Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa)

Abstract

Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11. From this effort, oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N-phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat Ki=0.10 nM; human TSPO genotypes Ki=1.4 nM; clogD=4.18).

Chart 1. Structures of Some PET TSPO Radioligands

Figure 1

Generalized structure of compounds tested in this study.

Scheme 1. Synthesis of Ligands 10a–w

Reagents and conditions: (i) PyBroP, DIPA, DCM, rt; (ii) propargyl bromide, LDA, THF, −78 °C; (iii) 10% CuCl/AgOTf, DCA, 100 °C.

Scheme 2. Synthesis of S-Tethered Ligand 12

Reagents and conditions: (i) PhNHMe, 190 °C; (ii) t-BuOK, t-BuOH, DMF, 135 °C.

Scheme 3. Synthesis of N-Tethered Ligand 14

Reagents and conditions: (i) NaN₃, DMF, 70 °C; (ii) Ph₃P, H₂O, THF, rt; (iii) HCl(g), toluene, rt; (iv) 4% Pd(OAc)₂, 8% DPEPhos, K₃PO₄, dioxane, 85 °C.

Scheme 4. Syntheses of O-Tethered Ligands 15a–c

Reagents and conditions: (i) Cs₂CO₃, acetone, rt.

Scheme 5. Syntheses of Naphthyridine, Quinazoline, and 2-Pyridylquinoline Analogues of 15a

Reagents and conditions: (i) PhCOCl, TEA, DCM, DMAP, rt; (ii) BuLi, THF, −78 °C then N-methoxy-N-methylacetamide, −30 °C; (iii) for 17c, PhCO₂H, PyBroP, DIPA, DMAP, DCM, rt; (iv) NaOH, dioxane, 110 °C; (v) for 18e, NaOH, DMSO, 110 °C; (vi) for 19a–e, Cs₂CO₃, acetone, rt; (vii) PyBroP, DIPA, DCM, rt; (viii) NaOH, dioxane, 110 °C; (ix) for 22a, K₂CO₃, MeCN, 50 °C; (x) Cs₂CO₃, acetone, rt.

Figure 2

Plot of rat pK_i versus clogD for ligands having different side chain tethers.

Figure 3

Plot of genotype sensitivity versus HAB TSPO binding affinity for tested ligands.