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%, ...
Angiogenesis is an essential event in many physiological processes such as wound repair, ovulation, and embryogenesis. Neovascularization is also a key component of many pathological processes such as inflammation, glaucoma, diabetic, myocardial ischemia, psoriasis and tumor formation (1, 2). New vessel formation in both physiological and pathological states begins with the activation of endothelial cells in established venules or capillaries in response to an angiogenic stimulus. For tumor‐induced angiogenesis, endothelial activation is mediated by a variety of soluble mitogens produced by the tumor cells that act in a paracrine manner via specific receptors on the endothelial cell (3). Angiogenesis inhibition has become a well‐described antitumor treatment strategy, because avascular tumors are incapable of growth and have little metastatic potential (4). Antagonists of receptors of specific mitogens have been used to inhibit neovascularization in experimental models (5, 6), but a specific receptor antagonist does not necessarily offer protection against tumors that are known to secrete a variety of angiogenic factors. Squalamine (1, Figure 1) is a natural aminosterol found in the tissues of the dogfish shark, which was initially identified based on its antimicrobial activity (7). Recently, we have synthesized (8) and shown that squalamine inhibits angiogenesis and tumor growth in multiple animals models (9). This effect is mediated, at least in part, by blocking mitogen‐induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Compound 1 has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, has no obvious effects on the growth of newborn vertebrates, and has remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Its fluorinated analog, N‐fluoropropylsqualamine (2) has similar biological properties as that of compound 1. Therefore, we have synthesized N‐[18F]fluoropropylsqualamine (2) and evaluated it as an angiogenesis imaging agent.
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