Polychelants

• US 6,274,713 B1
• Filed: 06/07/1995
• Issued: 08/14/2001
• Est. Priority Date: 04/07/1989
• Status: Expired due to Fees

• Current Assignee: Amersham Health Salutar Incorporated (GE Healthcare Technologies, Inc.)
• Original Assignee: Salutar, Inc. (GE Healthcare Technologies, Inc.)
• Inventors: Quay, Steven C., Watson, Alan David, Rocklage, Scott Michael, Sieving, Paul F.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US08/473,573
• Time in Patent Office: 2,260 Days
• Field of Search: 530/345, 530/391.5, 530/402, 514/12, 514/21, 424/9
• US Class Current: 530/402
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/128 comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
• CPC Class Codes: A61K 49/143 the protein being an albumin, e.g. HSA, BSA, ovalbumin
• CPC Class Codes: A61K 49/146 the peptide being a polyamino acid, e.g. poly-lysine
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: A61K 51/081 the protein being an albumin, e.g. human serum albumin [HSA], bovine serum albumin [BSA], ovalbumin
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: C08G 69/48 Polymers modified by chemical after-treatment

Abstract

Invention is directed to polychelants and their metal chelates which are useful in diagnostic imaging. The polychelants comprise a plurality of macrocyclic chelant moieties, eg. DOTA residues, conjugated by thiourea, urea or glycinamide linkages to a backbone moiety through a donor atom.

Claims

1. A polychelant compound comprising a backbone moiety to which is covalently bonded at least 20 macrocyclic chelant moieties, wherein the backbone moiety contains one or more amino groups;

each macrocyclic chelant moiety is capable of complexing metal ions;

each macrocyclic chelant moiety contains a donor atom; and

each macrocyclic chelant moiety is linked to said backbone moiety via a thiourea, an urea, or a glycinamide linkage bonded to the donor atom;

or a metal chelate or a salt thereof.

2. A compound according to claim 1 of formula I

3. A compound according to claim 2 having a substantially non-crosslinked structure.

4. A compound according to claim 2 wherein n is at least 60.

5. A compound according to claim 2 wherein n is at least 80.

6. A compound according to claim 2 wherein n is at least 100.

7. A compound according to claim 1 wherein at least some of the said chelant moieties are unmetallated.

8. A compound according to claim 1 wherein at least some of said chelant moieties are metallated by metal ions selected from group consisting of the paramagnetic ions of Fe, Mn, Co and the lanthanides.

9. A compound according to claim 1 wherein at least some of said chelant moieties are metallated by metal ions selected from the group consisting of the ions of Hf, W, Bi, Hg, Os, Pb, Zr and the lanthanides.

10. A compound according to claim 1 wherein at least some of said chelant moieties are metallated by metal ions selected from the group of the ions of ¹¹¹In, ^99mTc, ⁸⁸Y, ¹⁸⁶Re, and ²⁰³Pb.

11. A compound according to claim 1 wherein at least some of said chelant moieties are metallated by metal ions selected from the group of the ions of ¹⁸⁶Re, ¹⁸⁸Re, ⁹⁰Y, ⁶⁴Cu, ⁶⁷Cu, ⁶⁸Ga, ^211-214Bi, and ¹⁵³Sm.

12. A compound according to claim 1 wherein said backbone moiety is a backbone polymer containing a plurality of primary amine groups.

13. A compound according to claim 12 wherein said backbone moiety is a polymer selected from the group consisting of a polypeptide, a polyallylamine, a poly[N(2-aminoethyl)]methacryllamide, a starburst dendrimer, and a polyaminocarbohydrate.

14. A compound according to claim 1 wherein said macrocyclic chelant moieties are macrocyclic chelants of formula III

where a, b, d and e are independently zero or a positive integer;

c and f are positive integers, the product of c and f being at least 3;

the sum of b+d is at least 1;

each Z is independently a nitrogen, oxygen, sulphur, phosphorus, boron or arsenic;

each Y is independently an optionally substituted 5 to 7 membered carbocyclic or heterocyclic ring;

R¹ where present is independently hydrogen, optionally hydroxylated, optionally alkoxylated alkyl optionally carrying a group CO—

G where G is OR² or NR²₂ on where Z is phosphorus, oxo;

R¹ and R³ which may be the same or different each independently is hydrogen, optionally alkoxylated, optionally hydroxylated alkyl, aryl, alkaryl or aralkyl or R³ may also represent or be substituted by a group CO—

G; and

NR²₂ may also represent a nitrogen-attached optionally substituted 5 to 7 membered heterocyclic ring optionally containing a further nitrogen, oxygen or sulphur ring heteroatom; and

where in place of two CR²R³ groups, separated in either direction by at least one Z group, there may optionally be a bridging structure of formula

where u, g, h, i, j, k, l, m, n, q, r, s and t is each independently zero or a positive integer;

p is a positive integer;

h+l+j+n≧

1; and

each D is independently boron, carbon, nitrogen or phosphorous or PO.

15. A compound according to claim 1 wherein said macrocyclic chelants are selected from the group consisting of polyazacycloalkanepolycarboxylates, derivatized crown ethers, derivated hexaazamacrocycles (HAMs), and derivatized cryptates including sepulchrates and sarcophagines.

16. A compound according to claim 1 wherein said macrocyclic chelants are selected from the group consisting of 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (OTTA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl) amide and DOTA-N(2-aminophenethyl) amide.

17. A compound comprising at least one polychelant compound according to claim 1, wherein the backbone moiety of said polychelant compound is conjugated to a macromolecule, or a chelate or salt thereof.

18. A compound comprising a site-directed macromolecule capable of travelling to or binding specifically to a targeted cell or cells, tissue, organ, or other location in a mammalian body having conjugated thereto 1, 2, 3 or 4 said macrocyclic chelant moiety carrying backbone moieties recited in any one of claims 1 to 16, or a chelate or salt thereof.

19. A compound according to claim 17 wherein said macromolecule is selected from the group consisting of an antibody, a polymerized fibrin fragment, a serum amyloid precursor protein, a low density lipoprotein precursor, a serum albumin, a surface protein of intact red blood cells, a liver-specific macromolecule, a receptor binding protein and a fibrinogen.

20. A compound according to claim 19 wherein said macromolecule is a monoclonal antibody specific for a desired antigen.

21. A compound according to claim 19 wherein said macromolecule is bound to said backbone moieties by heterobifunctional linking agents bonded via reactive linking groups selected from the group consisting of amide, maleamide, disulfide, thiourea, isothiocyanate, and ester.