Imaging agents for neural flux
Provided herein are radiolabeled compounds useful for non-invasive imaging techniques. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography. The present application also provides unlabeled compounds useful in methods of treating diseases of the central nervous system or disease of the peripheral nervous system. Methods for preparing radiolabeled compounds, preparing unlabeled compounds, and diagnostic methods using labeled or unlabeled compounds are also provided.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
represents a single- or double-bond;
X 1 is CR A or NR B ;
X 2 is CR A or NR B ; wherein
one of X 1 and X 2 is CR A and the other is NR B ;
R A is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C 1-6 alkylene)-Cy 2 , OR a2 , C(═O)R b2 , C(═O)OR b2 , NR c2 R d2 , C(═O)NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , NR c2 C(═O)NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(O)R a2 , S(O) 2 R a2 , S(O)NR c2 R d2 , and S(O) 2 NR c2 R d2 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
R B is absent; or
R B is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C 1-6 alkylene)-Cy 2 , OR a2 , C(═O)R b2 , C(═O)OR b2 , NR c2 R d2 , C(═O)NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , NR c2 C(═O)NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(O)R a2 , S(O) 2 R a2 , S(O)NR c2 R d2 , and S(O) 2 NR c2 R d2 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
R 1 is NR N R N′ ;
R N is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
R N′ is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and —(C 1-6 alkylene)-Cy 1 , wherein the C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
R 2 is absent; or
R 2 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C 1-6 alkylene)-Cy 2 , OR a2 , C(═O)R b2 , C(═O)R b2 , NR c2 R d2 , C(═O)NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , NR c2 C(═O)NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(O)R a2 , S(O) 2 R a2 , S(O)NR c2 R d2 , and S(O) 2 NR c2 R d2 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
wherein at least two of R A , R B , and R 2 are independently H or absent;
R 3 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, NR c3 R d3 and NO 2 , wherein the C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
each R a2 , R b2 , R c2 , and R d2 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R c3 and R d3 are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C(═O)OR a2 , wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
each Cy is independently selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
each Cy 1 is independently selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups;
each Cy t is independently selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups; and
each R 4 is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, —(C 1-6 alkoxy)-(C 1-6 alkoxy), C 1-6 haloalkoxy, C 3-10 cycloalkyl, phenyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, —(C 1-6 alkylene)-amino, —(C 1-6 alkylene)-C 1-6 alkylamino, —(C 1-6 alkylene)-di(C 1-6 alkyl)amino, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, —(C 1-6 alkylene)-C 1-6 alkyoxycarbamyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 6-10 arylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
wherein the compound of Formula (II) comprises at least one radioisotope.
2. The compound of claim 1 , wherein R N is H or C 1-6 alkyl.
3. The compound of claim 1 , wherein R N′ is selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and —(C 1-6 alkylene)-Cy 1 .
4. The compound of claim 1 , wherein Cy 1 is selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, and 4-10 membered heteroaryl, and each is optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups.
5. The compound of claim 1 , wherein R 2 is selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C 1-6 alkylene)-Cy 2 , C(═O)R b2 , and NR c2 R d2 , wherein the C 1-6 alkyl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4 groups.
6. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, halo, NR c3 R d3 , and NO 2 .
7. The compound of claim 1 , wherein the radioisotope is selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 34m Cl, 38 K, 45 Ti, 51 Mn, 52m Mn, 52 Fe, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 68 Ga, 71 As, 72 As, 74 As, 75 Br, 76 Br 82 Rb, 86 Y, 89 Zr, 90 Nb, 94m Tc, 110m In, 118 Sb, 120 I, 121 I, 122 I, and 124 I.
8. The compound of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
10. A compound, which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
12. A compound, which is:
or a pharmaceutically acceptable salt thereof.