Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide): a potential β-cell imaging agent

The 11 C-labeled sulfonylurea receptor 1 (SUR1) ligand (S)-2-(( 11 C)methoxy)-4-(3-methyl-1-(2-piperidine-1-yl-phenyl)- butyl-carbamoyl)-benzoic acid (( 11 C)methoxy-repaglinide) was synthesized in an overall radiochemical yield of 35% after 55 min with a radiochemical purity higher than 99%. This compound is considered for the noninvasive investigation of the SUR1 receptor status of pancreatic b-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. The specific activity was 40-70 GBq/lmol. In vitro testing of the nonradioactive methoxy-repaglinide was performed to characterize the affinity for binding to the human SUR1 isoform. Methoxy-repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (KD) of 83 nM and an IC50 of 163 nM. Insulin secretion experiments on isolated rat islets were performed to prove biological activity, which was determined to be in the same range as that of original repaglinide. � 2004 Elsevier Ltd. All rights reserved. Diabetes mellitus comprises a heterogeneous group of disorders characterized by high blood glucose levels. Two major types of diabetes mellitus have been defined: type 1 and type 2 diabetes. Although hyperglycemia is the common denominator of both, the etiology and pathophysiology of these syndromes are distinct. Type 1 diabetes is a chronic autoimmune disease character- ized by the selective destruction of insulin-producing b-cells of the islets of Langerhans. When autoimmune destruction affects more than 90% of the b-cell mass, the resulting insulin deficiency culminates into the devel- opment of overt hyperglycemia. In type 2 diabetes, on the other hand, the pancreatic b-cells are initially in- tact, and the disease is associated with insulin resist- ance and loss of b-cell function, and eventual insulin