Design and development of neurokinin-1 receptor-binding agent delivery conjugates

Abstract

Neurokinin-1 (NK-1) receptor-binding agent delivery conjugates, compositions comprising NK-1 receptor-binding agent delivery conjugates, and methods for making and administering NK-1 receptor-binding agent delivery conjugates are provided. A conjugate may include an NK-1 receptor-binding moiety, a tinker group containing at least one linker selected from the group of a releasable linker and a spacer linker, and an active agent linked to the linker group. The active agent may be selected from the group of fluorophore-containing compounds, radionuclide-containing compounds, and therapeutic agents for treatment of tumor cells characterized by over-expression of the NK-1 receptor.

1 - 15 . (canceled) 
     
     
         16 . A neurokinin-1 (NK-1) receptor-binding conjugate comprising:
 an NK-1 receptor-binding moiety;   an active agent comprising a radionuclide; and   a linker, which links the NK-1 receptor-binding moiety and the active agent, comprises at least one spacer linker, and optionally further comprises a releasable linker.   
     
     
         17 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the active agent is a radio-imaging agent, an optical imaging agent, a position emission tomography (PET)imaging agent, a magnetic resonance imaging (MRI) contrast agent, a computed tomography (CT) contrast agent, or a fluorescence resonance energy transfer (FRET) imaging agent. 
     
     
         18 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the active agent comprises a chelator in complex with a radionuclide selected from the group consisting of technetium-99m ( 99m Tc), gallium-68 ( 68 Ga), indium-111 ( 111 In), yttrium-90 ( 90 Y), lutetium-177 ( 177 Lu), zirconium-89 ( 89 Zr), actinium-225 ( 225 Ac), cobalt-60 ( 60 Co), and copper-64 ( 64 Cu). 
     
     
         19 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the radionuclide is  99m Tc or  64 Cu. 
     
     
         20 . The NK-1 receptor-binding conjugate of  claim 18 , wherein the chelator is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein each R is independently H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, and wherein one R comprises a heteroatom, which is attached to the linker; X is oxygen, nitrogen, or sulfur, and is attached to the linker; and n is an integer from 1 to 5. 
     
     
         21 . The NK-1 receptor-binding conjugate of  claim 20 , wherein the heteroatom in R is oxygen, nitrogen or sulfur. 
     
     
         22 . The NK-1 receptor-binding conjugate of  claim 19 , wherein the chelator is a tripeptide or tetrapeptide. 
     
     
         23 . The NK-1 receptor-binding conjugate of  claim 22 , wherein the tripeptide has the formula: 
       
         
           
           
               
               
           
         
       
       wherein each R is independently H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, and wherein one R comprises a heteroatom, which is attached to the linker. 
     
     
         24 . The NK-1 receptor-binding conjugate of  claim 23 , wherein the heteroatom in R is oxygen, nitrogen or sulfur. 
     
     
         25 . The NK-1 receptor-binding conjugate of  claim 18 , wherein the chelator is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the NK-1 receptor-binding moiety comprises a selective NK-1 receptor antagonist or a derivative thereof. 
     
     
         27 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the NK-1 receptor-binding moiety is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the spacer linker comprises amino acids selected from the group consisting of naturally occurring amino acids and stereoisomers thereof. 
     
     
         29 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the linker comprises dithioalkyloxycarbonyl. 
     
     
         30 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the linker comprises 3-thiosuccinimid-1-ylalkyloxy. 
     
     
         31 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the linker comprises 3-cysteinylsuccinimid-1-ylalkyloxy, wherein the cysteinyl is optically active or optically inactive. 
     
     
         32 . The NK-1 receptor-binding conjugate of  claim 16 , wherein the conjugate is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         33 . A pharmaceutical composition comprising a NK-1 receptor-binding conjugate of  claim 16 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         34 . A method of using a NK-1 receptor-binding conjugate, which method comprises:
 (a) administering to a subject an effective amount of the NK-1 receptor-binding conjugate of  claim 16 , optionally as a pharmaceutical composition comprising the NK-1 receptor-binding conjugate and a pharmaceutically acceptable carrier, diluent, or excipient, and   (b) detecting the radionuclide in the subject.   
     
     
         35 . The method of  claim 34 , which further comprises diagnosing a disease, locating metastatic disease, detecting disease recurrence, or monitoring response to therapy. 
     
     
         36 . The method of  claim 35 , which further comprises selecting a patient for cholecystokinin 2 receptor targeted therapy.