Enhanced in Vivo Targeting of Site-Specific Drugs

Abstract

The present invention relates to a compound that inhibits the activity of a degrading enzyme for use in combination with a therapeutic or diagnostic compound, preferably a moiety conjugated peptide, in the diagnosis and/or treatment of a disease, in particular cancer, to enhance targeting of the therapeutic or diagnostic compound to the disease site.

1 - 40 . (canceled) 
     
     
         41 . A composition comprising a radiolabeled biodegradable peptide analog and a neutral endopeptidase (NEP) inhibitor,
 wherein the peptide-portion of the radiolabeled biodegradable peptide analog is a neurotensin, and   wherein the composition is a therapeutic or diagnostic compound.   
     
     
         42 . The composition of  claim 41 , wherein the NEP inhibitor comprises phosphoramidon or racecadotril. 
     
     
         43 . The composition of  claim 41 , wherein the composition further comprises an angiotensin-converting enzyme (ACE) inhibitor. 
     
     
         44 . The composition of  claim 43 , wherein the ACE inhibitor comprises lisinopril. 
     
     
         45 . The composition according to  claim 41 , wherein the radiolabeled biodegradable peptide analog is a radiometallated peptide-chelator conjugate or a peptide radiohalogenated via a prosthetic group. 
     
     
         46 . The composition according to  claim 41 , wherein the radiolabeled biodegradable peptide analog comprises a radioactive label selected from the group consisting of Tc, Re, In, Ga, Cu, F, I, Lu, Y, Bi, and Ac. 
     
     
         47 . The composition according to  claim 41 , wherein the radiolabeled biodegradable peptide analog comprises a radionuclide metal or halogen selected from the group comprising  111 In,  99m Tc,  94m Tc,  67 Ga,  66 Ga,  68 Ga,  52 Fe,  69 Er,  72 As,  97 Ru,  203 Pb,  62 Cu,  64 Cu,  67 Cu,  186 Re,  188 Re,  86 Y,  90 Y,  51 Cr,  52m Mn,  157 Gd,  177 Lu,  161 Tb,  169 Yb,  175 Yb,  105 Rh,  166 Dy,  166 Ho,  153 Sm,  149 Pm,  151 Pm,  172 Tm,  121 Sn,  177m Sn,  213 Bi,  142 Pr,  143 Pr,  198 Au,  199 Au,  18 F,  123 I,  124 I,  131 I,  75 Br,  76 Br,  77 Br, and  82 Br. 
     
     
         48 . The composition of  claim 41 , wherein the composition comprises:
 X-Demotensin 6 with a NEP inhibitor; or   X-Demotensin 1 with a NEP inhibitor and an ACE inhibitor,   
       wherein X is a radionuclide, and 
       wherein the composition is a therapeutic or diagnostic composition. 
     
     
         49 . The composition according to  claim 48 , wherein the composition comprises a combination selected from the group consisting of:
 [ 99m Tc]demotensin 6 with a NEP inhibitor; or   [ 99m Tc]demotensin 1 with a NEP inhibitor and an ACE inhibitor;   
       wherein the composition is a therapeutic or diagnostic composition. 
     
     
         50 . A method of diagnosing cancer, the method comprising co-administering a radiolabeled biodegradable peptide analog with a neutral endopeptidase (NEP) inhibitor,
 wherein the peptide-portion of the radiolabeled biodegradable peptide analog is a neurotensin, and   wherein the composition is a diagnostic compound.   
     
     
         51 . The method according to  claim 50 , wherein the neutral endopeptidase inhibitor comprises phosphoramidon or racecadotril. 
     
     
         52 . The method according to  claim 50 , wherein the administration of the radiolabeled biodegradable peptide analog is intravenous. 
     
     
         53 . The method according to  claim 50 , wherein the radiolabeled biodegradable peptide analog is a radiometallated peptide-chelator conjugate or a peptide modified with a prosthetic group for incorporation of radiohalogens. 
     
     
         54 . The method according to  claim 50 , wherein the radiolabeled biodegradable peptide analog comprises a radioactive label selected from the group consisting of Tc, Re, In, Ga, Cu, F, I, Lu, Y, Bi, and Ac. 
     
     
         55 . The method according to  claim 50 , wherein the radiolabeled biodegradable peptide analog comprises a radionuclide metal or halogen selected from the group comprising  111 In,  99m Tc,  94m Tc,  67 Ga,  66 Ga,  68 Ga,  52 Fe,  69 Er,  72 As,  97 Ru,  203 Pb,  62 Cu,  64 Cu,  67 Cu,  186 Re,  188 Re,  86 Y,  90 Y,  51 Cr,  52m Mn,  157 Gd,  177 Lu,  161 Tb,  169 Yb,  175 Yb,  105 Rh,  166 Dy,  166 Ho,  153 Sm,  149 Pm,  151 Pm,  172 Tm,  121 Sn,  177m Sn,  213 Bi,  142 Pr,  143 Pr,  198 Au,  199 Au,  18 F,  123 I,  124 I,  131 I,  75 Br,  76 Br,  77 Br, and  82 Br. 
     
     
         56 . The method according to  claim 50 , wherein the co-administration comprises:
 (i) administering the radiolabeled biodegradable peptide analog at the same time as the NEP inhibitor;   (ii) first administering the therapeutic radiolabeled biodegradable peptide analog, followed by administering the NEP inhibitor; or   (iii) first administering the NEP inhibitor, followed by administering the radiolabeled biodegradable peptide analog.   
     
     
         57 . The method according to  claim 50 , wherein the combination of a radiolabeled biodegradable peptide analog and a NEP inhibitor comprises X-Demotensin 6 with a neutral endopeptidase inhibitor;
 wherein X is a radionuclide, and   wherein the composition is a diagnostic composition.   
     
     
         58 . The method according to  claim 57 , wherein the combination comprises [ 99m Tc]demotensin 6 with a neutral endopeptidase inhibitor;
 wherein the composition is a diagnostic composition.   
     
     
         59 . The method according to  claim 50 , wherein the method further comprises administering an angiotensin converting enzyme (ACE) inhibitor. 
     
     
         60 . The method according to  claim 59 , wherein the ACE inhibitor is lisinopril. 
     
     
         61 . The method according to  claim 59 , wherein the combination comprises X-Demotensin 1 with a NEP inhibitor and an ACE inhibitor,
 wherein X is a radionuclide.   
     
     
         62 . The method according to  claim 61 , wherein the combination comprises [ 99m Tc]demotensin 1 with a NEP inhibitor and an ACE inhibitor. 
     
     
         63 . The method according to  claim 59 , wherein the co-administration comprises:
 (i) administering the radiolabeled biodegradable peptide analog at the same time as the NEP inhibitor and an ACE inhibitor;   (ii) first administering the therapeutic radiolabeled biodegradable peptide analog, followed by administering the NEP inhibitor and an ACE inhibitor; or   (iii) first administering the NEP inhibitor and an ACE inhibitor, followed by administering the radiolabeled biodegradable peptide analog.   
     
     
         64 . The method according to  claim 59 , wherein the ACE inhibitor is lisinopril. 
     
     
         65 . A method of treating cancer the method comprising co-administering a radiolabeled biodegradable peptide analog with a neutral endopeptidase (NEP) inhibitor,
 wherein the peptide-portion of the radiolabeled biodegradable peptide analog is a neurotensin, and   wherein the composition is a therapeutic compound.   
     
     
         66 . The method according to  claim 65 , wherein the NEP inhibitor comprises phosphoramidon or racecadotril. 
     
     
         67 . The method according to  claim 65 , wherein the administration of the radiolabeled biodegradable peptide analog is intravenous. 
     
     
         68 . The method according to  claim 65 , wherein the radiolabeled biodegradable peptide analog is a radiometallated peptide-chelator conjugate or a peptide modified with a prosthetic group for incorporation of radiohalogens. 
     
     
         69 . The method according to  claim 65 , wherein the radiolabeled biodegradable peptide analog comprises a radioactive label selected from the group consisting of Tc, Re, In, Ga, Cu, F, I, Lu, Y, Bi, and Ac. 
     
     
         70 . The method according to  claim 65 , wherein the radiolabeled biodegradable peptide analog comprises a radionuclide metal or halogen selected from the group comprising  111 In,  99m Tc,  94m Tc,  67 Ga,  66 Ga,  68 Ga,  52 Fe,  69 Er,  72 As,  97 Ru,  203 Pb,  62 Cu,  64 Cu,  67 Cu,  186 Re,  188 Re,  86 Y,  90 Y,  51 Cr,  52m Mn,  157 Gd,  177 Lu,  161 Tb,  169 Yb,  175 Yb,  105 Rh,  166 Dy,  166 Ho,  153 Sm,  149 Pm,  151 Pm,  172 Tm,  121 Sn,  177m Sn,  213 Bi,  142 Pr,  143 Pr,  198 Au,  199 Au,  18 F,  123 I,  124 I,  131 I,  75 Br,  76 Br,  77 Br, and  82 Br. 
     
     
         71 . The method according to  claim 65 , wherein the co-administration comprises:
 (i) administering the radiolabeled biodegradable peptide analog at the same time as the NEP inhibitor;   (ii) first administering the therapeutic radiolabeled biodegradable peptide analog, followed by administering the NEP inhibitor; or   (iii) first administering NEP inhibitor, followed by administering the radiolabeled biodegradable peptide analog.   
     
     
         72 . The method according to  claim 65 , wherein the combination of a radiolabeled biodegradable peptide analog and a NEP inhibitor comprises X-Demotensin 6 with a NEP inhibitor,
 wherein X is a radionuclide, and   wherein the composition is a therapeutic composition.   
     
     
         73 . The method according to  claim 72 , wherein the combination comprises [ 99m Tc]demotensin 6 with a neutral endopeptidase inhibitor,
 wherein the composition is a therapeutic composition.   
     
     
         74 . The method according to  claim 65 , wherein the method further comprises administering an angiotensin converting enzyme (ACE) inhibitor. 
     
     
         75 . The method according to  claim 74 , wherein the ACE inhibitor is lisinopril. 
     
     
         76 . The method according to  claim 74 , wherein the combination comprises X-Demotensin 1 with a NEP inhibitor and an ACE inhibitor,
 wherein X is a radionuclide.   
     
     
         77 . The method according to  claim 76 , wherein the combination comprises [ 99m Tc]demotensin 1 with a NEP inhibitor and an ACE inhibitor. 
     
     
         78 . The method according to  claim 74 , wherein the co-administration comprises:
 (i) administering the radiolabeled biodegradable peptide analog at the same time as the NEP inhibitor and an ACE inhibitor;   (ii) first administering the therapeutic radiolabeled biodegradable peptide analog, followed by administering the NEP inhibitor and an ACE inhibitor; or   (iii) first administering the NEP inhibitor and an ACE inhibitor, followed by administering the radiolabeled biodegradable peptide analog.   
     
     
         79 . The method according to  claim 78 , wherein the ACE inhibitor is lisinopril.