Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide
This study was aimed to assess pancreas beta cell activity using 99mTc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated.
DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30–120 min after injection of 99mTc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given 99mTc-DTPA. To demonstrate pancreas beta cell uptake of 99mTc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately—65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h.
The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. 99mTc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas 99mTc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with 99mTc-DTPA-GLP in normal rat, however, 99mTc-DTPA has poor uptake suggesting the specificity of 99mTc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug.
It is feasible to use 99mTc-DTPA-GLP to assess pancreas beta cell receptor recognition. 99mTc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors.
Keywords99mTc-DTPA-glipizide Sulfonylurea receptor Imaging Pancreas
- 6.Robertson C, Drexler AJ, Vernillo AT. Update on diabetes diagnosis and management. J Am Dent Assoc. 2003;134 Spec No:16S–23S.Google Scholar
- 14.Schneider S, Feilen PJ, Schreckenberger M, Schwanstecher M, Schwanstecher C, Buchholz HG, et al. In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans. Exp Clin Endocrinol Diabetes. 2005;113(7):388–95.PubMedCrossRefGoogle Scholar
- 16.Schneider S, Ueberberg S, Korobeynikov A, Schechinger W, Schwanstecher C, Schwanstecher M, et al. Synthesis and evaluation of a glibenclamide glucose-conjugate: a potential new lead compound for substituted glibenclamide derivatives as islet imaging agents. Regul Pept. 2007;139(1–3):122–7.PubMedCrossRefGoogle Scholar
- 20.Assadi M, Eftekhari M, Hozhabrosadati M, Saghari M, Ebrahimi A, Nabipour I, et al. Comparison of methods for determination of glomerular filtration rate: low and high-dose Tc-99m-DTPA renography, predicted creatinine clearance method, and plasma sample method. Int Urol Nephrol. 2008;40(4):1059–65.PubMedCrossRefGoogle Scholar
- 22.Wangler B, Beck C, Shiue CY, Schneider S, Schwanstecher C, Schwanstecher M, et al. Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbam oyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent. Bioorg Med Chem Lett. 2004;14(20):5205–9.PubMedCrossRefGoogle Scholar
- 23.Wangler B, Schneider S, Thews O, Schirrmacher E, Comagic S, Feilen P, et al. Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET). Nucl Med Biol. 2004;31(5):639–47.PubMedCrossRefGoogle Scholar
- 25.Mishra AK, Kakkar D, Tiwari AK, Chuttani K, Kaul A, Singh H. Comparative evaluation of glutamate-sensitive radiopharmaceuticals: technetium-99m-glutamic acid and technetium-99m-diethylenetriaminepentaacetic acid-bis(glutamate) conjugate for tumor imaging. Cancer Biother Radiopharm. 2010;25(6):645–55.PubMedCrossRefGoogle Scholar