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 io examine biological properties such as receptor binding, metabolism and bioavailability, [C-13]-, [C-14]-, and [H-3]-labeled LGD1069 is required. Herein, we describe synthetic methods for preparing isotopically labeled homologs of LGD1069 us well as comparative competition binding data for [6,7-H-3]-LGD1069 and [H-3]-9-cis retinoic acid with RXR active retinoids. The final radiolabeled products, [6,7-H-3]-LGD1069 and 3-[C-14]-LGD1069 have specific activities of 56 Ci/mmol and 49 mCi/mmol, respectively. Radiochemical purities are 99.5% for [6,7-H-3]-LGD1069 and 99.0% for 3-[C-14]-LGD1069. The chemical purity is 99.0% for 3-[(CD3)-C-13]-LGD1069, Competition binding studies with known retinoids show similar K-d values when either [6,7-H-3]-LGD1069 or [H-3]-9-cis retinoic acid is used as the radioligand.