Syntheses of isotopically labeled 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid x receptor-selective ligand

LGD1069, 4‐[1‐(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethenyl] benzoic acid, is the first retinoid X receptor (RXR) selective retinoid to enter clinical trials for treatment of dermatological diseases and cancer. In order to examine biological properties such as receptor binding, metabolism and bioavailability, [13C]‐, [14C]‐, and [3H]‐labeled LGD1069 is required. Herein, we describe synthetic methods for preparing isotopically labeled homologs of LGD1069 as well as comparative competition binding data for [6,7‐3H]‐LGD1069 and [3H]‐9‐cis retinoic acid with RXR active retinoids. The final radiolabeled products, [6,7‐3H]‐LGD1069 and 3‐[14C]‐LGD1069 have specific activities of 56 Ci/mmol and 49 mCi/mmol, respectively. Radiochemical purities are 99.5% for [6,7‐3H]‐LGD1069 and 99.0% for 3‐[14C]‐LGD1069. The chemical purity is 99.0% for 3‐[13CD3]‐LGD1069. Competition binding studies with known retinoids show similar Kd values when either [6,7‐3H]‐LGD1069 or [3H]‐9‐cis retinoic acid is used as the radioligand.