Linkers For Radiopharmaceutical Compounds

Abstract

A new and improved method for extending the half life of pharmaceutical compounds for use in diagnostic imaging or therapy uses a novel linker to attach a diagnostic or therapeutic moiety to a targeting peptide or another diagnostic or therapeutic moiety. The resulting compound may have the general formula M-N—O—P-Q, wherein M is the diagnostic or therapeutic moiety, N—O—P is the linker of the present invention, and Q is the targeting peptide. In another embodiment the compounds may have the formula M-N—O—P-M, wherein M is independently a diagnostic or therapeutic moiety and N—O—P is the linker of the invention. Methods for imaging or treating a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound are further provided. Methods for radiotherapy of a patient using the compounds are further provided, as are methods for preparing a radiotherapeutic agent from the compounds.

1 . A compound of the general formula:
   M-N—O—P-Q
   wherein
 M is a diagnostic moiety; 
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group; and 
 Q is a targeting moiety, and 
   wherein at least one of N, O or P is a substituted bile acid.   
     
     
         2 . The compound of  claim 1 , wherein the targeting moiety is attached to an amino group of the substituted bile acid or a carboxyl group of substituted bile acid. 
     
     
         3 . The compound of  claim 1 , wherein the targeting moiety is attached to an amino group of the substituted bile acid. 
     
     
         4 . The compound of  claim 1 , wherein the targeting moiety is attached to a carboxyl group of the substituted bile acid. 
     
     
         5 . The compound of  claim 1 , wherein the diagnostic moiety is attached to an amino group of the substituted bile acid and the targeting moiety is attached to a carboxyl group of the substituted bile acid. 
     
     
         6 . The compound of  claim 1 , wherein the diagnostic moiety is attached to a carboxyl group of the substituted bile acid and the targeting moiety is attached to an amino group of the substituted bile acid. 
     
     
         7 . The compound of  claim 1 , wherein the diagnostic moiety is attached to an amino group of the substituted bile acid and the targeting moiety is attached to said amino group of the substituted bile acid. 
     
     
         8 . A compound of any of  claims 1 - 7 , wherein M is selected from the group consisting of an x-ray imaging agent, a magnetic resonance imaging agent, an ultrasound imaging agent, a fluorescent agent, a radionuclide imaging agent and an optical imaging agent. 
     
     
         9 . A compound of any of  claim 1 , wherein M is an optical imaging agent. 
     
     
         10 . A compound of the general formula:
   M-N—O—P-Q
   wherein
 M is a therapeutic moiety; 
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group; and 
 Q is a targeting moiety, and 
   wherein at least one of N, O or P is a substituted bile acid.   
     
     
         11 . The compound of  claim 10 , wherein the targeting moiety is attached to an amino group of the substituted bile acid or a carboxyl group of the substituted bile acid. 
     
     
         12 . The compound of  claim 10 , wherein the targeting moiety is attached to an amino group of the substituted bile acid. 
     
     
         13 . The compound of  claim 10 , wherein the targeting moiety is attached to a carboxyl group of the substituted bile acid. 
     
     
         14 . The compound of  claim 10 , wherein the therapeutic moiety is attached to an amino group of the substituted bile acid and the targeting moiety is attached to a carboxyl group of the substituted bile acid. 
     
     
         15 . The compound of  claim 10 , wherein the therapeutic moiety is attached to a carboxyl group of the substituted bile acid and the targeting moiety is attached to an amino group of the substituted bile acid. 
     
     
         16 . The compound of  claim 10 , wherein the therapeutic moiety is attached to an amino group of the substituted bile acid and the targeting moiety is attached to said amino group of the substituted bile acid. 
     
     
         17 . A compound of any of  claims 10 - 16 , wherein M is selected from the group consisting of radiotherapeutic agents, phototherapeutic agents, antibiotics, hormones, enzymes, antibodies, and growth factors. 
     
     
         18 . A compound of  claim 17 , wherein M is insulin. 
     
     
         19 . A compound of the general formula:
   M-N—O—P-M
   wherein
 each M is independently a diagnostic or therapeutic moiety; 
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group; and 
   wherein at least one of N, O or P is a substituted bile acid.   
     
     
         20 . The compound of  claim 19 , wherein one M is attached to an amino group of the substituted bile acid and the second M is attached to a carboxyl group of the substituted bile acid. 
     
     
         21 . The compound of  claim 19 , wherein the first M is attached to an amino group of the substituted bile acid and the second M is attached to said amino group of the substituted bile acid. 
     
     
         22 . The compound of  claim 19 , wherein the first M and the second M are the same or different. 
     
     
         23 . The compound of  claim 19 , wherein the first M and the second M are the same. 
     
     
         24 . The compound of  claim 19 , wherein the first M and the second M are different. 
     
     
         25 . A method for improving the half life of a pharmaceutical compound comprising the step of using a linker having the formula N—O—P to attach a diagnostic moiety, therapeutic moiety, metal chelator or a radioactive halogen to a targeting peptide,
 wherein
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group, 
 
 wherein at least one of N, O or P is a substituted bile acid. 
 
     
     
         26 . The method of  claim 25 , wherein the substituted bile acid is selected from the group consisting of:
 (3β,5β)-3-aminocholan-24-oic acid;   (3β,5β,12α)-3-amino-12-hydroxycholan-24-oic acid;   (3β,5β,7β,12α)-3-amino-7,12-dihydroxycholan-24-oic acid;   Lys-(3,6,9)-trioxaundecane-1,11-dicarbonyl-3,7-dideoxy-3-aminocholic acid);   (3β,5β,7α)-3-amino-7-hydroxy-12-oxocholan-24-oic acid; and   (3β,5β,7α)-3-amino-7-hydroxycholan-24-oic acid.   
     
     
         27 - 34 . (canceled) 
     
     
         35 . A compound of  claim 24 , wherein at least one M is insulin or an analogue or derivative thereof. 
     
     
         36 . A compound of  claim 10 , wherein Q is insulin or an analogue or derivative thereof. 
     
     
         37 . A compound bovine N εB29 -[4-[[(3β,5β,12α)-23-carboxy-12-hydroxy-24-norcholan-3-yl]amino]-4-oxobutanoyl]-insulin. 
     
     
         38 . A compound 4-[[(3β,5β,12α)-23-carboxy-12-hydroxy-24-norcholan-3-yl]amino]-4-oxobutanoic acid N-hydroxysuccinimidyl ester. 
     
     
         39 . A compound bovine 1-[[(3β,5β,12α)-23-[(1,1-dimethyl)ethoxycarbonyl]-12-hydroxy-24-norcholan-3-yl]amino]carbonyl-3,5-bis[[4-(insulin-N eB29 -yl) 1,4-dioxobutyl]amino]benzene. 
     
     
         40 . A compound bovine 1-[[(3β,5β,12α)-23-[(1,1-dimethyl)ethoxycarbonyl]-12-hydroxy-24-norcholan-3-yl]amino]carbonyl-3-[[4-(insulin-N εB29 -yl)-1,4-dioxobutyl]amino]-5-[[[[2-[[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl]acetyl]amino]ethyl]amino]-1,4-dioxobutyl]amino]benzene. 
     
     
         41 . A compound of  claim 40 , wherein the compound is labeled with  111 Indium. 
     
     
         42 . A compound of the general formula:
   M-N—O—P-Q
   wherein
 M is a radioactive halogen; 
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group; and 
 Q is a targeting peptide, and 
   wherein at least one of N, O or P is a substituted bile amino acid.   
     
     
         43 . The compound of  claim 42 , wherein Q is a peptide hormone selected from the group consisting of LHRH, insulin, oxytosin, somatostatin, NK-1, VIP, Substance P, NPY, endothelin A, endothelin B, bradykinin, interleukin-1, EGF, CCK, galanan, MSH, Lanreotide, Octreotide, Maltose, arginine-vasopressin and analogues and derivatives thereof. 
     
     
         44 . The compound of  claim 42 , wherein the substituted bile acid is selected from the group consisting of:
 (3β,5β)-3-aminocholan-24-oic acid;   (3β,5β,12α)-3-amino-12-hydroxycholan-24-oic acid;   (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid;   Lys-(3,6,9)-trioxaundecane-1,11-dicarbonyl-3,7-dideoxy-3-aminocholic acid);   (3β,5β,7α)-3-amino-7-hydroxy-12-oxocholan-24-oic acid; and   (3β,5β,7α)-3-amino-7-hydroxycholan-24-oic acid.   
     
     
         45 . The compound of  claim 42 , wherein Q is insulin or an analogue or derivative thereof. 
     
     
         46 . A method of imaging comprising the steps of:
 administering to a patient a diagnostic imaging agent comprising the compound of  claim 23  or  35  complexed with a diagnostic radionuclide, and   imaging said patient.   
     
     
         47 . A method for preparing a diagnostic imaging agent comprising the step of adding to an injectable medium a substance comprising the compound of  claim 1 . 
     
     
         48 . A kit for preparing a diagnostic imaging agent comprising a first vial containing an injectable therapeutic medium and a second vial containing the compound of  claim 1 . 
     
     
         49 . A method of treating a patient comprising the step of administering to a patient a radiotherapeutic agent comprising the compound of  claim 10  complexed with a therapeutic radionuclide. 
     
     
         50 . A method of preparing a radiotherapeutic agent comprising the step of adding to an injectable therapeutic medium a substance comprising the compound of  claim 10 . 
     
     
         51 . A kit for preparing a radiopharmaceutical agent comprising a first vial containing an injectable therapeutic medium and a second vial containing the compound of  claim 10 . 
     
     
         52 . The method of  claim 49  further comprising administering a therapeutic agent. 
     
     
         53 . A compound of the general formula:
   N—O—P
   wherein
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group; and 
   wherein at least one of N, O or P is a substituted bile acid.   
     
     
         54 . The compound of  claim 53 , wherein the substituted bile acid is selected from the group consisting of:
 (3β,5β)-3-aminocholan-24-oic acid;   (3β,5β,12α)-3-amino-12-hydroxycholan-24-oic acid;   (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid;   Lys-(3,6,9)-trioxaundecane-1,11-dicarbonyl-3,7-dideoxy-3-aminocholic acid);   (3β,5β,7α)-3-amino-7-hydroxy-12-oxocholan-24-oic acid; and   (3β,5β,7α)-3-amino-7-hydroxycholan-24-oic acid.   
     
     
         55 . A method for improving the half life of a pharmaceutical compound comprising the step of attaching a linker having the formula N—O—P to a diagnostic moiety, therapeutic moiety, metal chelator or a radioactive halogen,
 wherein
 N is 0, an alpha amino acid, a substituted bile acid or other linking group; 
 O is an alpha amino acid or a substituted bile acid; and 
 P is 0, an alpha amino acid, a substituted bile acid or other linking group, 
 
 wherein at least one of N, O or P is a substituted bile acid. 
 
     
     
         56 . The method of  claim 55 , wherein the substituted bile acid is selected from the group consisting of:
 (3β,5β)-3-aminocholan-24-oic acid;   (3β,5β,12α)-3-amino-12-hydroxycholan-24-oic acid;   (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid;   Lys-(3,6,9)-trioxaundecane-1,11-dicarbonyl-3,7-dideoxy-3-aminocholic acid);   (3β,5β,7α)-3-amino-7-hydroxy-12-oxocholan-24-oic acid; and   (3β,5β,7α)-3-amino-7-hydroxycholan-24-oic acid.