Psma targeted compounds and uses thereof
AssigneeCase Western Reserve University
InventorsJames Basilion, Zhenghong Lee, Xinning Wang
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Abstract
PSMA targeted compounds, pharmaceutical compositions comprising these compounds, and methods for treating and detecting cancers in a subject are described herein.
Claims19
A compound comprising formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- L includes a C3-C7 linear alkylene and/or a ring selected from an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring or an optionally substituted C4-C7 cycloalkylene ring;
- B is a 2 to 5 amino acid peptide linker consisting of up to 4 amino acids selected from aspartic acid and glutamic acid and optionally one other amino acid;
- Y includes at least one of a metal chelating agent or a chelated metal nuclide;
- and
- wherein the compound has similar uptake in salivary glands and non-PSMA expressing muscle tissue and wherein said uptake is substantially lower than in PSMA-expressing cancer tissue upon administration to a subject.
The compound of claim 1, wherein the chelating agent comprises at least one of diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazadodecanetetraacetate (DOTA), 2,2′,2″-(10-(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DOTA-1Py), 2,2′-(7,10-(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4-diyl) diacetic acid (DOTA-2Py), 2-(4,7,10-tris (pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1-yl) acetic acid (DOTA-3Py), 1,4,7,10-tetraazadodecane-1,4,7-triacetate (DO3A), ethylenediaminetetraacetate (EDTA), 1,4,7,10-tetraazacyclotridecanetetraacetic acid (TRITA), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7,10-tetraazadodecanetetramethylacetate (DOTMA), 1,4,7,10-tetraazadodecane-1,4,7-trimethylacetate (DO3MA), N,N′,N″,N′″-tetraphosphonatomethyl-1,4,7,10-tetraazacyclododecane (DOTP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene methylphosphonic acid) (DOTMP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phenylphosphonic acid) (DOTPP), N,N′-ethylenedi-L-cysteine, 1,4,7-triazacyclononane (TACN), N,N′-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N′-diacetic acid (HBED-CC), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacylododecane tetracetic acid (p-SCN-Bn-DOTA), 2-(4-isothiocyanatobenzyl-1,4,7,10-tetraaza-1,4,7,10,tetra-(2-carbamonylmethyl)-cyclododecane (p-SCN-Bn-TCMC), MeO-DOTA-NCS, [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA-NCS), 2-[4-nitrobenzyl]-1,4,7,10,13-pentaazacyclopentadecane-N,N′,N″,N′″,N″″-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexaazacyclooctadecane-N,N′,N″,N′″,N″″-hexaacetic acid (HEHA), desferrioxamine B (DFO), macropa, macropa-NCS, macropid, bispa 2, EuK-106, 7-[2-(bis-carboxymethyl-amino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid (DEPA), 3p-C-DEPA, or derivatives thereof. The compound of claim 9, wherein the chelated metal nuclide includes at least one of Ga, I, In, Y, Lu, Bi, Ac, Re, In, Th, Tc, Tl, Tb, Zr, Cu, Rb, At, Pb, Gd, Sm, or Sr.
A compound comprising formula (II):
- or a pharmaceutically acceptable salt thereof, wherein:
- L includes a C3-C7 linear alkylene and/or a ring selected from an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring or an optionally substituted C4-C7 cycloalkylene ring;
- m is 1, 2, 3, or 4;
- X1 is an amino acid;
- and
- Y includes at least one metal chelating agent or chelated metal nuclide selected from 225Ac, 226Ac, 227Th, 211Bi, 212Bi, 213Bi, 203Pb, 212 Pb, or 177 Lu;
- wherein the compound has similar uptake in salivary glands and non-PSMA expressing muscle tissue and wherein said uptake is substantially lower than in PSMA-expressing cancer tissue upon administration to a subject;
- and
- wherein the compound in the absence of Y has a net negative charge under standard physiological conditions.
Dependencies are inferred from the claim text.