News Column

Patent Issued for PSMA-Binding Agents and Uses

July 29, 2014



By a News Reporter-Staff News Editor at Cancer Weekly -- The Johns Hopkins University (Baltimore, MD) has been issued patent number 8778305, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also The Johns Hopkins University).

The patent's inventors are Pomper, Martin (Baltimore, MD); Mease, Ronnie Charles (Fairfax, VA); Chen, Ying (Timonium, MD).

This patent was filed on July 31, 2009 and was published online on July 15, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "The present invention relates generally to radioisotope labeled prostate specific membrane antigen (PSMA) binding compounds, chemical precursors of radioisotope labeled PSMA binding compounds and imaging methods using the radioisotope labeled compounds.

"Prostate cancer (PCa) is the second leading cause of cancer-related death in men (1). Only one half of tumors due to PCa are clinically localized at diagnosis and one half of those represent extracapsular spread. Localization of that spread as well as determination of the total body burden of PCa have important implications for therapy, particularly as new combination and focal therapies become available. Also critically needed are targeted agents that can provide a readout on the biology of the tumor, with the ability to predict which tumors will lie dormant and which will develop into aggressive, metastatic disease. The current clinical standard for localizing cancer--including PCa--is shifting from the anatomic techniques such as computed tomography (CT) and magnetic resonance (MR) imaging to more physiologically relevant methods that employ molecular imaging, such as MR spectroscopy, single photon emission computed tomography (SPECT) and positron emission tomography (PET) (2). Such newer methods that utilize molecular imaging may provide the biological readout necessary for understanding tumor physiology, enabling more accurate prognosis and therapeutic monitoring. Molecular imaging may provide a way to not only detect tumors in vivo, but also to provide information regarding the biology of the lesion, if a mechanism-specific agent is used. For example, [.sup.18F]FDHT can be used to study the androgen receptor status of tumors (3).

"Unlike many other cancers, PCa is particularly difficult to detect using existing molecular imaging tracers. There are several reasons for this, including the relatively slow growth and metabolic rate of PCa compared to other malignancies as well as the small size of the organ and proximity to the urinary bladder, into which most radiopharmaceuticals are eventually excreted.

"Because of the relatively low metabolism of PCa, PET with [.sup.18F]fluorodeoxyglucose (FDG-PET) has proved ineffectual for diagnostic imaging of this disease. Other promising, experimental radiopharmaceuticals for imaging PCa are emerging, including those of the choline series (4)(5)(6), radiolabeled acetates (7), anti-1-amino-3-[.sup.18F]fluorocyclobutyl-1-carboxylic acid (anti[.sup.18F]F-FACBC) (8)(9), 1-(2-deoxy-2-[.sup.18F]fluoro-L-arabinofuranosyl)-5-methyluracil ([.sup.18F]FMAU) (10) and [.sup.18F]fluorodihydrotestosterone ([.sup.18F]FDHT) (3). Each has its benefits and detriments, with no single agent ideal, i.e., easy to synthesize, little metabolism and demonstrating tumor-specific uptake, in all PCa phenotypes.

"Overexpressed on most solid tumor neovasculature (11) as well as in prostate cancer, the prostate-specific membrane antigent (PSMA) is becoming an attractive target for cancer imaging and therapy (12)(13). PSMA-based agents can report on the presence of this marker, which is increasingly recognized as an important prognostic determinate in PCa (14). It is also the target for a variety of new PCa therapies (15). ProstaScint.TM. is an .sup.111In-labeled monoclonal antibody against PSMA that is clinically available for imaging PCa. ProstaScint.TM. and radiolabeled variations of this antibody are fraught with long circulation times and poor target to nontarget tissue contrast, limiting the utility of these agents (16)(17)(18)."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The present invention satisfies the long standing and unmet need for new tissue-specific compounds for imaging prostate cancer and angiogenesis. The present invention, in particular, provides imaging agents which differ from the prior art in modifications which were not previously known or suggested. Furthermore, the invention provides imaging agents that offer better contrast between target tissues and non-target tissues.

"The invention relates to compounds having the structure (I) shown below.

"##STR00001## wherein Z is tetrazole or CO.sub.2Q; each Q is independently selected from hydrogen or a protecting group.

"In some embodiments of Formula I, m is 0, 1, 2, 3, 4, 5, or 6; R is a pyridine ring with the structure

"##STR00002## wherein X is fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine, NO.sub.2, NH.sub.2, N.sup.+(R.sup.2).sub.3, Sn(R.sup.2).sub.3, Si(R.sup.2).sub.3, Hg(R.sup.2), B(OH).sub.2, --NHNH.sub.2, --NHN.dbd.CHR.sup.3, --NHNH--CH.sub.2R.sup.3; n is 1, 2, 3, 4, or 5; Y is O, S, N(R'), C(O), NR'C(O), C(O)N(R'), OC(O), C(O)O, NR'C(O)NR', NR'C(S)NR', NR'S(O).sub.2, S(CH.sub.2).sub.p, NR'(CH.sub.2).sub.p, O(CH.sub.2).sub.p, OC(O)CHR.sup.8NHC(O), NHC(O)CHR.sup.8NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R' is H or C.sub.1-C.sub.6 alkyl, and R.sup.8 is alkyl, aryl or heteroaryl, each of which may be substituted; R.sup.2 is C.sub.1-C.sub.6 alkyl; and R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, bromine, a radioisotope of bromine, a radioisotope of astatine, NO.sub.2, NH.sub.2, N.sup.+(R.sup.2).sub.3, Sn(R.sup.2).sub.3, Si(R.sup.2).sub.3, Hg(R.sup.2), or B(OH).sub.2.

"In some embodiments of Formula I, m is 0, 1, 2, 3, 4, 5, or 6; Y is O, S, N(R'), C(O), NR'C(O), C(O)N(R'), OC(O), C(O)O, NR'C(O)NR', NR'C(S)NR', NR'S(O).sub.2, S(CH.sub.2).sub.p, NR'(CH.sub.2).sub.p, O(CH.sub.2).sub.p, OC(O)CHR.sup.8NHC(O), NHC(O)CHR.sup.8NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R' is H or C.sub.1-C.sub.6 alkyl, and R.sup.8 is alkyl, aryl or heteroaryl, each of which may be substituted; R is

"##STR00003## wherein X' is selected from the group consisting of NHNH.sub.2, --NHN.dbd.CHR.sup.3, and --NHNH--CH.sub.2R.sup.3; wherein R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO.sub.2, NH.sub.2, N.sup.+(R.sup.2).sub.3, Sn(R.sup.2).sub.3, Si(R.sup.2).sub.3, Hg(R.sup.2), or B(OH).sub.2; and n is 1, 2, 3, 4, or 5.

"In other embodiments of Formula I, m is 4, Y is NR', and R is

"##STR00004## wherein G is O, NR' or a covalent bond; R' is H or C.sub.1-C.sub.6 alkyl; p is 1, 2, 3, or 4, and R.sup.7 is selected from the group consisting of NH.sub.2, N.dbd.CHR.sup.3, NH--CH.sub.2R.sup.3, wherein R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine, NO.sub.2, NH.sub.2, N.sup.+(R.sup.2).sub.3, Sn(R.sup.2).sub.3, Si(R.sup.2).sub.3, Hg(R.sup.2), or B(OH).sub.2.

"Some compounds of the present invention interact with the prostate-specific membrane antigen (PSMA). As a result, when the compounds comprise a radioisotope, they may be suitable as imaging agents, diagnostic agents, and/or therapeutic agents.

"In many cases, the radioisotope used in the compound is short-lived. Therefore, radioisotopically labeled compounds are prepared immediately or shortly before use, or only in sufficient quantity for administration. For this reason, the invention also includes precursors to radioisotopically labeled compounds, which may be chemically converted into the radioisotopically labeled compounds of the invention."

For the URL and additional information on this patent, see: Pomper, Martin; Mease, Ronnie Charles; Chen, Ying. PSMA-Binding Agents and Uses. U.S. Patent Number 8778305, filed July 31, 2009, and published online on July 15, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8778305.PN.&OS=PN/8778305RS=PN/8778305

Keywords for this news article include: Bromine, Cancer, Emerging Technologies, Fluorine, Halogens, Imaging Technology, Indicators and Reagents, Iodine, Molecular Imaging, Nanotechnology, Oncology, Radioisotopes, Radiopharmaceuticals, The Johns Hopkins University.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


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Source: Cancer Weekly


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