Radiolabeled monoacylglycerol lipase occupancy probe
Provided herein are monoacylglycerol lipase (MGLL) occupancy probes comprising a MGLL inhibitor containing a positron emission tomography (PET) tracer radionuclide. Also provided are methods of assessing MGLL enzyme occupancy of a MGLL inhibitor using the radiolabeled occupancy probes described herein.
1. A radiolabeled monoacylglycerol lipase (MGLL) occupancy probe comprising an MGLL inhibitor containing a positron emission tomography (PET) tracer radionuclide, wherein the MGLL inhibitor has the structure of Formula (Ib):
wherein
L 3 is —CH 2 —;
R 7 is phenyl; wherein R 7 is substituted by one, two, or three moieties independently selected from R h ;
R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring, which may have an additional heteroatom selected from O, S, and N, wherein the 4-6 membered saturated heterocyclic ring is substituted by C 1-6 haloalkyl; and
R h is selected from the group consisting of: halogen, C 1-6 alkyl (optionally substituted by one, two, or three halogens), and R a R b N—, wherein at least one R h is R a R b N—;
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
2. The radiolabeled MGLL occupancy probe of claim 1 , wherein the PET tracer radionuclide is 18 F.
3. The radiolabeled MGLL occupancy probe of claim 2 , wherein the radiolabeled MGLL occupancy probe forms a covalent adduct with the active-site serine in MGLL.
4. The radiolabeled MGLL occupancy probe of claim 1 having the structure:
5. A compound having the structure of Formula (V):
wherein
p is 0, 1, or 2;
R d is H or C 1-6 alkyl;
L 3 is a bond, —CH 2 —, —S(O) 2 —, or —C(O)—;
R 7 is phenyl substituted by R a R b N— and a moiety selected from the group consisting of: halogen and C 1-6 alkyl (optionally substituted by one, two, or three halogens);
R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocycle or spirocyclic ring, which may have an additional heteroatom selected from O, S, and N; wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocycle or spirocycle is substituted by C 1-6 haloalkyl;
or a solvate, hydrate, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein p is 0.
7. The compound of claim 6 , wherein L 3 is —CH 2 —.
8. The compound of claim 7 , wherein R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, and N; wherein the 4-6 membered heterocyclic ring is substituted by C 1-6 haloalkyl.
9. The compound of claim 8 , wherein the 4-6 membered heterocyclic ring is piperazine.
10. The compound of claim 9 having the structure