Rhenium and technetium complexes containing a hypoxia-localizing moiety
AssigneeBracco International B.V.
InventorsKaren Linder, Adrian D. Nunn, David P. Nowotnik, Kondareddiar Ramalingam, Richard J. DiRocco, William L. Rumsey, John P. Pirro
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Abstract
Novel methods, processes and metal complexes attached to a hypoxia-localizing moiety comprising a metal, preferably radionuclide of rhenium or technetium; a hypoxia-localizing moiety; and, a complexing ligand, wherein said ligand and said radionuclide combined have cell membrane permeabilities greater than that of sucrose, are disclosed.
Claims52
A complex comprising a metal and a ligand, which ligand comprises formula Ia, Ib or Ic:
- wherein at least one R′ is —(A)p—R2 where (A)p is a linking group and R2 is a nitro-heterocyclic hypoxia localizing moiety;
- and wherein the other R′ groups, that are not —(A)p—R2, and the R groups are the same, or different and are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, —COOR3,
- —NH2, hydroxyalkyl, alkoxyalkyl, hydroxyaryl, haloalkyl, arylalkyl, alkyl-COOR3, -alkyl-CON(R3)2, -alkyl-N(R3)2, -aryl-COOR3, -aryl-CON(R3)2, -aryl-N(R3)2, 5- or 6-membered nitrogen- or oxygen-containing heterocycle;
- or two R groups taken together with the one or more atoms to which they are attached form a carbocyclic or heterocyclic, saturated or unsaturated spiro or fused ring which may be substituted with R groups;
- R1 is hydrogen, a thiol protecting group or —(A)p—R2;
- R3 is hydrogen, alkyl or aryl;
- m=2 to 5;
- p=0 to 20.
A complex comprising a metal and a ligand, wherein said ligand comprises formula Ia or Ib:
- where at least one R′ is —(A)p—R2 where (A)p is a linking group and R2 is a nitro-heterocyclic hypoxia localizing moiety;
- and wherein the other R′ groups, that are not —(A)p—R2, and the R groups are the same, or different and are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, —COOR3,
- —NH2, hydroxyalkyl, alkoxyalkyl, hydroxyaryl, haloalkyl, arylalkyl, -alkyl-COOR3, -alkyl-CON(R3)2, -alkyl-N(R3)2, -aryl-COOR3, -aryl-CON(R3)2, -aryl-N)R3)2, 5- or 6-membered nitrogen- or oxygen-containing heterocycle;
- or two R groups taken together with the one or more atoms to which they are attached form a carbocyclic or heterocyclic, saturated or unsaturated spiro or fused ring which may be substituted with R groups;
- R1 is hydrogen, a thiol protecting group or —(A)p—R2;
- R3 is hydrogen, alkyl or aryl;
- m=2 to 5;
- p=0 to 20.
Dependencies are inferred from the claim text.