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

Background: The serotonin precursor 5-hydroxy-L-[β-C]tryptophan ([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-CH]tryptophan ([C]DHTP), an isotopologue of [C]HTP, labeled with C and H at the β-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [C]DHTP was evaluated and compared to non-deuterated [C]HTP. Results: [C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 ± 190 MBq, and deuterium (H or H2) incorporation at the β-position of 22% ±5%. Retention and resistance to MAO-A-mediated degradation of [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.