BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have the ability to breakdown matrix and other proteins. Upregulation of MMPs is associated with a wide range of diseases, including cancer, as well as pulmonary, musculoskeletal and cardiovascular diseases. MMP inhibitors have thus been proposed as potential therapeutic agents against these diseases. For example, hydroxamate-based MMP inhibitors act by binding to the active site Zn(II) ion in activated MMPs. However, MMP inhibitors as a class of drugs are generally toxic, have debilitating side effects at effective doses (such as musculoskeletal pain or inflammation) and/or exhibit mutagenic properties.

Further, due to the involvement of MMPs in diseases and disorders, there is a high demand for imaging agents that bind to MMPs, helping characterize their expression and/or activation. Such imaging agents would allow physicians to accurately diagnose and treat MMP-associated diseases, such as cardiovascular inflammation. Unfortunately, currently available MMP imaging agents (e.g.,99mTc-RP805;FIG. 12, D) exhibit poor target specificity, prolonged blood circulation time, poor stability and/or poor aqueous solubility of their precursors. Such undesired properties limit their utility in clinical applications.

Abdominal aortic aneurysm (AAA) accounts for 10,000-15,000 recorded deaths per year, mainly due to rupture, in the U.S. Current clinical guidelines for surgical repair of AAA are based on aneurysm size, expansion rate and clinical symptoms. However, a significant portion of AAA ruptures occurs in patients who do not meet the criteria for AAA repair, while some large AAA may remain stable for many years. As such, new risk stratification tools are needed to overcome limitations of the current approach to patient selection for AAA repair. Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard. MMP activation is a main pathophysiological feature of AAA, and is believed to be closely related to aneurysm progression and rupture risk. Thus, molecular imaging of MMP activation can be a useful tool for AAA risk stratification.

There is a need in the art for clinically useful imaging agents that can be used to image MMP activity and/or activation in a patient. There is also a need in the art for compounds that can bind and inhibit MMP activity and/or activation. Such compounds can be used to treat MMP-related diseases and/or evaluate aneurysm (e.g., AAA) progression and rupture risk. The present invention addresses these needs.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula I, or a salt, solvate, stereoisomer, or tautomer thereof:


wherein: R is selected from the group consisting of OH, —NH2, —NHR′, —NR′R′, —NH(aryl), —NH(heteroaryl) and —NHR1; R1is selected from the group consisting of:


R2is selected from the group consisting of:


R3is selected from the group consisting of H, OH, OCH3, F,18F,


each occurrence of n is independently an integer ranging from 0 to 30; each occurrence of R′ is independently selected from the group consisting of C1-C6alkyl and C3-C7cycloalkyl; and LG is a group capable of undergoing nucleophilic displacement.

The invention further provides a compound of formula II or a salt, solvate, stereoisomer, or tautomer thereof:


wherein R is selected from the group consisting of H, OH, OR′, aroxy, heteroaroxy, SH, thioalkoxy, thiocycloalkoxy, —NH2, —NHR′ [such as but not limited to —NHCH3, —NHCH2CH3, —NH(CH2)2CH3or —NHCH(CH3)2], —NR′R′ [such as but not limited to —N(CH3)2, —N(CH3)CH2CH3, or —N(CH2CH3)2], —NH(aryl) and —NH(heteroaryl), wherein each occurrence of R′ is independently selected from the group consisting of C1-C6alkyl and C3-C7cycloalkyl.

In certain embodiments, the compound of formula I is at least one selected from the group consisting of:


or a salt, solvate, stereoisomer, or tautomer thereof.

In certain embodiments, R3is present, and the compound of formula I further comprises a radioisotope-containing group, wherein the radioisotope is bound to and/or present in R3. In other embodiments, the radioisotope is at least one selected from the group consisting of99mTc,18F,111In,64Cu and68Ga. In yet other embodiments, the radioisotope-containing group further comprises one or more ligands that are bound to the radioisotope. In yet other embodiments, the one or more ligands help stabilize the radioisotope within the compound of formula I.

In certain embodiments, R3is present, and the compound of formula I further comprises a fluorophore-containing group.

In certain embodiments, R3is present, and the compound further comprises a radioisotope- and/or fluorophore-containing group comprising a radioisotope selected from the group consisting of99mTc,18F,111In64Cu and68Ga, and optionally further comprising one or more additional ligands, wherein the radioisotope is bound to R3.

In certain embodiments, R3is present, and the compound further comprises a radioisotope- and/or fluorophore-containing group comprising a radioisotope selected from the group consisting of99mTc,18F,111In64Cu and68Ga, and further comprising one or more additional ligands, wherein the radioisotope is bound to R3.

In certain embodiments, R1and/or R2comprises the group N3or C≡CH, and the compound is capable of undergoing a click reaction with a substrate comprising the group C≡CH or N3, respectively.

In certain embodiments, the compound of formula I is at least one selected from the group consisting of:


or a salt, solvate, stereoisomer, or tautomer thereof, wherein M is a metal, such as but not limited to a metal radioisotope.

In certain embodiments, the compound of formula II is at least one selected from the group consisting of:



In certain embodiments, the compound is part of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, such as but not limited to normal saline, 5% dextrose, sodium bicarbonate, sodium phosphate and/or citrate.

The invention further provides a method of evaluating a subject's risk of developing a cardiovascular disease or disorder. The invention further provides a method of treating a matrix metalloproteinase-related disease or disorder in a subject.

In certain embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention. In other embodiments, the method comprises administering to a subject at least one compound of the invention, wherein the at least one compound comprises a radioisotope or fluorophore. In yet other embodiments, the method comprises acquiring an image of at least a portion of the subject's body. In yet other embodiments, the method comprises measuring the amount of compound bound to the imaged portion of the subject's body. In yet other embodiments, if the measured amount of bound compound is above a determined control amount, the subject is diagnosed as having an increased risk of developing the cardiovascular disease or disorder.

The invention further provides a kit comprising at least one compound and/or at least one pharmaceutical composition of the invention, an applicator, and instructions to use the at least one compound and/or the at least one composition to evaluate a subject's risk of developing a cardiovascular disease or disorder and/or treat a matrix metalloproteinase-related disease or disorder in a subject.

In certain embodiments, the subject is a mammal. In other embodiments, the subject is a human. In yet other embodiments, the disease or disorder is at least one selected from the group consisting of cancers, inflammatory diseases, cardiovascular diseases, stroke, aneurysm, periodontitis, hepatitis, cirrhosis, portal hypertension, glomerulonephritis, atherosclerosis, emphysema, asthma, pulmonary fibrosis, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution and bone resorption.

In certain embodiments, the therapeutically effective amount of the at least one compound ranges from about 10 ng to 1000 mg. In other embodiments, the at least one compound is administered to the subject through a route selected from the group consisting of oral, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, intra-peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

