Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

Heteroatom analogues of hydrocodone, in which the <i>N</i>-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone

New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects

σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)­ethyl)­benzo­[<i>d</i>]­thiazol-2­(3<i>H</i>)-one ([¹⁸F]­FTC-146, [¹⁸F]<b>13</b>). [¹⁸F]<b>13</b> was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (<i>n</i> = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [¹⁸F]<b>13</b> in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (<b>2</b>), nonradioactive <b>13</b>, or BD1047 (<b>18</b>) reduced the binding of [¹⁸F]<b>13</b> in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [¹⁸F]<b>13</b> accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [¹⁸F]<b>13</b> is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects