Synthesis and PET evaluation of (R)‐[S‐methyl‐11C]thionisoxetine,a candidate radioligand for imaging brain norepinephrine transporters

Introduction: (R)‐3‐(2‐(methylthio)phenoxy)‐N‐methyl‐3‐phenylpropan‐1‐amine (R)–thionisoxetine; 1 ] is a potent inhibitor of the norepinephrine transporter (NET). We aimed to label 1 with carbon‐11 (t_1/2 = 20.4 min) for evaluation as a radioligand for imaging NET in living brain with positron emission tomography (PET). Methods: Methyl 3‐(2‐((R)‐3‐(methylamino)‐1‐phenylpropoxy)phenylthio)‐propanoate (MPPP) and 1 were each prepared from o‐hydroxythiophenol in three steps. Treatment of MPPP with potassium t‐butoxide and ¹¹C]methyl iodide in tetrahydrofuran gave S‐methyl‐¹¹C]thionisoxetine (¹¹C] 1 ), which was purified with HPLC. The distribution of radioactivity in brain after intravenous injection of ¹¹C] 1 into cynomolgus monkey was followed with PET and the appearance of radiometabolites in plasma monitored with radio‐HPLC. Results: ¹¹C] 1 was obtained in high yield from ¹¹C]methyl iodide. Of the radioactivity injected into monkey, 2.4% entered brain. Ratios of radioactivity in thalamus, mesencephalon, occipital cortex and caudate to that in cerebellum at 93 min were 1.3, 1.2, 1.2 and 1.1, respectively. The radioactivity in plasma corresponding to unchanged radioligand decreased to 53% at 45 min, with the remainder represented by hydrophilic radiometabolites. Conclusions: MPPP is an effective precursor for ¹¹C‐methylation to ¹¹C] 1 , suggesting that the S‐γ‐propionic acid methyl ester protecting group may have wider value in the ¹¹C‐labeling of aryl methyl sulfides. However, the relatively low ratios of radioactivity to the cerebellum together with an unexpected accumulation of radioactivity in the caudate, makes ¹¹C] 1 an unpromising NET radioligand. Copyright © 2006 John Wiley & Sons, Ltd.