Radiolabeled cationic steroid antimicrobials and diagnostic methods
The disclosure provides compounds, methods, and kits for diagnosis, detection, screening, and imaging of a disease condition (e.g., infection, cancer, tumor, neoplasia), in vitro, ex vivo, and/or in vivo. Certain embodiments include administering a cationic steroid antimicrobial (a “CSA” or “ceragenin”), the CSA including a steroidal backbone and a heterocyclic ring separated from the steroidal backbone by at least 4 atoms (and up to 24 atoms or more), to a subject having or at risk of having a disease condition in an amount effective to diagnose, detect, screen for or image the disease condition in the subject.
1. A cationic steroidal antimicrobial (CSA) compound of Formula III, or salt thereof:
wherein,
R 3 , R 7 , and R 12 are independently selected from the group consisting of hydrogen, unsubstituted (C 1 -C 6 ) alkyl, unsubstituted (C 1 -C 6 ) hydroxyalkyl, unsubstituted (C 1 -C 16 ) alkyloxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 16 ) alkylcarboxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 5 )alkyl, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 5 ) alkylamino, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 16 ) alkylamino-(C 1 -C 5 ) alkylamino, unsubstituted (C 1 -C 16 ) aminoalkyl, unsubstituted arylamino-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) aminoalkyloxy, unsubstituted (C 1 -C 16 ) aminoalkyloxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) aminoalkylcarboxy, unsubstituted (C 1 -C 5 ) aminoalkylaminocarbonyl, unsubstituted (C 1 -C 5 ) aminoalkylcarboxamido, unsubstituted di(C 1 -C 5 alkyl)amino-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) guanidinoalkyloxy, unsubstituted (C 1 -C 16 ) quaternary ammonium alkylcarboxy, and unsubstituted (C 1 -C 16 ) guanidinoalkylcarboxy, wherein 0 or 1 of R 3 , R 7 , and R 12 is hydrogen; and
R 18 is
wherein,
R 20 is an alkyl, alkenyl, alkynyl, or aryl connected to R 22 by a urea;
R 21 is selected from the group consisting of hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 7 -C 13 aralkyl, C 1 -C 6 alkyl-(5 to 10 membered heteroaryl), C 3 -C 10 carbocyclyl, C 4 -C 10 (carbocyclyl)alkyl, and amido; and
R 22 is a heterocyclic ring chelator having at least 2 heteroatoms and being attached to the urea by a linkage selected from the group consisting of alkyl, -[alkoxy] n , -[alkoxy] n -alkyl, alkylcarboxamido-alkyl, alkylcarboxamido-[alkoxy] n , alkylcarboxamido-[alkoxy] n -alkyl, alkylcarboxyalkyl, alkylaminoalkyl, aryl, arylaminoalkyl, alkenyl, and alkynyl, where n is 1 to 10,
wherein each of R 20 , R 21 , and R 22 may be optionally substituted, and
wherein the heterocyclic ring chelator is spaced apart from the steroidal backbone by a linkage having at least 10 atoms.
2. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is selected from the group consisting of: 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA), 1,4,7-triazacyclodecane-N,N′,N″-triacetic acid (DETA), 1,4,8-triazacycloundecane-N,N′,N″-triacetic acid (UNTA), 1,5,9-triazacyclododecane-N,N′,N″-triacetic acid (DOTRA), 9,10-benzylidene-1,4,7-triazacyclotridecane-N,N′,N″-triacetic acid (BUNTA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA).
3. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the steroidal backbone by a linkage having at least 12 atoms.
4. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the steroidal backbone by a linkage having at least 16 atoms.
5. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the steroidal backbone by a linkage having at least 20 atoms.
6. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the steroidal backbone by a linkage having at least 24 atoms.
7. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is a 5 to 13 member ring.
8. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is an 8 to 12 member ring.
9. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is a 9-10 member ring.
10. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl; di(alkyl)aminoalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
11. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy.
12. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are the same.
13. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; C 8 -alkylamino-C 5 -alkyl; C 8 -alkoxy-carbonyl-C 4 -alkyl; C 8 -alkyl-carbonyl-C 4 -alkyl; di-(C 5 -alkyl)amino-C 5 -alkyl; C 13 -alkylamino-C 5 -alkyl; C 6 -alkoxy-carbonyl-C 4 -alkyl; C 6 -alkyl-carboxy-C 4 -alkyl; and C 16 -alkylamino-C 5 -alkyl.
14. The CSA compound of claim 1 , wherein the CSA compound is
15. The CSA compound of claim 1 , further comprising a detectable label that is 64 Cu.
16. The CSA compound of claim 1 , further comprising a detectable label that is a metal crystal or metal oxide crystal.
17. The CSA compound of claim 1 , further comprising a detectable label that is selected from the group consisting of: gold, silver, copper, boron, manganese, gadolinium, iron, chromium, barium, europium, erbium, praseodymium, indium, and technetium.
18. The CSA compound of claim 1 , further comprising a detectable label that is a metal oxide selected from the group consisting of: Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), or Er(III).
19. A cationic steroidal antimicrobial (CSA) compound of Formula III, or salt thereof:
wherein,
R 3 , R 7 , and R 12 are independently selected from the group consisting of hydrogen, unsubstituted (C 1 -C 6 ) alkyl, unsubstituted (C 1 -C 6 ) hydroxyalkyl, unsubstituted (C 1 -C 16 ) alkyloxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 16 ) alkylcarboxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 5 )alkyl, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 5 ) alkylamino, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 16 ) alkylamino-(C 1 -C 5 ) alkylamino, unsubstituted (C 1 -C 16 ) aminoalkyl, unsubstituted arylamino-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) aminoalkyloxy, unsubstituted (C 1 -C 16 ) aminoalkyloxy-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) aminoalkylcarboxy, unsubstituted (C 1 -C 5 ) aminoalkylaminocarbonyl, unsubstituted (C 1 -C 5 ) aminoalkylcarboxamido, unsubstituted di(C 1 -C 5 alkyl)amino-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) guanidinoalkyloxy, unsubstituted (C 1 -C 16 ) quaternary ammonium alkylcarboxy, and unsubstituted (C 1 -C 16 ) guanidinoalkylcarboxy, wherein 0 or 1 of R 3 , R 7 , and R 12 is hydrogen; and
R 18 has the following structure:
wherein,
R 20 is an alkyl, alkenyl, alkynyl, or aryl connected to R 22 by a urea;
R 21 is selected from the group consisting of hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 7 -C 13 aralkyl, C 1 -C 6 alkyl-(5 to 10 membered heteroaryl), C 3 -C 10 carbocyclyl, C 4 -C 10 (carbocyclyl)alkyl, and amido; and
R 22 is a 5 to 13 member, 8 to 12 member, or 9 to 10 member heterocyclic ring attached to the urea by a linkage selected from the group consisting of alkyl, -[alkoxy] n , -[alkoxy] n -alkyl, alkylcarboxamido-alkyl, alkylcarboxamido-[alkoxy] n , alkylcarboxamido-[alkoxy] n -alkyl, alkylcarboxyalkyl, alkylaminoalkyl, aryl, arylaminoalkyl, alkenyl, and alkynyl, where n is 1 to 10,
wherein the heterocyclic ring is selected from triazamacrocyclic ring and tetraazamacrocyclic ring,
wherein each of R 20 , R 21 , and R 22 may be optionally substituted, and
wherein the heterocyclic ring is spaced apart from the steroidal backbone by a linkage having at least 14 atoms,
the CSA compound further comprising a detectable label, the detectable label comprising a metal or metal compound bound or complexed to the heterocyclic ring.
20. A cationic steroidal antimicrobial (CSA) compound selected from the group consisting of:
21. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the urea by 1 to 6 ether moieties.
22. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the urea by 3 ether moieties.
23. The CSA compound of claim 1 , wherein the heterocyclic ring chelator is spaced apart from the urea by 4 ether moieties.
24. The CSA compound of claim 19 , wherein the heterocyclic ring is spaced apart from the urea by 1 to 6 ether moieties.
25. The CSA compound of claim 19 , wherein the heterocyclic ring is spaced apart from the urea by 3 ether moieties.
26. The CSA compound of claim 19 , wherein the heterocyclic ring is spaced apart from the urea by 4 ether moieties.