Molecular Probe for Imaging of Pancreatic Islets and Use of the Same

Abstract

To provide a molecular probe for imaging of pancreatic islets. A molecular probe for use in imaging of pancreatic islets is provided. The molecular probe includes any one of the following polypeptides: polypeptides represented by the following formulae (1), (5), and (9); and polypeptides having homology with the foregoing polypeptides: Z-DLSXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (1) Z-DLSKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2  (5) B-DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (9) where X in the formulae (1) and (5) and B- in the formula (9) indicate that an amino group is labeled with a group represented by the formula (I) below having an aromatic ring, wherein A represents either an aromatic hydrocarbon group or an aromatic heterocyclic group, R 1 represents a substituent that contains radioactive iodine, R 2 represents either a hydrogen atom or a substituent different from that represented by R 1 , and R 3 represents any one of a bond, a methylene group, and an oxymethylene group.

1 . A molecular probe for use in imaging of pancreatic islets, the molecular probe comprising any one of the following polypeptides:
 a polypeptide represented by any one of the following formulae (1) to (12);   a polypeptide obtained by deletion, insertion, or substitution of one to several amino acids with respect to a polypeptide represented by any one of the following formulae (1) to (12), the polypeptide being capable of binding to pancreatic islets; and   a polypeptide having a homology of 80% or higher with any one of the amino acid sequences of polypeptides represented by the following formulae (1) to (12), the polypeptide being capable of binding to pancreatic islets,   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO. 1) 
                 
                     
                   Z-DLSXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (1) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 2) 
                 
                     
                    Z-LSXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (2) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 3) 
                 
                     
                     Z-SXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (3) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 4) 
                 
                     
                      Z-XQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (4) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 5) 
                 
                     
                   Z-DLSKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2  (5) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 6) 
                 
                     
                    Z-LSKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2  (6) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 7) 
                 
                     
                     Z-SKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2  (7) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 8) 
                 
                     
                      Z-KQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2  (8) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 9) 
                 
                     
                   B-DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (9) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 10) 
                 
                     
                    B-LSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (10) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 11) 
                 
                     
                     B-SKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (11) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 12) 
                 
                     
                      B-KQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (12) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       where
 in the foregoing formulae (1) to (8), 
 Z- indicates that an α-amino group at an N-terminus is either not modified, or is modified with a modifying group having no electric charge, and 
 X represents a lysine residue, an amino group of a side chain of the lysine residue being labeled with a group represented by the formula (I) below having an aromatic ring, 
 in the formulae (9) to (12), B- indicates that an α-amino group at an N-terminus is labeled with a group represented by the formula (I) below having an aromatic ring, and 
 in the foregoing formulae (1) to (12), —NH 2  indicates that a carboxyl group at a C-terminus is amidated, 
 
       
         
           
           
               
               
           
         
       
       wherein
 A represents either an aromatic hydrocarbon group or an aromatic heterocyclic group, 
 R 1  represents a substituent that contains any one of  123 I,  124 I,  125 I, and  131 I, 
 R 2  represents either a hydrogen atom, or one or more substituents different from that represented by R 1 , and 
 R 3  represents any one of a bond, a methylene group, and an oxymethylene group. 
 
     
     
         2 . The molecular probe for imaging of pancreatic islets according to  claim 1 , wherein the group having an aromatic ring is a group represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a substituent that contains any one of  123 I,  124 I,  125 I, and  131 I. 
     
     
         3 . A kit for performing imaging of pancreatic islets, comprising the molecular probe for imaging of pancreatic islets according to  claim 1 . 
     
     
         4 . The kit according to  claim 3 , wherein the molecular probe for imaging of pancreatic islets included in the kit is in a form of a parenteral solution. 
     
     
         5 . A reagent for performing imaging of pancreatic islets, comprising the molecular probe for imaging of pancreatic islets according to  claim 1 . 
     
     
         6 . A method for imaging of pancreatic islets comprising detecting a signal of the molecular probe for imaging of pancreatic islets according to  claim 1  bound to pancreatic islets preliminarily. 
     
     
         7 . The method for imaging of pancreatic islets according to  claim 6 , further comprising determining a state of pancreatic islets from results of the imaging of pancreatic islets using the molecular probe for imaging of pancreatic islets. 
     
     
         8 . A method for determining an amount of pancreatic islets, comprising:
 detecting a signal of the molecular probe for imaging of pancreatic islets according to  claim 1 , the molecular probe being bound to pancreatic islets preliminarily; and   calculating an amount of pancreatic islets from the detected signal of the molecular probe for imaging of pancreatic islets.   
     
     
         9 . The method for determining an amount of pancreatic islets according to  claim 8 , further comprising presenting the calculated amount of pancreatic islets. 
     
     
         10 . A method for producing the molecular probe for imaging of pancreatic islets according to  claim 1 , comprising labeling and deprotecting a precursor of the molecular probe for imaging of pancreatic islets,
 wherein the precursor of the molecular probe for imaging of pancreatic islets includes any one of the following polypeptides:   a polypeptide represented by any one of the following formulae (13) to (24);   a polypeptide obtained by deletion, insertion, or substitution of one to several amino acids with respect to a polypeptide represented by any one of the following formulae (13) to (24), the polypeptide being capable of binding to pancreatic islets after being labeled and deprotected; and   a polypeptide having a homology of 80% or higher with any one of the amino acid sequences of polypeptides represented by the following formulae (13) to (24), the polypeptide being capable of binding to pancreatic islets after being labeled and deprotected,   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO. 13) 
                 
                     
                   *-DLSKQMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (13) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 14) 
                 
                     
                    *-LSKQMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (14) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 15) 
                 
                     
                     *-SKQMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (15) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 16) 
                 
                     
                      *-KQMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (16) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 17) 
                 
                     
                   *-DLSK* QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (17) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 18) 
                 
                     
                    *-LSK*QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (18) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 19) 
                 
                     
                     *-SK*QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (19) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 20) 
                 
                     
                      *-K* QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2  (20) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 21) 
                 
                     
                   DLSK* QMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (21) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 22) 
                 
                     
                    LSK* QMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (22) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 23) 
                 
                     
                     SK* QMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (23) 
                 
                     
                     
                 
                     
                   (SEQ ID NO. 24) 
                 
                     
                      K* QMEEEAVRLFIEWLK* NGGPSSGAPPPS-NH 2  (24) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 in the foregoing formulae (13) to (20), 
 *- indicates that an α-amino group at an N terminus is either protected by a protecting group or modified by a modifying group having no electric charge, and 
 in the foregoing formulae (13) to (24), 
 K* indicates that an amino group of a side chain of a lysine is protected by a protecting group, and 
 —NH 2  indicates that a carboxyl group at a C-terminus is amidated. 
 
     
     
         11 . The method for producing the molecular probe for imaging of pancreatic islets according to  claim 10 ,
 wherein the labeling of the precursor of the molecular probe for imaging of pancreatic islets includes labeling of the precursor with a labeling compound having a group represented by the following formula (I) having an aromatic ring:   
       
         
           
           
               
               
           
         
       
       wherein
 A represents either an aromatic hydrocarbon group or an aromatic heterocyclic group, 
 R 1  represents a substituent that contains any one of  123 I,  124 I,  125 I, and  131 I, 
 R 2  represents either a hydrogen atom, or one or more substituents different from that represented by R 1 , and 
 R 3  represents any one of a bond, a methylene group, and an oxymethylene group. 
 
     
     
         12 . A method for radioactively labeling a peptide having a plurality of amino acids having radioactively-labelable functional groups on side chains, the method comprising:
 synthesizing a peptide using a protected amino acid in which an α-amino group at an N-terminus and a functional group of a side chain are protected by protecting groups;   deprotecting a functional group by removing a protecting group therefrom, wherein the functional group to be deprotected is a functional group that is not to be radioactively labeled, among the radioactively labelable functional groups of the side chains of the amino acids of the synthesized peptide;   protecting, again, the deprotected functional group of the side chain of the amino acid by a protecting group different from that removed upon the deprotecting;   deprotecting, by removing protecting groups, the other functional groups than the functional group of the side chain of the amino acid that is again protected, so as to obtain a peptide to be radioactively labeled;   radioactively labeling the obtained peptide with a labeling compound; and   deprotecting the radioactively-labeled peptide by removing protecting groups.   
     
     
         13 . A method for producing a radioactively-labeled peptide, wherein the peptide has a plurality of amino acids having radioactively labelable functional groups on side chains, the method comprising:
 synthesizing a peptide to be radioactively labeled, using protected amino acids in each of which an α-amino group at an N-terminus and a functional group of a side chain are protected by protecting groups;   deprotecting a functional group by removing a protecting group therefrom, wherein the functional group to be deprotected is a functional group that is not to be radioactively labeled, among the radioactively labelable functional groups of the side chains of the amino acids of the synthesized peptide;   protecting, again, the deprotected functional group of the side chain of the amino acid by a protecting group different from that removed upon the deprotecting;   deprotecting, by removing protecting groups, the other functional groups than the functional group of the side chain of the amino acid that is again protected, so as to obtain a peptide to be radioactively labeled;   radioactively labeling the obtained peptide with a labeling compound; and   deprotecting the radioactively-labeled peptide by removing protecting groups.