Tricarbonyl technetium-99m, rhenium-185/187, or rhenium-188 labeled cyclic RGD derivatives and uses thereof

1. Tricarbonyl technetium-99m, rhenium-188, or rhenium-185/187 labeled cyclic RGD derivative selected from the group consisting of compounds expressed by Chemical Formula 1A, 1B, and 1C or a pharmaceutically acceptable salt thereof:

wherein,

M is 99 mTc, 188 Re, or 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

wherein,

M is 99m Tc, 188 Re, or 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 is an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

and

wherein,

M is 99m Tc, 188 Re, or 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 and A 2 are each an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8.

2. The tricarbonyl technetium-99m, rhenium-188, or rhenium 185/187 labeled cyclic RGD derivative as set forth in claim 1 , wherein the tricarbonyl technetium-99m, rhenium-188, or rhenium-185/187 labeled cyclic RGD derivative is selected from the group consisting of:

cyclic {(tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-NH 2 (CH 2 CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-NH 2 (CH 2 CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-NH 2 (CH 2 CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-glycine-CONH(CH 2 CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-glycine-CONH(CH 2 CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

cyclic {(tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-glycine-CONH(CH2CH 2 O) 4 CH 2 CH 2 CONH-lysine)-alginine-glycine-aspartic acid-D-phenylalanine};

(tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 ;

(tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 ;

(tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 ;

{tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 , (n=0-8);

{tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 , (n=0-8);

{tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 , (n=0-8);

{tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)]} 2 , (n=0-8);

{tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)]} 2 , (n=0-8);

{tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)]} 2 , (n=0-8);

(tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 ;

(tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 };

(tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-aspartic acid)-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 ;

{tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8);

{tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8);

{tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8);

{tricarbonyl-[ 99m Tc]technetium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8);

{tricarbonyl-[ 188 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8); and

{tricarbonyl-[ 185/187 Re]rhenium-N-α-bis-hydroxycarbonyl methyl-(polyethylene glycol) n -aspartic acid}-{aspartic acid-(polyethylene glycol) n -[cyclic (lysine-alginine-glycine-aspartic acid-D-phenylalanine)] 2 } 4 , (n=0-8).

3. A preparation method of the tricarbonyl technetium-99m or tricarbonyl rhenium-188 labeled cyclic RGD derivative selected from a group of compounds expressed by Chemical Formula 1A, 1B, and 1C comprising:

reacting tricarbonyl technetium-99m ( 99m Tc(CO) 3 (H 2 O) 3 + ) or tricarbonyl rhenium-188 ( 188 Re(CO) 3 (H 2 O) 3 + ) with a precursor compound of Chemical Formula 2A, 2B, or 2C to prepare the tricarbonyl technetium-99m or rhenium-188 labeled cyclic RGD derivative of Chemical Formula 1A, 1B, or 1C, respectively:

wherein,

M is 99 mTc or 188 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

wherein,

M is 99m Tc or 188 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 is an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

and

wherein,

M is 99m Tc or 188 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 and A 2 are each an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

wherein R 1 , R 3 , and R 4 are as defined in Chemical Formula 1A,

wherein R 1 , R 2 , R 3 , R 4 , and A 1 are as defined in Chemical Formula 1B,

wherein R 1 , R 2 , R 3 , R 4 , A 1 , and A 2 are as defined in Chemical Formula 1C.

4. The preparation method as set forth in claim 3 comprising:

diluting the tricarbonyl technetium-99m or tricarbonyl rhenium-188 in 0.5-5 mL of distilled water,

adding the solution of the tricarbonyl technetium-99m or tricarbonyl rhenium-188 in water to the precursor of Chemical Formula 2A, 2B, or 2C in a reaction container, and

heating the mixture of the tricarbonyl technetium-99m or tricarbonyl rhenium-188 and the precursor at 70-80° C. for 30 or 60 minutes, to thereby prepare the tricarbonyl technetium-99m or tricarbonyl rhenium-188 labeled cyclic RGD derivative of Chemical Formula 1A, 1B, or 1C, respectively.

5. A preparation method of the tricarbonyl rhenium-185/187 labeled cyclic RGD derivative comprising:

introducing (NEt 4 ) 2 185/187 Re(CO) 3 Br 3 into a precursor compound of Chemical Formula 2A, 2B, or 2C to react, thereby preparing cyclic RGD derivative of Chemical Formula 1A, 1B, or 1C, respectively:

wherein,

M is 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

wherein,

M is 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 is an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

and

wherein,

M is 185/187 Re;

R 1 is N, N(CH 2 CH 2 O) n CH 2 CH 2 CONH or N(CH 2 CONH)(CH 2 CH 2 O) 4 CH 2 CH 2 CONH;

A 1 and A 2 are each an amino acid selected from the group consisting of aspartic acid, lysine, glutamic acid, tyrosine, cysteine, threonine, and serine;

R 2 is NH or NH(Z) n CH 2 CH 2 CONH;

Z is —CH 2 CH 2 O— or —CH 2 CONH—;

n is an integer between 0 and 8;

R 3 is H or OH;

R 4 is —(CH 2 ) m — or —(CH 2 ) m —COO—; and

m is an integer between 1 and 8,

wherein R 1 , R 3 , and R 4 are as defined in Chemical Formula 1A,

wherein R 1 , R 2 , R 3 , R 4 , and A 1 are as defined in Chemical Formula 1B,

wherein R 1 , R 2 , R 3 , R 4 , A 1 , and A 2 are as defined in Chemical Formula 1C.

6. The preparation method of claim 5 comprising:

diluting a reagent, (NEt 4 ) 2 185/187 Re(CO) 3 Br 3 in 0.5˜5 mL of distilled water,

adding the reagent solution to the precursor of Chemical Formula 2A, 2B, or 2C in a reaction container, and

heating the mixture of the reagent and the precursor at 70-80° C. for 55-65 minutes, thereby preparing cyclic RGD derivative Chemical Formula 1A, 1B, or 1C, respectively.

7. A pharmaceutical composition comprising the tricarbonyl technetium-99m labeled cyclic RGD derivative or the pharmaceutically acceptable salt thereof as set forth in claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising the tricarbonyl rhenium-188, or rhenium-185/187 labeled cyclic RGD derivative or the pharmaceutically acceptable salt thereof as set forth in claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

9. A method for diagnosing angiogenesis-related disease in a subject, comprising a step of administering a diagnostically effective amount of the tricarbonyl technetium-99m labeled cyclic RGD derivative and imaging the subject or the pharmaceutically acceptable salt, thereof as set forth in claim 1 ,

wherein the angiogenesis-related disease is a disease with over-expression of integrin α v β 3 which is selected from the group consisting of thrombosis, myocardial ischemia, solid tumor, and metastatic tumor.

10. The method as set forth in claim 9 , wherein the tricarbonyl technetium-99m labeled cyclic RGD derivative or the pharmaceutically acceptable salt thereof is administered by intravenous injection and the angiogenesis-related disease is diagnosed with single photon emission computer tomography (SPECT).