Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging

Abstract

SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed.

Figure 1

Key structural features of SRX246.

Scheme 1

Syntheses of fluoro, iodo and methyl analogs of SRX246. Reagents and conditions: (a) (R)-methylbenzylamine, HOBt, EDC·HCl, CH₂Cl₂, rt, 18 h; (b) H₂, Pd/C 5%, MeOH, 18 h; (c) Na₂SO₄ anhydrous, CH₂Cl₂; (c′) oxalyl chloride, DMF cat., CH₂Cl₂; (d) NEt₃, CH₂Cl₂, 0 °C to rt, 1 h; (e) HCO₂H; (f) 4-(1-piperidinyl) piperidine, HOBt, EDC, HCl, CH₂Cl₂, rt, 18 h.

Scheme 2

Preparation of meta-substituted-trans-cinnamaldehydes. Reagents and conditions: (a) EDC·HCl, DMAP, EtOH, CH₂Cl₂, rt, 18 h; (a′) triethyl phosphonoacetate, nBuLi in hexanes, THF, −78 °C, 10 min; 3-iodobenzaldehyde, THF, −78 °C, 40 min, to rt 45 min; (b) DIBAL, CH₂Cl₂, −78 °C, 2 h; 10% aqueous NaOH, −78 °C to rt, 15 min; (c) pyridinium dichromate, CH₂Cl₂; (d) hexamethylditin, Pd(PPh₃)₄, dioxane, 150 min.

Scheme 3

Synthesis of radiolabeling precursor 16. Reagents and conditions: (a) HCO₂H; (b) 4-(1-piperidinyl) piperidine, HOBt, EDC·HCl, CH₂Cl₂, rt, 18 h; (c) H₂, Pd/C 5%, MeOH, 18 h; (d) Na₂SO₄ anhydrous, CH₂Cl₂; (d′) oxalyl chloride, DMF cat., CH₂Cl₂; (e) NEt₃, CH₂Cl₂, 0 °C to rt, 1 h.

Scheme 4

Conversion of trimethyltin derivative 16 to 11a, [¹²³I]11a and 11b. Reagents and conditions: (a) NaI, chloramine T, 1 M HCl, ethanol, rt, 5 min; (a′) [¹²³I]NaI, chloramine T, 1 M HCl, ethanol, rt, 5 min; (b) Selectfluor^™ (BF⁻₄), AgOTf, acetone, rt, 30 min.