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

• US 6,093,382 A
• Filed: 05/16/1998
• Issued: 07/25/2000
• Est. Priority Date: 05/16/1998
• Status: Expired due to Term

• Current Assignee: Bracco Suisse SA
• Original Assignee: Bracco Research USA Inc (Bracco U.S.A., Inc)
• Inventors: Raju, Natarajan, Linder, Karen E., Tweedle, Michael F., Nunn, Adrian D., Ramalingam, Kondareddiar, Wager, Ruth E., Ranganathan, Ramachandran S., Arunachalam, Thangavel, Wedeking, Paul W.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/080,157
• Time in Patent Office: 801 Days
• Field of Search: 534/7, 534/10-16, 424/1.11, 424/1.65, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/1.69, 530/400, 530/403, 435/7.1
• US Class Current: 424/1.65
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/122 dimers of complexes or complex-forming compounds
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 49/146 the peptide being a polyamino acid, e.g. poly-lysine
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Diagnostic and therapeutic compositions in the form of complexes for enhancing transmembrane transport of a diagnostic or therapeutic agent and methods for their use. The complexes contain the α, γ, or bis isomers of folate receptor-binding analogs of folate, a metal chelated by a ligand, and in one embodiment, a chemotherapeutic agent.

Claims

1. A diagnostic, therapeutic or radiotherapeutic or chemotherapeutic composition for visualization, therapy, chemotherapy or radiotherapy of tissues or organs that overexpress folate-binding protein comprising:

a) a folate-receptor binding ligand comprising one or more folate-receptor binding moieties, at least one of which is conjugated through its alpha carboxylate via a linking group to one or more macrocyclic or non-macrocyclic metal-chelating ligand radicals that are chelated to paramagnetic, superparamagnetic, radioactive or non-radioactive metals for detection outside the body by imaging means for diagnosis or for providing a therapeutic, chemotherapeutic, or radiotherapeutic effect; and

b) a pharmaceutically acceptable carrier.

2. The diagnostic, therapeutic or radiotherapeutic composition of claim 1 wherein said folate receptor binding ligand has the structure of formula II:

##STR81## wherein R₀ is a folate-receptor binding moiety of formula;

##STR82## each X is independently --O--, --S--, --NH--, or --NR₁ --;

n1 is 0 or 1;

b1 is 1 to 3;

m1 is 1 to 81;

each K₁ is independently

a) a macrocyclic or non-macrocyclic metal-chelating ligand radical that is optionally chelated to a paramagnetic, superparamagnetic, radioactive or non-radioactive metal M₁, or

b) a chemotherapeutic drug;

--K₂ is --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, -polyglutamate, or --K₃ ;

--K₃ is ##STR83## wherein --K₅ is either

a) a macrocyclic or non-macrocyclic metal-chelating ligand that is optionally chelated to a paramagnetic, superparamagnetic, radioactive or non-radioactive metal M₅, or

b) a chemotherapeutic drug

n5 is 0 or 1;

b5 is 1 to 3;

m5 is 1 to 81;

--(A)p-- and --(A)p*-- are each independently optional linkers comprising a straight or branched chain wherein the moieties "A" are the same or different and selected from the group consisting of;

--CH₂ --, --CHR₃ --, --CR₄ R₅ --, --CH═

CH--, --CH═

CR₆ --, >

CR₇ --CR₈ <

, --C═

C--, --CR₉ ═

CR₁₀ --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC═

N--, --CR₁₁ ═

N--, --NR₁₂ --, --CS--, ##STR84## and p and p* are independently 0 to 24, or --X--[(A)]p-- and --X--[(A)p]*-- may each independently be the group --Q-- wherein --Q-- is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_s3 --X3--Y--X4--;

wherein

each s1, s2, s3, and s4 is independently 0 to 2;

each X3, X4, X5, and X6 is independently a single bond, --O--, --S--, or --N(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1 wherein,

Y1 is --C(═

X5)--X6--W--, wherein

W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms may or may not be substituted;

t is H, R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄, --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each R'"'"' and R" is independently a single bond, H, alkyl, alkoxy, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted,

each R₃ through R₅, R₇, R₈, R₂₁ through R₂₃, and R₂₅ through R₂₇ is independently H, alkyl, alkoxy, halogen, hydroxy, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted;

each R₁, R₂, R₆, R₉ through R₁₂, R₂₄, and R₂₈ through R₃₇ is independently H, alkyl, alkenyl, cycloalkyl, aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle;

or a pharmaceutically acceptable salt thereof.

3. The composition of claim 2 for use in nuclear medicine or magnetic resonance imaging applications wherein K₁ of the compounds of formula II is a macrocyclic or non-macrocyclic metal-chelating ligand that is optionally chelated to a paramagnetic, superparamagnetic, radioactive or non-radioactive metal M₁, and K₂ is other than K₃.

4. The diagnostic, therapeutic, or radiotherapeutic composition of claim 2 wherein said folate-receptor binding ligand has the structure:

##STR85##

5. The diagnostic, therapeutic, or radiotherapeutic composition of claim 2 wherein said folate-receptor binding ligand has the structure:

6. The diagnostic, therapeutic, or radiotherapeutic composition of claim 2 wherein said folate-receptor binding ligand, 12-N-(N-Pteroyl-(α

)-L-glutamyl)-3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecanedione dioxime has the structure;

7. The diagnostic, therapeutic, or radiotherapeutic composition of claim 2 wherein said folate-receptor binding ligand, Technetium oxo-12-N-(N-Pteroyl-(α

)-L-glutamyl)-3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecanedione dioxime has the structure;

8. The composition of claim 2 wherein b1=1 to 3;

m1=1;

K₂ is other than K₃ ; and

K₁ is a metal chelating ligand radical of formula IIIa-IIIc;

##STR86## wherein Q is the group --(C(RR))_m1 --Y¹ (C(RR))_m2 --(Y² --(C(RR))_m3)_n --,

wherein

Y¹ and Y² are independently --CH₂ --, --NR--, --O--, --S--, --SO--, --SO₂ -- or --Se--;

n is 0 or 1; and

m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;

all R and R* groups are independently --R², --Cl, --F, --Br, --OR², --COOR², --CON(R²)₂, --N(R²)₂, -alkyl--COOR², -alkyl--C(O)--N(R²)₂ ;

-alkyl--N(R²)₂ ;

--C(O)--OR² ;

--C(O)--N(R²)₂ ;

-aryl--N(R²)₂ ;

acyl;

acyloxy;

heterocyclo;

hydroxyalkyl;

--SO₂ --R² ;

-alkyl--SO₂ --R² ;

or --R³, wherein --R³ is a folate-receptor binding residue of formula IV;

or

two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups R or R* groups above,

with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom; and

that one to three of R or R* is, or contains a folate-receptor binding radical --R³ of formula IV;

##STR87## wherein R₀ is a folate-receptor binding moiety of formula;

##STR88## each X is independently --O--, --S--, --NH-- or --N(R₂)--;

K₂ is --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, or -polyglutamate;

--(A)p-- is an optional linker comprising a straight or branched chain wherein the moieties "A" are the same or different and selected from the group consisting of;

--CH₂ --, --CHR₃ --, --CR₄ R₅ --, --CH═

CH--, --CH═

CR₆ --, >

CR₇ --CR₈ <

, >

C═

C<

, --CR₉ ═

CR₁₀ --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC═

N--, --CR₁₁ ═

N--, --NR₁₂ --, --CS--, ##STR89## and p and p* are independently 0 to 24,

R¹ is hydrogen, a thiol protecting group, or the group --R³ defined above;

R₂ is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, aryl, or arylalkyl;

R₃ through R₈ are independently hydrogen, alkyl, alkoxy, hydroxy, or aryl;

R² and R⁹ through R₁₂ are independently hydrogen, alkyl, or aryl;

or a pharmaceutically acceptable salt thereof.

9. The composition of claim 2 wherein

b1=1 to 3;

m1=1;

K₂ is other than K₃ ; and

K₁ is a metal chelating ligand radical of formula V;

##STR90## wherein Q is the group --(C(RR))_m1 --(Y¹)_n --(C(RR))_m2 --(Y² --(C(RR))_m3)_n1 ;

Y¹ and Y² are each independently --CH₂ --, --NR--, --O--, --S--, --SO--, --SO₂ -- or --Se--;

n and n1 are each independently 0 or 1; and

m1, m2 and m3 are independently 0 or an integer from 1 to 4;

provided that m1 and m2 are not both 0, that m1+m2+n+n1 is less than 6 and that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;

each R and R* group is independently;

R¹, -alkoxy, -hydroxy, -halogen, especially fluoro, -haloalkyl, --OR¹, --C(O)--R¹, --C(O)--N(R¹)², --N(R¹)², --N(R¹)--COR¹, -alkyl--C(O)--OR¹, -alkyl--C(O)--N(R¹)₂, -alkyl--N(R¹)₂ --, -alkyl--N(R¹)--COR¹, -aryl--C(O)--OR¹, -aryl--C(O)--N(R¹)₂, aryl--N(R¹)₂ --, -aryl--N(R¹)--COR¹, -nitrile, -acyl, -acyloxy, -heterocyclo, -hydroxyalkyl, alkoxyalkyl, hydroxyaryl, arylalkyl, --SO₂ --R¹, -alkyl--SO₂ --R¹, or --R³, wherein --R³ is a folate-receptor binding residue of formula IV;

or

two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups R or R* groups above;

each R¹ is independently hydrogen, alkyl, alkenyl, alkynyl or aryl; and

each G¹ and G² is each independently --OH or --(NR²)² ;

with the proviso that at least one of G¹ or G² is --(NR²)₂, where each R² is independently hydrogen, alkyl, aryl, acyl or --R³ ;

and one to three of R, R*, or R² is, or contains a folate-receptor binding radical --R³ of formula IV;

##STR91## wherein R₀ is a folate-receptor binding moiety of formula;

##STR92## each X is independently --O--, --S--, --NH-- or --N(R₂)--;

K₂ is --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, or -polyglutamate;

wherein R₂ is independently hydrogen, alkyl, or aryl;

A is a linking group as defined in claim 1; and

p is 0 to 24;

or a salt thereof.

10. The composition of claim 2 wherein

b₁ is 1;

m1=1;

--K₂ is other than --K₃ ;

--X--[(A)p]-- is, in its entirety, the group --Q-- as defined below;

--K₁ is a macrocyclic ligand radical of formula VI;

##STR93## wherein n is 0 or 1;

each m, o, and p is independently 1 or 2;

--Q-- is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_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(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1, wherein

Y¹ is --C(═

X5)--X6--W--, wherein

W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is H, R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each G is independently --C(O)OR'"'"'", --P(O)(OR'"'"'")OH, --P(O)(OR'"'"'")₂, --P(O)(OR'"'"'")R", --P(O)(OH)R"C(O)N(R'"'"'")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 a H, alkyl, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted,

each R₁₃ through R₂₃, and R₂₅ through R₂₇ is independently H, alkyl, alkoxy, halogen, hydroxy, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted;

each R₂₄, and R₂₈ through R₃₇ is independently H, alkyl, alkenyl, cycloalkyl, aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, each of which is optionally substituted;

or R₁₃ together with R₁₅, and R₁₇ together with R₁₈, 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 R₁₃ and R₁₅ are each hydrogen and R₁₇, together with R₁₈, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R₁₃, together with R₁₅, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R₁₇ and R₁₈ are hydrogen;

or a pharmaceutically acceptable salt thereof.

11. The composition of claim 2 wherein

--K₂ is ##STR94## and both --K₁ and --K₅ are macrocyclic or non-macrocyclic metal chelates that are each optionally chelated to radioactive, nonradioactive, paramagnetic or superparamagnetic metals M₁ or M₅.

12. The composition of claim 11 for use in nuclear medicine or magnetic resonance imaging applications comprising a folate-receptor binding ligand of formula IIa:

##STR95## wherein b1 and b5=1;

m1 and m5=1;

M₁ and M₅ are independently paramagnetic, superparamagnetic or radioactive metals;

n1 and n2 are independently=0 or 1;

X is --O--, --S--, or --NR² --;

--R² is -hydrogen, -alkyl, -cycloalkyl, -hydroxyalkyl, -aryl, or -arylalkyl;

--[(A)p]-- and --[(A)p*]-- are optional linking groups;

R₀ is a folate-receptor binding moiety of formula;

##STR96## and K₁ and K₅ are metal chelating ligand radicals.

13. The composition of claim 11 wherein said folate receptor binding ligand has the structure:

##STR97##

14. The composition of claim 11 comprising the folate receptor binding ligand Bis (Gd-DO3A-APA)-folate having the structure:

15. The composition of claim 11 wherein both --X--[(A)p]--K₁ and --X--[(A)p*]--K₅ are each in their entirety, macrocyclic ligand radicals of formula VI:

wherein

n is 0 or 1;

each m, o, and p is independently 1 or 2;

Q is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_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(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1;

wherein

Y1 is --C(═

X5)--X6--W--, wherein

W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is --H, --R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each G is independently --C(O)OR'"'"'", --P(O)(OR'"'"'")OH, --P(O)(OR'"'"'")₂, --P(O)(OR'"'"'")R", --P(O)(OH)R"C(O)N(R'"'"'")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 a H, alkyl, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted,

each R₁₃ through R₂₃, and R₂₅ through R₂₇ is independently H, alkyl, alkoxy, halogen, hydroxy, cycloalkyl, hydroxyalkyl, aryl, or heterocyclo, each of which is optionally substituted;

each R₂₄, and R₂₈ through R₃₇ is independently H, alkyl, alkenyl, cycloalkyl, aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, each of which is optionally substituted;

or R₁₃ together with R₁₅, and R₁₇ together with R₁₈, independently form, together with the carbon atoms in the poly-aza macrocycle 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 R₁₃ and R₁₅ are each hydrogen and R₁₇, together with R₁₈, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R₁₃, together with R₁₅, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R₁₇ and R₁₈ are hydrogen;

or a pharmaceutically acceptable salt thereof.

24. The diagnostic or radiotherapeutic composition of formula II of claim 2, wherein K₁ is chelated to a radioactive, paramagnetic or superparamagnetic metal and K₂ is other than --K₃.

25. The radiodiagnostic or radiotherapeutic composition of claim 2 wherein both K₁ and K₅ of formula II are metal-chelating ligand radicals that are chelated to a radioactive metal.

26. The diagnostic composition of claim 2 for visualization of tissues that overexpress folate binding protein using Nuclear Medicine imaging techniques, wherein either K₁, or both K₁ and K₅ is chelated to a radioisotope of technetium, indium, copper, ruthenium, gallium or gadolinium.

27. The diagnostic composition of claim 2 for visualization of tissues that overexpress folate binding protein using magnetic resonance imaging, wherein either K₁, or both K₁ and K₅ is chelated to a paramagnetic or superparamagnetic metal.

28. The diagnostic composition of claim 2 for visualization of tissues that overexpress folate binding protein using magnetic resonance imaging, wherein either K₁, or both K₁ and K₅ is chelated to gadolinum.

29. The diagnostic composition of claim 2 for use in Magnetic Resonance imaging applications, wherein said paramagnetic metal is selected from the group consisting of:

chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and ytterbium (III).

30. The diagnostic composition of claim 2, for visualization of tissues that overexpress folate binding protein using magnetic resonance imaging, wherein K₁ is chelated to gadolinium.

31. The radiodiagnostic or radiotherapuetic composition of claim 2 wherein either K₁, or both K₁ and K₅ is a metal-chelating ligand radical of formula IIIa, IIIb, IIIc, that can chelate to a radioactive isotopes, ##STR108## wherein Q is the group --(C(RR))_m1 --Y¹ (C(RR))_m2 --(Y--(C(RR))_m3)_n --,

wherein

Y¹ and Y² are independently --CH₂ --, --NR--, --O--, --S--, --SO--, --SO₂ -- or --Se--;

n is 0 or 1; and

m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;

all R and R* groups are independently --R⁴, --Cl, --F, --Br, --OR⁵, --COOR⁵, --CON(R⁵)₂, --N(R⁵)₂, -alkyl-COOR⁵, -alkyl--C(O)--N(R⁵)₂, -alkyl--N(R⁵)₂, --C(O)OR⁵, --C(O)N(R⁵)₂, -aryl--N(R⁵)₂, acyl, acyloxy, heterocyclo, hydroxyalkyl, --SO₂ --R⁵, -alkyl--SO₂ --R⁵, or --[R³ ]--;

wherein --[R³ ]-- is a linking group --[(A)p]-- that couples the metal chelating radical of formula IIIa, IIIb, or IIIc to the remainder of the molecule;

--[(A)p]-- comprises a straight or branched chain of individual moieties that are the same or different and selected from the group consisting of;

--CH₂ --, --CHR₃ --, --CR₄ R₅ --, --CH═

CH--, --CH═

CR₆ --, >

CR₇ --CR₈ <

, --C═

C--, --CR₉ ═

CR₁₀ --, --C--C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl --(CO)--, --O--, --S--, --NH--, --HC.tbd.N--, --CR₁₁ ═

N--, --NR₁₂, --CS--, ##STR109## and p is an integer from 0 to 24;

each --R⁴ and --R₃ through --R₅ is independently --H, -alkyl, -alkoxy, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;

each --R⁵ and --R₆ through --R₁₂ is independently --H, -alkyl, -aryl, -cycloalkyl or -hydroxyalkyl, each of which is independently substituted;

with the provisos that a carbon atom bearing an --R group is not directly bonded to more than one heteroatom; and

that at least one --R or --R* group on the metal chelating radical --K₁ of formulae IIIa, IIIb, or IIIc is --[R³ ]--;

or a pharmaceutically acceptable salt thereof.

32. The diagnostic composition of claim 28, wherein either K₁, or both K₁ and K₅ is a metal-chelating ligand radical of formula VI, that is chelated to a paramagnetic or superparamagnetic metal ##STR110## wherein n is 0 or 1;

each m, o, and p is independently 1 or 2;

Q is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_s3 --X3--Y--X4--;

wherein

s1, s2, s3, and s4 are independently 0 to 2;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1 wherein,

Y1 is --C(═

X5)--X6--W--, wherein

W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is H, R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each G is independently --C(O)OR'"'"'", --P(O)(OR'"'"'")OH, --P(O)(OR'"'"'")₂, --P(O)(OR'"'"'")R", --P(O)(OH)R"C(O)N(R'"'"'")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 a --H, -alkyl, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,

each --R₁₃ through --R₂₃, and --R₂₅ through --R₂₇ is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, aryl, or -heterocyclo, each of which is optionally substituted;

each --R₂₄, and --R₂₈ through --R₃₇ is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, each of which is optionally substituted;

or R₁₃ together with R₁₅, and R₁₇ together with R₁₈, 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 R₁₃ and R₁₅ are each hydrogen and R₁₇, together with R₁₈, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R₁₃, together with R₁₅, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R₁₇ and R₁₈ are hydrogen;

or a pharmaceutically acceptable salt thereof.

33. A composition for radiographic imaging or radiotherapy in a kit form comprising

a) a ligand of formula II in claim 2;

b) a pharmaceutically acceptable reducing agent; and

c) an optional buffering agent;

in a lyophilized form.

34. A composition for radiographic imaging or radiotherapy in a kit form comprising

a) a folate receptor binding ligand of formula II in claim 2;

b) a pharmaceutically acceptable reducing agent; and

c) an optional buffering agent;

in a lyophilized form.

35. A composition of claim 1 for radiographic imaging or radiotherapy in a kit form comprising

a) a folate receptor-binding ligand of folate coupled through either the alpha carboxylate of folic acid or through both the alpha and gamma carboxylates of folic acid to;

b) a metal chelating ligand for complexation with a radioisotope;

c) a pharmaceutically acceptable reducing agent; and

d) a buffering agent;

in a lyophilized form.

16. 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 --K₁ is --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, or -polyglutamate;

--K₅ is a polydentate metal chelating ligand;

M₅ is a radioactive, paramagnetic or superparamagnetic metal;

each --X-- is independently --O--, --S--, --NH--, or --NR₁ --;

b5=1 to 3, m5=1;

n5 is 0 or 1;

--R₀ 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;

--CH₂ --, --CHR₃ --, --CR₄ R₅ --, --CH═

CH--, --CH═

CR₆ --, >

CR₇ --CR₈ <

, >

C═

C<

, --CR₉ ═

CR₁₀ --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC═

N--, --CR₁₁ ═

N--, --NR₁₂ --, --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'"'"'")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_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(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or --Y1--

wherein,

Y1 is --C(═

X5)--X6--W--, wherein

W is a single bond, -alkylidene, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is H, R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each --R'"'"' and --R" is independently a single bond, --H, -alkyl, -alkoxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,

each --R₃ through --R₅, --R₇, --R₈, --R₂₁, through --R₂₃, and --R₂₅ through --R₂₇ is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;

each --R₁, --R₂, --R₆, --R₉ through --R₁₂, --R₂₄, and --R₂₈ through --R₃₇ is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, or a 5- or 6-membered nitrogen or oxygen containing heterocycle;

or a pharmaceutically acceptable salt thereof.

17. The composition of claim 16 wherein M₅ is a paramagnetic or superparamagnetic metal and --K₅ is an enhanced relaxivity polyaza macrocyclic radical of formula VI:

##STR101## wherein n is 0 or 1;

each m, o, and p is independently 1 or 2;

--Q-- is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_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(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1

wherein Y1 is --C(═

X5)--X6--W--,

wherein W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, -alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is --H, --R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each G is independently --C(O)OR'"'"'", --P(O)(OR'"'"'")OH, --P(O)(OR'"'"'")₂, --P(O)(OR")R'"'"'", --P(O)(OH)R"C(O)N(R'"'"'")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 a --H, -alkyl, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted,

each --R₁₃ through --R₂₃, and R₂₅ through --R27 is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;

each --R₂₄, and --R₂₈ through --R₃₇ is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, or a 5- or 6-membered nitrogen or oxygen containing -heterocycle, each of which is optionally substituted;

or R₁₃ together with R₁₅, and R₁₇ together with R₁₈, independently form, together with the carbon atoms in the poly-aza macrocycle 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 R₁₃ and R₁₅ are each hydrogen and R₁₇, together with R₁₈, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R₁₃, together with R₁₅, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R₁₇ and R₁₈ are hydrogen;

or a pharmaceutically acceptable salt thereof.

18. The compositions of claim 16 wherein --K₅ is a metal chelating polydentate ligand radical of formula IIIa-IIIc:

##STR102## wherein Q is the group --(C(RR))_m1 --Y¹ (C(RR))_m2 --(Y² --(C(RR))_m3)_n --,

wherein

Y¹ and Y² are independently --CH₂ --, --NR--, --O--, --S--, --SO--, --SO2-- or --Se--;

n is 0 or 1; and

m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;

all R and R* groups are independently --R⁴, --Cl, --F, --Br, --OR⁵, --COOR₅, --CON(R⁵)₂, --N(R⁵)₂, -alkyl-COOR⁵, -alkyl-C(O)-N(⁵)₂, -alkyl-N(R⁵)₂, --C(O)OR⁵, --C(O)N(R⁵)₂, -aryl--N(R⁵)₂, acyl, acyloxy, heterocyclo, hydroxyalkyl, --SO2-R⁵, -alkyl--SO₂ --R⁵, or --[R³ ]--;

wherein each --[R³ ]-- is, in its entirety, the linking group --[(A)p*]-- that serves to couple the metal chelating ligand radical --M₅ to --X--;

each --R⁴ is independently --H, -alkyl, -alkoxy, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;

each --R⁵ is independently --H, -alkyl, -aryl, -cycloalkyl or -hydroxyalkyl, each of which is independently substituted;

with the provisos that a carbon atom bearing an -R group is not directly bonded to more than one heteroatom; and

that one to three R or R* groups on --K₅ is --[R³ ]--;

or a pharmaceutically acceptable salt thereof.

19. The composition of claim 16 wherein said folate-receptor binding ligand, N-Pteroyl-γ

-glutamyl-APADO3A, has the structure;

##STR103##20.

20. The composition of claim 16 containing the folate-receptor binding ligand Gd-DO3A-APA-(γ

)-folate, having the structure;

21. The composition of claim 16 containing the folate-receptor binding ligand 12-N-(N-Pteroyl-γ

-L-glutamyl)-3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecanedione dioxime, having the structure;

22. The composition of claim 16 containing the folate-receptor binding ligand Technetium oxo 12-N-(N-Pteroyl-γ

-L-glutamyl)-3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecanedione dioxime, having the structure;

36. The diagnostic composition of claim 16 for visualization of tissues that overexpress folate binding protein using magnetic resonance imaging, wherein K₅ is chelated to gadolinium.

23. 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

R₀ is a folate-receptor binding moiety of formula;

##STR104## each X is independently --O--, --S--, --NH--, or --NR₁ --;

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 --K₁ is independently --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, -polyglutamate, or --K₄ ;

each --K₂ is independently --H, -alkyl, -alkenyl, -alkynyl, -alkoxy, -aryl, -alkyl, --CON(R₂)₂, -glutamate, -polyglutamate, or --K₃ ;

--K₃ is ##STR105## M₁ and M₅ are paramagnetic or superparamagnetic metals; and

--K₄ and --K₅ are each independently enhanced-relaxivity polyaza macrocyclic metal-chelating ligand radicals of formula VI that are optionally chelated to M₁ and M₅ ;

##STR106## wherein n is 0 or 1;

each m, o, and p is independently 1 or 2;

Q is --[C(R'"'"')(R")]_s1 --[C(t)(R₂₁)]_s2 --[C(R₂₂)(R₂₃)]_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(R₂₄)--;

Y is a single bond, --C(R₂₅)(R₂₆)--, or Y1,

wherein

Y1 is --C(═

X5)--X6--W--,

wherein

W is a single bond, -alkylidene-, -cycloalkylidene-, -arylidene-, alkenylidene-, or -alkynylidene-, whose carbon atoms are optionally substituted;

t is H, R₂₇, --C(O)OR₂₈, --P(O)(OR₂₉))OH, --P(O)(OR₃₀))OR₃₁, --P(O)(OR₃₂)R₃₃, --P(O)(OH)R₃₄ --C(O)N(R₃₅)(R₃₆), or C(O)NH(R₃₇);

each G is independently --C(O)OR'"'"'", --P(O)(OR'"'"'")OH, --P(O)(OR'"'"'")₂, --P(O)(OR'"'"'")R", --P(O)(OH)R"C(O)N(R'"'"'")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 --R₁₃ through --R₂₃, and --R₂₅ through --R₂₇ is independently --H, -alkyl, -alkoxy, -halogen, -hydroxy, -cycloalkyl, -hydroxyalkyl, -aryl, or -heterocyclo, each of which is optionally substituted;

each --R₂₄, and --R₂₈ through --R₃₇ is independently --H, -alkyl, -alkenyl, -cycloalkyl, -aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, each of which is optionally substituted;

or R₁₃ together with R₁₅, and R₁₇ together with R₁₈, 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

R₁₃ and R₁₅ are each hydrogen and R₁₇, together with R₁₈, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R₁₃, together with R₁₅, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, and R₁₇ and R₁₈ 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;

--CH₂ --, --CHR₃ --, --CHR₄ R₅ --, --CH═

CH--, --CH═

CR₆ --, >

CR₇ --CR₈ <

, --C═

C--, --CR₉ ═

CR₁₀ --, --C.tbd.C--, -cycloalkylidene-, -cycloalkenyl-, -arylidene-, -heterocyclo-, carbonyl (--CO--), --O--, --S--, --NH--, --HC═

N--, --CR₁₁ ═

N--, --NR₁₂ --, --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 --R₃ through --R₅, --R₇ and --R₈ is independently --H, -alkyl, -alkenyl, -alkoxy, -aryl, a 5- or 6-membered nitrogen or oxygen containing heterocycle, halogen, hydroxy or -hydroxyalkyl; and

each --R₁, --R₂, --R₆, --R₁₂ through --R₁₂ is independently --H, -alkyl, -alkoxy, -cycloalkyl, -aryl, -heterocyclo, -hydroxy or -hydroxyalkyl;

or a pharmaceutically acceptable salt thereof.