ARSENIC COMPLEXES FOR POTENTIAL DIAGNOSTIC APPLICATIONS
The present invention provides radioactive arsenic complex useful in diagnostic and therapeutic applications and methods for forming those arsenic complexes.
1 . A composition comprising a compound of Formula (I):
wherein arsenic is radioactive;
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl, substituted hydrocarbyl, aromatic, and heteroaromatic rings;
X represents ligand atoms wherein X is chosen from carbon, sulfur, and nitrogen; and
X may be further substituted by hydrogen, hydrocarbyl or substituted hydrocarbyl.
2 . The composition of claim 1 , wherein the arsenic is chosen from 72 As or 77 As.
3 . The composition of claim 1 , wherein R 3 is NH 2 .
4 . The composition of claim 1 , wherein R 3 is NH 2 ; and R 1 , R 2 , R 4 , and R 5 are each hydrogen.
5 . The composition of claim 1 , wherein each X is sulfur and is substituted by hydrogen, hydrocarbyl or substituted hydrocarbyl.
6 . The composition of claim 1 , wherein one or both X are substituted by carboxylic acids, phenyl groups or amines.
7 . The composition of claim 1 , wherein one or both X are substituted by CH 2 COOH.
8 . The composition of claim 5 , wherein one or both X are substituted by CH 2 Ph.
9 . The composition of claim 5 , wherein one or both X are substituted by CH 2 CH 2 NH 2 .
10 . The composition of claim 5 , wherein the composition is isolated.
11 . A composition comprising Formula (II):
wherein arsenic is radioactive;
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl, substituted hydrocarbyl, aromatic and heteroaromatic rings; and
R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl and substituted hydrocarbyl rings and aromatic and heteroaromatic rings.
12 . The composition of claim 11 , wherein the arsenic is chosen from 72 As or 77 As.
13 . The composition of claim 11 , wherein R 3 is NH 2 ; and R 1 , R 2 , R 4 , and R 5 are each hydrogen.
14 . The composition of claim 11 , wherein R 6 , R 7 , R 8 , and R 9 are each hydrogen.
15 . The composition of claim 11 , wherein one or more of R 6 , R 7 , R 8 , and R 9 are substituted with a C 1 -C 10 carboxylic acid.
16 . The composition of claim 11 , wherein R 6 and R 8 are substituted by COOH.
17 . The composition of claim 16 , wherein R 7 and R 9 are substituted by hydrogen.
18 . The composition of claim 11 , where one of R 6 , R 7 , R 8 , or R 9 is substituted by a linear C 1 -C 5 carboxylic acid.
19 . The composition of claim 11 , wherein R 6 , R 7 , R 8 , or R 9 are substituted such to form a fused ring system with one or more hydrocarbyl, substituted hydrocarbyl, aromatic or heteroaromatic rings.
20 . The composition of claim 11 , wherein the composition is isolated.
21 . A composition comprising Formula (III):
wherein arsenic is radioactive;
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl, substituted hydrocarbyl rings, aromatic and heteroaromatic rings; and
R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl, substituted hydrocarbyl, aromatic and heteroaromatic rings.
22 . The composition of claim 21 , wherein the arsenic is chosen from 72 As or 77 As.
23 . The composition of claim 21 , wherein R 3 is NH 2 and R 1 , R 2 , R 4 , and R 5 are each hydrogen.
24 . The composition of claim 21 , wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen.
25 . The composition of claim 21 , wherein one or more of R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are substituted with a C 1 -C 10 carboxylic acid.
26 . The composition of claim 21 , wherein one or more of R 6 , R 8 , or R 10 are substituted by COOH.
27 . The composition of claim 21 , where one of R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is substituted by a C 1 -C 5 carboxylic acid.
28 . The composition of claim 21 , wherein two or more of R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are substituted such to form a fused ring system with one or more hydrocarbyl, substituted hydrocarbyl, aromatic or heteroaromatic ring systems.
29 . The composition of claim 21 , wherein the composition is isolated.
30 . A radiopharmaceutical comprising Formula (I), (II), or (III):
wherein arsenic is radioactive;
X represents ligand atoms wherein X is chosen from carbon, sulfur, and nitrogen;
X may be further substituted with hydrogen, hydrocarbyl or substituted hydrocarbyl;
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl, substituted hydrocarbyl, aromatic and heteroaromatic rings; and
R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, amines, substituted amines, halogens, hydroxyl, thiol, or nitro groups or are joined together to form one or more fused ring systems selected from hydrocarbyl and substituted hydrocarbyl rings and aromatic and heteroaromatic rings.
31 . The radiopharmaceutical of claim 30 , wherein the arsenic is chosen from 72 As or 77 As.
32 . The radiopharmaceutical of claim 30 , wherein R 3 is NH 2 ; and R 1 , R 2 , R 4 , and R 5 are each hydrogen.
33 . The radiopharmaceutical of claim 30 , wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl.
34 . The radiopharmaceutical of claim 30 , wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, carboxylic acid, and C 1 -C 10 carboxylic acids.
35 . The radiopharmaceutical of any one of claim 30 , wherein the compound of Formula (I), (II), or (III) is conjugated to a peptide.
36 . The radiopharmaceutical of claim 35 , wherein the peptide is bombesin.
37 . The radiopharmaceutical of claim 35 , wherein the peptide is a site-specific antibody.
38 . A method of producing radiolabeled phenylarsonic acid, the method comprising:
(a) contacting a radiolabeled arsenous acid with a carbonate to form a first solution;
(b) optionally contacting the first solution with a copper-based catalyst to form a second solution; and
(c) contacting the second solution with a phenyldiazonium salt to give a third solution comprising the radiolabeled phenylarsonic acid.
39 . The method of claim 38 , wherein the radiolabeled arsenous acid is chosen from As 2 O 3 or H 3 AsO 3 .
40 . The method of claim 38 , wherein the carbonate is sodium carbonate.
41 . The method of claim 38 , wherein the phenyldiazonium salt is tetrafluoroborate salt.
42 . The method of claim 38 , wherein the first solution is heated to about 70° C. to about 90° C.
43 . The method of claim 38 , wherein the copper-based catalyst is selected from the group consisting of copper(I) bromide (CuBr), copper(I) cyanide (CuCN), copper(I) chloride (CuCl), copper(I) fluoride (CuF), copper(I) iodide (CuI), copper chromite (Cu 2 Cr 2 O 5 ), copper(I) oxide (Cu 2 O), copper(I) sulfide (Cu 2 S), copper(I) phosphate (Cu 3 (PO 4 ) 2 ), copper(I) phosphide (Cu 3 P), copper tetrafluoroborate (Cu(BF 4 ) 2 ), copper(II) bromide (CuBr 2 ), copper(II) carbide (CuC 2 ), copper(II) cyanide (Cu(CN) 2 ), copper(II) carbonate (CuCO 3 ), copper(II) chloride (CuCl 2 ), copper(II) fluoride (CuF 2 ), copper(II) nitrate (Cu(NO 3 ) 2 ), copper(II) oxide (CuO), copper(II) hydroxide (Cu(OH) 2 ), copper(II) iodide (CuI 2 ), copper(II) sulfide (CuS), copper(II) sulfate (CuSO 4 ), copper(II) arsenate (Cu 3 (AsO 4 ) 2 ), potassium hexafluorocuprate (K 3 CuF 6 ), copper(III) oxide (Cu 2 O 3 ), and cesium hexafluorocuprate (Cs 2 CuF 6 ).
44 . The method of claim 43 , wherein the copper-based catalyst is CuSO 4 ; and the mole to mole ratio of arsenous acid to CuSO 4 ranges from about 1:2 to 1:3 arsenous acid to CuSO 4 .
45 . The method of claim 38 , wherein step (c) is conducted at about 0° C.
46 . The method of claim 38 , wherein the process further comprises neutralizing and filtering the third solution.
47 . The method of claim 38 , wherein the radiolabeled phenylarsonic acid is isolated.
48 . The method of claim 38 , wherein the radiolabeled phenylarsonic acid is further reacted with a thioamine and a monothiol or dithiol.