Labeled evans blue dye derivative for in vivo serum albumin labeling
Inventors
Chen, Xiaoyuan • Lang, Lixin • Niu, Gang
Assignees
US Department of Health and Human Services
Publication Number
US-10258701-B2
Publication Date
2019-04-16
Expiration Date
2035-03-31
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed is a compound of formula (I): wherein L, R1-R5, A, B, M, and n are as defined in the specification, as well as a method of preparing the compound. Also disclosed are a method of blood-pool imaging in a mammal and a method of imaging a lymph node in a mammal, comprising use of the compound.
Core Innovation
The invention provides a compound of formula (I), comprising a linker group L selected from aryl, biaryl, heteroaryl, and biheteroaryl optionally substituted with groups such as alkyl, halo, hydroxy, and alkyloxy; A selected from a bond, C═O, and C1-C6 alkyl; a chelating group B selected from 1,4,7-triazacyclononane-N,N′,N″-triacetic acid, 1,4,7,10-tetrazacyclononane-N,N′,N″-triacetic acid, triethylenetetramine, diethylenetetramine pentaacetic acid, and hydrazinonicotinamide; R1-R5 independently selected from hydrogen, OH, NH2, and SO3H; n as 0 or 1; and M selected from diagnostic or therapeutic metals including 18F-AlF, various Cu isotopes, 68Ga, 89Zr, 99mTc, Gd3+, Mn2+, and others.
The invention additionally provides methods of blood pool imaging and lymph node imaging in a mammal by administering the compound of formula (I) followed by PET imaging. Furthermore, a method of preparation of the compound is provided involving stepwise reactions including coupling a bis amino compound with triazacyclononane triacetic acid, reacting with a diazotization reagent, and subsequent coupling with 4-amino-5-hydroxynaphthalene-1,3-disulfonic acid, culminating in a radiolabeled product.
The problem being addressed is the need for improved methods for imaging blood pools and the lymphatic system due to limitations of existing agents. Existing blood pool imaging agents such as 99mTc-labeled red blood cells and radiolabeled albumin have drawbacks including complexity, short half-lives of radioisotopes, disruption of albumin structure, and risk of toxicity. Existing lymph node imaging methods require two-step administration of separate agents and suffer from low sensitivity and poor spatial resolution in scintigraphy and SPECT. There is a need for a safe, efficient, and multimodal imaging agent that accurately reflects serum albumin distribution and enables sensitive visualization of blood pools and lymph nodes.
Claims Coverage
The patent contains one independent claim pertaining to a method of lymph node imaging using a compound of formula (I). There are additional dependent claims specifying compound structure and metal selection. The main inventive features involve the compound’s structure, radiolabeling, and its use in mammalian lymph node imaging by PET.
Method of imaging lymph nodes using a labeled compound
A method for imaging a lymph node in a mammal consists of administering a compound of formula (I) followed by PET imaging, wherein the compound includes a linker group selected from aryl, biaryl, heteroaryl, and biheteroaryl optionally substituted and a chelating group selected from specific groups such as triazacyclononane triacetic acid derivatives, with R1-R5 substituents and M representing various suitable diagnostic or therapeutic metals.
Compound structure specifying metal radionuclide
The compound of formula (I) where M is selected from the group consisting of 18F-AlF, 64Cu, or 68Ga, specifically tailored for in vivo binding to albumin for imaging purposes.
The claims cover the use of a novel labeled Evans blue dye derivative compound structurally defined by formula (I) with specific chelating groups and metals for in vivo albumin labeling, enabling PET imaging of lymph nodes, including sentinel lymph nodes, through administration of this compound to mammals.
Stated Advantages
The compound enables rapid and efficient in vivo labeling of endogenous albumin leading to imaging comparable to in vitro labeled albumin, simplifying preparation and reducing procedure time.
It allows non-invasive PET blood pool imaging with stable retention in circulation and the ability to evaluate cardiac function and vascular permeability with high sensitivity and specificity.
Due to the low dose required, it avoids the toxicity issues related to vital dyes like Evans blue and the risks of blood product handling, supporting clinical translation.
The multimodal imaging capability, combining PET, optical fluorescence, and visible dye, facilitates pre-surgical lymph node mapping and intra-surgical guidance, enhancing detection and surgical accuracy.
The compound provides high specificity in differentiating hepatic hemangiomas from other focal hepatic lesions, thus aiding accurate diagnosis and reducing unnecessary treatments.
Documented Applications
Blood pool imaging in mammals via in vivo labeling of serum albumin assessed by PET imaging.
ECG-gated evaluation of cardiac function, including measurement of left ventricular volume and ejection fraction during cardiac cycles.
Visualization and quantification of vascular leakage in models of inflammation and malignant tumors by assessing albumin permeability.
Sentinel lymph node and lymphatic system imaging using PET combined with visible blue dye and fluorescence for surgical mapping and intraoperative guidance.
Differential diagnosis of focal hepatic lesions in humans, such as distinguishing hepatic hemangiomas from hepatic carcinoma, cysts, and metastases through blood volume imaging.
Interested in licensing this patent?