Synthesis of β‐cell imaging agents

Abstract

Diabetes mellitus is a major public problem, affecting -7.8% of the population (1) and is characterized by a deficiency in insulin secretion and losing 0cells. Two major types of diabetes mellitus have been defined: Type 1 (insulindependent diabetes) and Type 2 (non-insulin dependent diabetes). Type 1 is a chronic autoimmune disease characterized by the selective destruction of insulinproducing p-cells of the islets of Langerhans, leading to a near total deficiency in insulin secretion. Type 2 is caused by two physiological defects: resistance to the action of insulin combined with a deficiency in insulin secretion (2,3). To date, there have been no reported techniques to image the endocrine pancreas. The basis of our inability to image the endocrine pancreas has been due to the unavailability of a marker specific for islet @-cells. A reliable method to monitor the progressive loss of p-cells mass during the silent phase of prediabetes will have great impact on the treatment of diabetes mellitus. Tolbutamide (1) and glyburide (2) are hypoglycemic drugs used to stimulate insulin secretion in Type 2 diabetic patients. These drugs block pancreatic ATP-sensitive K' channels, located at the insulin. producing p-cells of the islets of Langerhans, either directly or via a plasma membrane-associated protein, resulting in an increase of intracellular Ca" and consequent insulin secretion (43). Inhibition constants (Ki) of tolbutamide and glyburide to HIT-P-cells are 25-55 pM (6) and 0.7-7 nM (7), respectively. Therefore, if we labeled glyburide or other sulfonureas that have high binding affinity to sulfonylurea receptor (8) with positron emitters, they may serve as p-cell imaging agents. We report here the synthesis of 2-['8F]fluoroethoxyglyburide (S), 2-['8F]fluoroethoxy-5-iodoglyburide (6) and their biological properties (Figure 1).The precursors, 2-hydroxyglyburide (3) and 2-hydroxy-5-iodoglyburide (4),were synthesized in a similar manner as reported in the literature (9). Nonradioactive compounds 5 and 6 were synthesized from halogen-substituted salicylic acid in 42 and 17% yield, respectively, as shown in Scheme1.The identities of these precursors and authentic samples were verified by NMR and elemental analysis. Fluorine-18 labeled compounds 5 and 6 were synthesized by alkylation of the corresponding hydroxy precursor (3,4) with l-['8F]fluoro-2-tosylethane in DMSO at 12OoC for 20 min followed by HPLC purifications (Phenomenex, Luna 2, C1g, 10 x 250 mm, CH30H:H20, 7:3; 3 mWmin) in an overall yield of 5 1 0 % yield in a synthesis time of 100 min from EOB. The identities of compound 5 and J. LobeNed Cpd. Radiupharm 44, Suppl. 1 (2001) S114Symposium Abstracts compound 6 were verified by both TLC and HPLC compared to the nonradioactive authentic samples.Insulin secretion experiments of compounds 5 and 6 on rat islets showed that both compounds have similar stimulating effect on insulin secretion as that of glyburide (Figure 2). In vitro binding experiments showed that -10% of compound 6 bound to PTC3 cells (8.3921.20%, ...

Radiosynthesis of 1‐(4‐(2‐[18F]fluoroethoxy)benzenesulfonyl)‐3‐butyl urea: a potential β‐cell imaging agent

“…In comparison to the recently described compound 1-(4-[ 18 F]fluorobenzenesulfonyl)-3-butyl urea 12 the new compound 3 could be obtained in much higher yields. Due to the nature of nucleophilic aromatic substitution with [ 18 F]fluoride the aromatic system must be activated for obtaining reasonable radiochemical yields.…”

“…12 The high lipophilicity of these tracers might result in a higher liver uptake and will lead to a difficulty in differentiation between pancreatic and liver radioactivity uptake. A less lipophilic compound such as compound 3 decreases the liver uptake and enhances the imaging quality of b-cell islets in pancreas.…”

“…[ 18 F]fluorobenzenesulfonyl)-3-butyl urea, was synthesized recently in a low overall yield of 1-2%. 12 This low yield makes it difficult to eventually use this radiopharmaceutical routinely in nuclear medicine. To overcome this problem partially, we have synthesized its 18 F-fluoroethoxylated derivative (3) (Figure 1) and tested its efficacy in insulin secretion.…”