1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents

A pharmaceutical composition comprising a compound having the following structure:

• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, and halo-alkyl;
• and wherein R2 is selected from the group consisting of straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, and amino-aryl;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, and amino-aryl;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, or carboxylic ester, nitro, amino, and substituted-amino;
• and at least one pharmaceutically acceptable carrier.

A method of treating depression comprising the steps of:

• administering to a subject in need thereof a compound having the following structure:
• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, and halo-alkyl;
• and wherein R2 is selected from the group consisting of straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, and amino-aryl;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, and amino-aryl;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, or carboxylic ester, nitro, amino, and substituted-amino.

A radiotracer having the following structure:

• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, halo-alkyl, and 3H, 18F, and 11C;
• and wherein R2 is selected from the group consisting of straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, carboxylic ester, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C.

A pharmaceutical composition comprising a radiotracer having the following structure:

• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, halo-alkyl, and 3H, 18F, and 11C;
• and wherein R2 selected from the group consisting of alkyl (straight chain or branched), O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, carboxylic ester, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and at least one pharmaceutically acceptable carrier.

A method for in vivo imaging comprising the steps of administering to a subject a radiotracer having the following structure:

• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, halo-alkyl, and 3H, 18F, and 11C;
• and wherein R2 is selected from the group consisting of straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, carboxylic ester, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and detecting the radiotracer wherein the radiotracer is associated with the norepinephrine transporter protein.

A method for tissue imaging comprising the steps of contacting a tissue that contains norepinephrine transporter protein with a radiotracer having the following structure:

• wherein, * independently denotes an R or S configuration or a racemic mixture;
• and wherein R1 is selected from the group consisting of H, methyl, alkyl, halo-alkyl, and 3H, 18F, and 11C;
• and wherein R2 is selected from the group consisting of straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R3 is selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, S-alkyl, aryl-alkyl-, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, alkyl-oxy-alkyl ether-, halo-substituted-alkyl-oxy-alkyl ether-, aryl-oxy-alkyl ether-, O-aryl, S-aryl, amino, amino-alkyl, amino-aryl, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and wherein R4, R5, R6, and R7 are independently selected from the group consisting of H, halogen, straight chain alkyl, branched alkyl, O-alkyl, halo-substituted-alkyl-, halo-substituted-alkenyl-, substituted-alkenyl-, carboxyl acid, carboxylic ester, and 3H, 18F, 75Br, 76Br, 123I, 124I, 125I, 131I, and 11C;
• and detecting the radiotracer.