Synthesis and characterization of a highly potent and selective isotopically labeled retinoic acid receptor ligand, ALRT1550

The syntheses of two labeled homologues of (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3- methylocta-2,4,6-trienoic acid (ALRT1550, 2), [(CD3)-C-13]ALRT1550 (3) and [H-3]ALRT1550 (4), are described in this report. ALRT1550 is an exceptionally potent antiproliferative agent which is currently in phase I/II clinical trials for acute chemotherapy. Both homologues were prepared from commercially available 3,5-di-tert-butylbenzoic acid. Homologue [(CD3)-C-13]ALRT1550 was labeled at the 7-position of the trienoic acid chain via addition of [(CD3)-C-13]MgI to a Weinreb amide precursor. The preparation of [H-3]ALRT1550 utilized novel methodology to synthesize a sterically hindered and site-specific tritium-labeled tert-butyl group. Saturation binding and Scatchard analysis of this ligand at the retinoic acid receptors are also described, along with competition binding (K-i) values for a series of known retinoids using [H-3]ALRT1550 or [H-3]ATRA as the labeled probes.