Compounds for Delivery of Therapeutic And Imaging Moieties to Nerve Cells

Abstract

The invention features compounds of the general formula: B-L-M where B is a binding agent capable of selectively binding to a nerve cell surface receptor and mediating absorption of the compound by the nerve cell; M is a moiety which performs a useful non-cytotoxic function when absorbed by a nerve cell, and can be a therapeutic moiety or an imaging moiety; and L is a linker coupling B to M. The invention also features methods of use of the compounds in, for example, treating conditions such as viral infections and pain, as well as in labeling nerve cells.

What is claimed is: 
     
         1 . A conjugate comprising the formula:
   B-L-M   where B is a binding agent that selectively binds a nerve cell surface receptor and mediating absorption of the compound by the nerve cell;   M is a therapeutic moiety or an imaging moiety which performs a useful non-cytotoxic function when absorbed by a nerve cell, with the proviso that M is other than a nerve growth factor or horse radish peroxidase; and   L is a linker covalently coupling B to M.   wherein said binding moiety selectively binds a trkA or trkB receptor of a nerve cell and facilitates internalization of the conjugate into the nerve cell.   
     
     
         2 . The conjugate of  claim 1 , wherein the binding agent B is a neurotrophin or a fragment or derivative thereof. 
     
     
         3 . The conjugate of  claim 1 , wherein M is a therapeutic moiety TM. 
     
     
         4 . The conjugate of  claim 3 , wherein the therapeutic moiety TM is chosen from an antiviral, an analgesic, an adrenergic agent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, a steroid hormone, a Na+/K+/Ca++ channel blocker, a mitochondrial modifier, an anti-oxidant, an anti-bacterial agent, an anti-arrthymic agent, and an NMDA antagonist. 
     
     
         5 . The conjugate of  claim 3 , wherein the therapeutic moiety TM which is chosen from a nucleic acid, N-acetyl aspartic acid, and WHI-P131. 
     
     
         6 . The conjugate of  claim 3 , wherein the therapeutic moiety TM is chosen from acyclovir, trifluridine, cortisone, prednisolone, methylprednisolone, betamethasone, fluocinolone acetonide, etodolac, tranylcypromine, ganciclovir, meclofenamate, propoxycaine, dexamethasone, tauroursodeoxycholic acid, flumethasone, N-acetyl-cysteine, procaine, piroxicam, N-acetyl-aspartic acid, phentolamine, creatine, mexilitine, minocycline, creatine phosphate, gabapentin, hyoscyamine, ceftriaxone, baclofen, zidovudine (AZT), ketamine, lamivudine (3TC), phenformin, enviroxime, pentamidine, adenosine, amantadine, buprenorphine, butorphanol, celecoxib, dextromethorphan, DNA oligomers, etorphine, levorphanol, morphine, naltrexone, oxymorphone, testosterone, estradiol, progesterone and WHI-P131; 
     
     
         7 . The conjugate of  claim 1 , wherein the binding agent comprises an amino acid sequence and the linker is covalently attached to the binding agent at a lysine epsilon amino group. 
     
     
         8 . The conjugate of  claim 1 , wherein the moiety M is an imaging moiety IM. 
     
     
         9 . The conjugate of  claim 8 , wherein the imaging moiety IM is chosen from a fluorophore, a radioisotope, and a luminophores. 
     
     
         10 . The conjugate of  claim 8 , wherein the imaging moiety is Alexa Fluor 488® or Alexa Fluor 647®. 
     
     
         11 . A method of delivering a therapeutic moiety to a nerve cell having a trkA or a trkB receptor, the method comprising:
 contacting a nerve cell having a trkA or a trkB receptor with a conjugate according to  claim 3 .   
     
     
         12 . The method of  claim 11 , wherein the therapeutic moiety TM is an antiviral, and is administered in an amount effective to reduce or retard advancement of symptoms caused by viral infection of a trkA-positive or a trkB-positive neuron. 
     
     
         13 . The method of  claim 11 , wherein said therapeutic moiety is a steroid, and is administered in an amount effective to reduce inflammation or pain. 
     
     
         14 . A method of labeling a nerve cell, comprising:
 contacting a nerve cell having a trkA or trkB receptor with a conjugate according  claim 8  in an amount effective to detectably label the nerve cell or nerve cell components.