Claims for Patent: 12,390,540

Summary for Patent: 12,390,540

Title:	Dual mode radiotracer and -therapeutics
Abstract:	The present invention relates to a ligand-SIF A-chelator conjugate, comprising, within in a single molecule three separate moieties: (a) one or more ligands which are capable of binding to a disease-relevant target molecule, (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, optionally containing a chelated nonradioactive or radioactive cation.
Inventor(s):	Alexander Josef Wurzer, Hans-Jürgen Wester, Matthias Johannes Eiber
Assignee:	Technische Universitaet Muenchen Klinikum Rechts Der Isar , Technische Universitaet Muenchen
Application Number:	US17/849,297
Patent Claims:	1. A ligand-SIFA-chelator conjugate, comprising, within in a single molecule three separate moieties: (a) one or more ligands which are capable of binding to prostate-specific membrane antigen (PSMA), (b) a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon and a fluorine atom and which can be labelled with 18F by isotopic exchange of 19F by 18F or which is labelled with 18F, and (c) one or more chelating groups, optionally containing a chelated nonradioactive or radioactive cation, wherein the one or more chelating groups comprises a hydrophilic chelator; wherein the conjugate is formulated for in vivo administration for nuclear diagnostic imaging or targeted radiotherapy of a disease associated with an overexpression of prostate-specific membrane antigen. 2. The conjugate according to claim 1, wherein the silicon-fluoride acceptor (SIFA) moiety has the structure represented by formula (I): wherein R1S and R2S are independently a linear or branched C3 to C10 alkyl group; R3S is a C1 to C20 hydrocarbon group comprising one or more aromatic and/or aliphatic units and/or up to 3 heteroatoms selected from O and S; and wherein the SIFA moiety is attached to the remainder of the conjugate via the bond marked by . 3. The conjugate according to claim 2, wherein the silicon-fluoride acceptor (SIFA) moiety has the structure represented by formula (Ia): wherein t-Bu indicates a tert-butyl group. 4. The conjugate according to claim 3, wherein the chelating group comprises at least one of (i) a macrocyclic ring structure with 8 to 20 ring atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms; (ii) an acyclic, open chain chelating structure with 8 to 20 main chain atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms; or (iii) a branched chelating structure containing a quarternary carbon atom. 5. The conjugate according to claim 4, wherein the chelating group is selected from bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N′-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutandiamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecan (DO2A) 1,4,7,10-tetracyclododecan-N,N′,N″, N′-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), 1,4,7,10 tetraazacyclododecane N,N′, N″, N″ 1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N′-dipyridoxylethylendiamine-N,N′-diacetate-5,5′-bis(phosphat) (DPDP), diethylene triamine N,N′,N″ penta(methylene)phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N′-tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), tetra 3-hydroxy-N-methyl-2-pyridinone chelators (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), abbreviated as Me-3,2-HOPO, 1,4,7-triazacyclononan-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carbooxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridin-bis(methyleneamintetraacetic acid (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecan-N,N′,N″,N′-tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazonan-1-yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraaminehexaacetic acid (TTHA). 6. The conjugate according to claim 4, wherein the chelating group is 1,4,7,10-tetracyclododecan-N,N′,N″,N″-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) or 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP). 7. The conjugate according to claim 4, wherein the chelator contains a chelated cation selected from the cations of 43Sc, 44Sc, 47Sc, 64Cu, 67Cu, 67Ga, 68Ga, 90Y, 111In, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 212Pb, 212Bi, 213Bi, 225Ac, and 227Th or a cationic molecule comprising 18F. 8. The conjugate according to claim 1, wherein the SIFA fluorine atom is 18F. 9. The conjugate according to claim 1, which is a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: SIFA is a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon and a fluorine atom; m is an integer of 2 to 6; n is an integer of 2 to 6; R1L is CH2, NH or O; R3L is CH2, NH or O; R2L is C or P(OH); X1 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, an urea bridge, and an amine bond; X2 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, an urea bridge, and an amine bond; L1 is a divalent linking group with a structure selected from an oligoamide, an oligoether, an oligothioether, an oligoester, an oligothioester, an oligourea, an oligo (ether-amide), an oligo (thioether-amide), an oligo (ester-amide), an oligo (thioester-amide), oligo (urea-amide), an oligo (ether-thioether), an oligo (ether-ester), an oligo (ether-thioester), an oligo (ether-urea), an oligo (thioether-ester), an oligo (thioether-thioester), an oligo (thioether-urea), an oligo (ester-thioester), an oligo (ester-urea), and an oligo (thioester-urea), wherein L1 is optionally substituted with one or more substitutents independently selected from —OH, —OCH3, —COOH, —COOCH3, —NH2, and —NHC(NH)NH2; X3 is selected from an amide bond, an ester bond, an ether, and an amine; RB is a trivalent coupling group; X4 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, a linking group of the formula: wherein the amide bond marked by is formed with the chelating group, and the other bond marked by is bound to RB, and a linking group of the formula: wherein the bond marked by at the carbonyl end is formed with the chelating group, and the other bond marked by is bound to RB; RCH is chelating group optionally containing a chelated radioactive or nonradioactive cation. 10. The conjugate according to claim 9, wherein —X1-L1-X2— represents one of the following structures (L-1) and (L-2): —NH—C(O)—R6—C(O)—NH—R7—NH—C(O)— (L-1) —C(O)—NH—R8—NH—C(O)—R9—C(O)—NH—R10—NH—C(O)— (L-2) wherein R6 to R10 are independently selected from C2 to C10 alkylene, which alkylene groups may each be substituted by one or more substitutents independently selected from —OH, —OCH3, —COOH, —COOCH3, —NH2, and —NHC(NH)NH2 or wherein —X1-L1-X2— represents one of the following structures (L-3) and (L-4): —NH—C(O)—R11—C(O)—NH—R12—CH(COOH)—NH—C(O)— (L-3) —C(O)—NH—CH(COOH)—R13—NH—C(O)—R14—C(O)—NH—R15—CH(COOH)—NH—C(O)— (L-4) wherein R11 to R15 are independently selected from C2 to C8 alkylene. 11. The conjugate according to claim 9, wherein RB has the structure represented by formula (IV): wherein: A is selected from N, CR16, wherein R16 is H or C1-C6 alkyl, and a 5 to 7 membered carbocyclic or heterocyclic group; the bond marked by at (CH2) a is formed with X2, and a is an integer of 0 to 4; the bond marked by at (CH2) is formed with X3, and b is an integer of 0 to 4; and the bond marked by at (CH2), is formed with X4, and c is an integer of 0 to 4. 12. The conjugate according to claim 1, which is a compound of formula (IIIa): or a pharmaceutically acceptable salt thereof, wherein: m is an integer of 2 to 6; n is an integer of 2 to 6; b is an integer of 0 to 4; C is an integer of 0 to 4; R1L is CH2, NH or O; R3L is CH2, NH or O; R2L is C or P(OH); X1 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, an urea bridge, and an amine bond; L1 is a divalent linking group with a structure selected from an oligoamide, an oligoether, an oligothioether, an oligoester, an oligothioester, an oligourea, an oligo (ether-amide), an oligo (thioether-amide), an oligo (ester-amide), an oligo (thioester-amide), oligo (urea-amide), an oligo (ether-thioether), an oligo (ether-ester), an oligo (ether-thioester), an oligo (ether-urea), an oligo (thioether-ester), an oligo (thioether-thioester), an oligo (thioether-urea), an oligo (ester-thioester), an oligo (ester-urea), and an oligo (thioester-urea), wherein L1 is optionally substituted with one or more substitutents independently selected from —OH, —OCH3, —COOH, —COOCH3, —NH2, and —NHC(NH)NH2; X4 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, a linking group of the formula: wherein the amide bond marked by is formed with the chelating group, and a linking group of the formula: wherein the bond marked by at the carbonyl end is formed with the chelating group; and RCH is chelating group optionally containing a chelated radioactive or nonradioactive cation. 13. The conjugate according to claim 1, wherein the conjugate is a compound selected from the group consisting of: and pharmaceutically acceptable salts and individual isomers thereof, optionally containing a chelated nonradioactive or radioactive cation and wherein the fluorine atom is optionally 18F. 14. A pharmaceutical or diagnostic composition comprising or consisting of one or more conjugates or compounds according to claim 1. 15. The conjugate of claim 1, wherein the SIFA moiety comprises 19F. 16. A ligand-SIFA-chelator conjugate, comprising, within a single molecule three separate moieties: (a) one or more ligands which are capable of binding to prostate-specific membrane antigen (PSMA), (b) a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon and a fluorine atom and which can be labelled with 18F by isotopic exchange of 19F by 18F or which is labelled with 18F, and (c) one or more chelating groups, optionally containing a chelated nonradioactive or radioactive cation, wherein the one or more chelating groups comprises a hydrophilic chelator, wherein the SIFA moiety and the hydrophilic chelator exhibit a spatial proximity and not more than 20 chemical bonds separate an atom of the SIFA moiety and an atom of the hydrophilic chelator; and wherein the conjugate is formulated for in vivo administration for nuclear diagnostic imaging or targeted radiotherapy of a disease associated with an overexpression of prostate-specific membrane antigen.