Synthesis of Mercapto-(+)-methamphetamine Haptens and Their Use for Obtaining Improved Epitope Density on (+)-Methamphetamine Conjugate Vaccines

Carroll, F., Blough, B., Pidaparthi, R., Abraham, P., Gong, P. K., Deng, L., ... Owens, S. M. (2011). Synthesis of Mercapto-(+)-methamphetamine Haptens and Their Use for Obtaining Improved Epitope Density on (+)-Methamphetamine Conjugate Vaccines. Journal of Medicinal Chemistry, 54(14), 5221-5228. DOI: 10.1021/jm2004943

This study reports the synthesis of the mercapto-hapten (S)-N-(2-(mercaptoethyl)-6-(3-(2-(methylamino)propyl)phenoxy)hexanamide [3, (+)-METH HSMO9] and its use to prepare METH-conjugated vaccines (MCV) from maleimide-activated proteins. MALDI-TOF mass spectrometry analysis of the MCV synthesized using 3 showed there was a high and controllable epitope density on two different carrier proteins. In addition, the MCV produced a substantially greater immunological response in mice than previous METH haptens, and a monoclonal antibody generated from this MCV in mice showed a very high affinity for (+)-METH (K(D) = 6.8 nM). The efficient covalent coupling of (+)-METH HSMO9 to the activated carrier proteins suggests that this approach could be cost-effective for large-scale production of MCV. In addition, the general methods described for the synthesis of (+)-METH HSMO9 (3) and its use to synthesize MCV will be applicable for conjugated vaccines of small molecules and other substances of abuse such as morphine, nicotine, and cocaine