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

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

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