Synthesis and preliminary evaluation of benzylaminoimidazoline derivatives as novel norepinephrine transporter ligands.

A series of benzylaminoimidazoline derivatives was synthesized and evaluated for norepinephrine transporter (NET) targeting. Among them, N-(3-iodobenzyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 9) displayed the highest affinity for NET (IC50  = 5.65 ± 0.97 μM). The corresponding radiotracer [125 I]9 was further prepared by copper-mediated radioiodination and evaluated both in vitro and in vivo. The cellular uptake results suggested that [125 I]9 was specifically taken up by the NET-expressing SK-N-SH cell line. Biodistribution studies showed that [125 I]9 accumulated in the heart (5.54 ± 1.24 %ID/g at 5 min p.i. and 0.79 ± 0.08 %ID/g at 2 h p.i.) and adrenal gland (14.83 ± 3.47 %ID/g at 5 min p.i. and 3.87 ± 0.24 %ID/g at 2 h p.i.). The uptake in the heart and adrenal gland could be significantly inhibited by preinjection of desipramine (DMI). These results indicated that the benzylaminoimidazoline derivatives retained affinity for NET, which could provide structure-activity relationship data for further studies.