F. The method includes administering a radiologically effective amount of these compounds to a subject, followed by PET imaging to detect and localize fungal infections, especially those caused by filamentous fungi. The imaging allows clinicians to differentiate fungal nodules from other causes, assess infection extent, and monitor therapeutic efficacy noninvasively.

Claims Coverage

The patent discloses five inventive features centered on a novel compound, compositions including the compound, and methods of detecting and monitoring filamentous fungal infections using the compound with PET imaging.

The claims collectively cover the chemical entity, pharmaceutical compositions thereof, and diagnostic and monitoring methods of fungal infections, particularly those caused by filamentous fungi, employing the compound in conjunction with PET imaging to provide noninvasive and specific fungal detection and assessment.

Stated Advantages

Documented Applications