Strategy to develop a MAO-A-resistant 5-hydroxy- l -[β- 11 C]tryptophan isotopologue based on deuterium kinetic isotope effects

Background The serotonin precursor 5-hydroxy- l -[β- 11 C]tryptophan ([ 11 C]HTP) is in clinical use for localization of neuroendocrine tumors and has been suggested as a proxy marker for pancreatic islet cells. However, degradation by monoamine oxidase-A (MAO-A) reduces retention and the contrast to non-endocrine tissue. Methods A synthesis method was developed for 5-hydroxy- l -[β - 11 C 2 H]tryptophan ([ 11 C]DHTP), an isotopologue of [ 11 C]HTP, labeled with 11 C and 2 H at the β-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [ 11 C]DHTP was evaluated and compared to non-deuterated [ 11 C]HTP. Results [ 11 C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 ± 190 MBq, and deuterium ( 2 H or 2 H 2 ) incorporation at the β-position of 22% ±5%. Retention and resistance to MAO-A-mediated degradation of [ 11 C]DHTP were increased in cells but not in non-human primate pancreas. Conclusions Partial deuteration of the β-position yields improved resistance to MAO-A-mediated degradation in vitro but not in vivo .