Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical composition containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.

The present invention relates to a ligand-SIFA-chelator conjugate, comprising, within a single molecule three separate moieties: (a) one or more ligands which are capable of binding to PSMA, (b) a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon atom and a fluorine atom, and (c) one or more chelating groups, containing a chelated nonradioactive cation.

The present invention relates to a compound of formula (1), and to a complex comprising said compound and a radionuclide, and to the respective pharmaceutical composition, the compound having the following structure

##STR00001##

or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H or —CH.sub.3, preferably H, wherein R.sup.2, R.sup.3 and R.sup.4 are independently of each other, selected from the group consisting of —CO.sub.2H, —SO.sub.2H, —SO.sub.3H, —OSO.sub.3H, —PO.sub.2H, —PO.sub.3H and —OPO.sub.3H.sub.2, Q.sup.1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, Q.sup.2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, A is a chelator residue derived from a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (=DOTA), N,N″-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid, (NODAGA), 2-(4,7, 10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA), 1,4,7-riazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid](NOPO), 3,6,9, 15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), Diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7, 10-triazacyclododecane-4,7, 10-triacetic acid (oxo-Do3A) p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA), X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, Z.sup.1 and Z.sup.2, are independently of each other, charged amino acids, q is an integer of from 0-3, n, m and p, are independently of each other an integer of from 0 to 9, n1, n2, m1, m2, p1, p2, are independently of ach other, an integer of from 0 to 3, and wherein n1+n2>0, m1+m2>0 and p1+p2>0, and wherein n+m+p>0. Further, the present invention relates to the compound, the complex, and the pharmaceutical composition for use in treating, ameliorating or preventing PSMA-expressing cancers, in particular prostate cancer

A method for the synthesis of specialized pro-resolving mediators, structural isomers thereof and analogs thereof is disclosed herein. The method comprises reacting a compound of the formula (I):

##STR00001## wherein R.sub.1 is alkyl.sub.(C≤12), cycloalkyl.sub.(C≤12), alkenyl.sub.(C≤12), alkylidene.sub.(C≤12), alkynyl.sub.(C≤12), aryl, aralkyl, heteroaryl or heteroaralkyl; and X.sub.1, X.sub.2 and X.sub.3 are each independently hydroxy or OP, wherein P is a hydroxy protecting or hydroxy activating group; with a reducing agent under conditions sufficient to produce a compound of the formula (II):

##STR00002## wherein: R.sub.1, X.sub.1, X.sub.2 and X.sub.3 are as defined above.

Novel protectins, more specifically novel structural isomers and analogs of PD1 and PDX are also disclosed.

The radiopharmaceutical .sup.177Lu-PSMA I&T is provided, including in high purities with extended shelf life. Further provided are methods of synthesis of .sup.177Lu-PSMA I&T and pharmaceutical compositions and methods of treatment that comprise .sup.177Lu-PSMA I&T.

The present invention provides compounds according to General Formula (1)(i) or (1)(ii): wherein A is a diagnostic or therapeutic agent comprising a binding site for a tumor antigen, and the spacer comprises at least one C—N bond.

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Conjugates derived from non-steroidal anti-inflammatory drugs (NSAIDs) and methods of use thereof are disclosed, useful for, inter alia, identifying and localizing the site of pathology and/or inflammation responsible for the sensation of pain in a patient; for identifying the sites of primary, secondary, benign, or malignant tumors; and for diagnosing infection or confirming or ruling out suspected infection. The NSAID-based conjugates contain an imaging moiety. The conjugates concentrate at sites of increased cyclooxygenase expression, thus revealing the sites of increased prostaglandin production, which is correlated with pain and inflammation, and correlated with tumor presence and/or location. Identifying areas of increased COX expressing can also aid in screening for infections.

An imaging agent and a method of its use for imaging a necrosis in a tissue of a subject. The imaging method may be positron emission tomography (PET). In at least one embodiment the imaging agent comprises 2-deoxy-2-[.sup.18F]fluoroglucaric acid (.sup.18F-FGA), or a pharmaceutically-acceptable salt thereof. The imaging agent may be disposed in a pharmaceutically-acceptable excipient, carrier, diluent, or vehicle. The imaging agent may be contained within a kit. The disclosure includes in at least one embodiment a method of preparing a radiopharmaceutical such as .sup.18F-FGA for use in imaging. The .sup.18F-FGA binds preferentially to necrotic cells versus living cells.

The present technology provides compounds as well as compositions including such compounds useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) where the compounds are represented by the following Formulas (I), or a pharmaceutically acceptable salt thereof (IA), or a pharmaceutically acceptable salt thereof (II), or a pharmaceutically acceptable salt thereof, wherein M.sup.1 is independently at each occurrence an alpha-emitting radionuclide. Equivalents of such compounds are also disclosed.

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Provided herein are compositions and methods for preparing albumin-targeting moieties that feature a thioamide linkage. Methods to use the albumin targeting molecules to generate drugs with improved in vivo pharmacodynamics and biodistribution are described. Therapeutic compounds incorporating these thioamide linked albumin-targeting moieties are disclosed.