SYNTHESES OF ISOTOPICALLY LABELED THYL-5,6,7,8-TETRAHYDRO-2-NAPHTHYL)ETHENYL]BENZOIC ACID (LGD1069), A POTENT RETINOID-X RECEPTOR-SELECTIVELIGAND

LGD1069, pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl] benzoic ac id, 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, me tabolism and bioavailability, [C-13]-, [C-14]-, and [H-3]-labeled LGD1 069 is required. Herein, we describe synthetic methods for preparing i sotopically labeled homologs of LGD1069 us well as comparative competi tion 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 an d 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 9 9.0% for 3-[(CD3)-C-13]-LGD1069, Competition binding studies with know n 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.