Metal complexes derivatized with folate for use in diagnostic and therapeutic applications

A diagnostic, therapeutic or radiotherapeutic composition for visualization, therapy or radiotherapy of tissues or organs that overexpress folate-binding protein using nuclear medicine, magnetic resonance imaging or neutron capture radiotherapy applications comprising:

• a) a folate-receptor binding ligand and
• b) a pharmaceutically acceptable carrier wherein said folate-receptor binding ligand has the structure of formula IIb:
• ##STR98## wherein --K.sub.1 is --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R.sub.2).sub.2, -glutamate, or -polyglutamate;
• --K.sub.5 is a polydentate metal chelating ligand;
• M.sub.5 is a radioactive, paramagnetic or superparamagnetic metal;
• each --X-- is independently --O--, --S--, --NH--, or --NR.sub.1 --;
• b5=1 to 3, m5=1;
• n5 is 0 or 1;
• --R.sub.0 is a folate-receptor binding moiety of formula:
• ##STR99## each --[(A)p*]-- is an optional linker independently comprising a straight or branched chain made up of "p*" individual (A) moieties that are the same or different and are selected from the group consisting of:
• --CH.sub.2 --, --CHR.sub.3 --, --CR.sub.4 R.sub.5 --, --CH.dbd.CH--, --CH.dbd.CR.sub.6 --, >CR.sub.7 --CR.sub.8 <, >C.dbd.C<, --CR.sub.9 .dbd.CR.sub.10 --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC.dbd.N--, --CR.sub.11 .dbd.N--, --NR.sub.12 --, --CS--, and ##STR100## and p* is 0 to 24;
• or --X--[(A)]p*-- is, in its entirety, the group --Q-- wherein
• --Q-- is --[C(R')(R'")].sub.s1 --[C(t)(R.sub.21)].sub.s2 --[C(R.sub.22)(R.sub.23)].sub.s3 --X3--Y--X4--;
• wherein
• s1, s2, s3, and s4 are independently 0 to 2;
• X3, X4, X5, and X6 are independently a single bond, --O--, --S--, or --N(R.sub.24)--;
• Y is a single bond, --C(R.sub.25)(R.sub.26)--, or --Y1--
• wherein,
• Y1 is --C(.dbd.X5)--X6--W--, wherein
• W is a single bond, -alkylidene, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;
• t is H, R.sub.27, --C(O)OR.sub.28, --P(O)(OR.sub.29))OH, --P(O)(OR.sub.30))OR.sub.31, --P(O)(OR.sub.32)R.sub.33, --P(O)(OH)R.sub.34 --C(O)N(R.sub.35)(R.sub.36), or C(O)NH(R.sub.37);
• each --R' and --R" is independently a single bond, --H, -alkyl, -alkoxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,
• each --R.sub.3 through --R.sub.5, --R.sub.7, --R.sub.8, --R.sub.21, through --R.sub.23, and --R.sub.25 through --R.sub.27 is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;
• each --R.sub.1, --R.sub.2, --R.sub.6, --R.sub.9 through --R.sub.12, --R.sub.24, and --R.sub.28 through --R.sub.37 is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, or a 5- or 6-membered nitrogen or oxygen containing heterocycle;
• or a pharmaceutically acceptable salt thereof.

The composition for visualization or radiotherapy of tissues or organs that overexpress folate-binding protein using magnetic resonance imaging or neutron capture therapy techniques comprising one or more folate-receptor binding residues conjugated to one or more enhanced relaxivity polyaza macrocyclic radicals which are optionally chelated to a paramagnetic or superparamagnetic metal capable of either being detected outside the body by imaging means for diagnosis or capable of providing a radiotherapeutic effect using neutron capture therapy;

• wherein said folate-receptor binding compound has the structure of formula IIc:
• wherein
• R.sub.0 is a folate-receptor binding moiety of formula:
• ##STR104## each X is independently --O--, --S--, --NH--, or --NR.sub.1 --;
• n1 and n5 are independently 0 or 1;
• b1 and b5 are independently 1 to 3;
• m1 and m5 are independently 1 to 81;
• each --K.sub.1 is independently --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R.sub.2).sub.2, -glutamate, -polyglutamate, or --K.sub.4 ;
• each --K.sub.2 is independently --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R.sub.2).sub.2, -glutamate, -polyglutamate, or --K.sub.3 ;
• --K.sub.3 is ##STR105## M.sub.1 and M.sub.5 are paramagnetic or superparamagnetic metals;
• and --K.sub.4 and --K.sub.5 are each independently enhanced-relaxivity polyaza macrocyclic metal-chelating ligand radicals of formula VI that are optionally chelated to M.sub.1 and M.sub.5 :
• ##STR106## wherein n is 0 or 1;
• each m, o, and p is independently 1 or 2;
• Q is --[C(R')(R")].sub.s1 --[C(t)(R.sub.21)].sub.s2 --[C(R.sub.22)(R.sub.23)].sub.s3 --X3--Y--X4--;
• wherein s1, s2, s3, and s4 are independently 0 to 2;
• X3, X4, X5, and X6 are independently a single bond, --O--, --S--, or --N(R.sub.24)--;
• Y is a single bond, --C(R.sub.25)(R.sub.26)--, or Y1,
• wherein
• Y1 is --C(.dbd.X5)--X6--W--,
• wherein
• W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;
• t is H, R.sub.27, --C(O)OR.sub.28, --P(O)(OR.sub.29))OH, --P(O)(OR.sub.30))OR.sub.31, --P(O)(OR.sub.32)R.sub.33, --P(O)(OH)R.sub.34 --C(O)N(R.sub.35)(R.sub.36), or C(O)NH(R.sub.37);
• each G is independently --C(O)OR'", --P(O)(OR'")OH, --P(O)(OR'").sub.2, --P(O)(OR'")R", --P(O)(OH)R"C(O)N(R'").sub.2, or C(O)NH(R'");
• each R' and R" is independently a single bond, --H, -alkyl, -alkoxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,
• each R'" is independently --H, -alkyl, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,
• each --R.sub.13 through --R.sub.23, and --R.sub.25 through --R.sub.27 is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;
• each --R.sub.24, and --R.sub.28 through --R.sub.37 is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, each of which is optionally substituted;
• or R.sub.13 together with R.sub.15, and R.sub.17 together with R.sub.18, independently form, together with the carbon atoms in the polyazamacrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy, or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or
• R.sub.13 and R.sub.15 are each hydrogen and R.sub.17, together with R.sub.18, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R.sub.13, together with R.sub.15, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R.sub.17 and R.sub.18 are hydrogen;
• --(A)p-- and --(A)p*-- are optional linkers each independently comprising a straight or branched chain made up of moieties that are the same or different and selected from the group consisting of:
• --CH.sub.2 --, --CHR.sub.3 --, --CHR.sub.4 R.sub.5 --, --CH.dbd.CH--, --CH.dbd.CR.sub.6 --, >CR.sub.7 --CR.sub.8 <, --C.dbd.C--, --CR.sub.9 .dbd.CR.sub.10 --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC.dbd.N--, --CR.sub.11 .dbd.N--, --NR.sub.12 --, --CS--, ##STR107## and p and p* are each individually 0 to 24;
• or --X--[(A)p]-- or --X--[(A)p*]-- in its entirety is the group --Q-- as defined above each --R.sub.3 through --R.sub.5, --R.sub.7 and --R.sub.8 is independently --H, -alkyl, -alkenyl, -alkoxy, -aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, halogen, hydroxy or -hydroxyalkyl;
• and
• each --R.sub.1, --R.sub.2, --R.sub.6, --R.sub.12 through --R.sub.12 is independently --H, -alkyl, -alkoxy, -cycloalkyl, -aryl, -heterocyclo, -hydroxy or -hydroxyalkyl;
• or a pharmaceutically acceptable salt thereof.