11C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

Determination of the residual beta-cell mass using noninvasive tools might help to follow up the efficacy of new treatments in both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, including islet transplantation. beta-cells are neuroendocrine cells that can take up and metabolize the serotonin precursor 5-hydroxytryptophan. The serotonin pathway may therefore be an attractive target for the development of an imaging tracer for residual beta-cell mass. The aim of this study was to evaluate the uptake mechanism and the retention of the PET tracer C-11-hydroxytryptophan in endocrine and exocrine pancreas in vitro and in vivo. Methods: The exocrine human pancreas carcinoma cell line (PANC-1) and the endocrine human insulinoma cell line (CM) were applied for in vitro C-11-hydroxytryptophan accumulation/efflux experiments and blocking studies using inhibitors of key enzymes and transporters involved in the serotonin pathway. Animal experiments were performed on normal Wistar rats and on rats pretreated with the monoamine oxidase (MAO) inhibitor clorgyline. After intravenous injection of C-11-hydroxytryptophan, a 60-min dynamic PET scan was acquired followed by an ex vivo biodistribution study. Autoradiography and hematoxylin-eosin staining were performed on the dissected pancreas to localize the radioactivity within the pancreatic tissue. Results: C-11-hydroxytryptophan accumulated rapidly in both endocrine CM cells and exocrine PANC-1 cells. In the exocrine cells, a rapid efflux of radioactivity was observed, whereas most radioactivity remained trapped in the endocrine cells. PET images showed clear accumulation of C-11-hydroxytryptophan in the pancreas in both animal groups, but with a significant 3-fold higher retention of the radiopharmaceutical in clorgyline-treated animals. Ex vivo biodistribution studies confirmed the results obtained by PET. Autoradiographs did not discriminate between the exocrine and endocrine pancreas in control animals, whereas autoradiographs showed intense radioactive spots colocalized with the islets of Langerhans in clorgyline-treated animals. Conclusion: C-11-hydroxytryptophan is trapped in beta-cells but not in exocrine pancreatic cells. beta-cell selectivity can be strongly enhanced by inhibition of MAO-A. This observation offers perspectives for the development of a more selective PET tracer for beta-cell mass, based on an C-11-hydroxytryptophan derivative with increased resistance toward degradation by MAO-A.