Annals of Nuclear Medicine

, Volume 26, Issue 3, pp 253–261 | Cite as

Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide

  • Chang-Sok Oh
  • Saady Kohanim
  • Fan-Lin Kong
  • Ho-Chun Song
  • Nathan Huynh
  • Richard Mendez
  • Mithu Chanda
  • E. Edmund Kim
  • David J. Yang
Original article

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

99mTc-DTPA-glipizide Sulfonylurea receptor Imaging Pancreas 

References

  1. 1.
    Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965;14(10):619–33.PubMedGoogle Scholar
  2. 2.
    Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia. 2005;48(11):2221–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes. 2004;53(1):250–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Dwarakanathan A. Diabetes update. J Insur Med. 2006;38(1):20–30.PubMedGoogle Scholar
  6. 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
  7. 7.
    Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C, et al. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Investig. 1988;81(2):435–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Kargar C, Ktorza A. Anatomical versus functional beta-cell mass in experimental diabetes. Diabetes Obes Metab. 2008;10(Suppl 4):43–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Singhal T, Ding YS, Weinzimmer D, Normandin MD, Labaree D, Ropchan J, et al. Pancreatic beta cell mass PET imaging and quantification with [(11)C]DTBZ and [(18)F]FP-(+)-DTBZ in rodent models of diabetes. Mol Imaging Biol. 2011;13(5):973–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Aguilar-Bryan L, Clement JPt, Gonzalez G, Kunjilwar K, Babenko A, Bryan J. Toward understanding the assembly and structure of KATP channels. Physiol Rev. 1998;78(1):227–45.PubMedGoogle Scholar
  11. 11.
    Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002;51(Suppl 3):S368–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Schwanstecher M, Schwanstecher C, Dickel C, Chudziak F, Moshiri A, Panten U. Location of the sulphonylurea receptor at the cytoplasmic face of the beta-cell membrane. Br J Pharmacol. 1994;113(3):903–11.PubMedGoogle Scholar
  13. 13.
    Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS. The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy: a retrospective analysis. Diabetes Care. 2010;33(6):1224–9.PubMedCrossRefGoogle Scholar
  14. 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
  15. 15.
    Schmitz A, Shiue CY, Feng Q, Shiue GG, Deng S, Pourdehnad MT, et al. Synthesis and evaluation of fluorine-18 labeled glyburide analogs as beta-cell imaging agents. Nucl Med Biol. 2004;31(4):483–91.PubMedCrossRefGoogle Scholar
  16. 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
  17. 17.
    Portha B, Tourrel-Cuzin C, Movassat J. Activation of the GLP-1 receptor signalling pathway: a relevant strategy to repair a deficient beta-cell mass. Exp Diabetes Res. 2011;2011:376509.PubMedGoogle Scholar
  18. 18.
    Kitabchi AE, Kaminska E, Fisher JN, Sherman A, Pitts K, Bush A, et al. Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus. Am J Med Sci. 2000;319(3):143–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Prendergast BD. Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents. Clin Pharm. 1984;3(5):473–85.PubMedGoogle Scholar
  20. 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
  21. 21.
    Hui YH, Huang NH, Ebbert L, Bina H, Chiang A, Maples C, et al. Pharmacokinetic comparisons of tail-bleeding with cannula- or retro-orbital bleeding techniques in rats using six marketed drugs. J Pharmacol Toxicol Methods. 2007;56(2):256–64.PubMedCrossRefGoogle Scholar
  22. 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. 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
  24. 24.
    Mishra AK, Hazari PP, Shukla G, Goel V, Chuttani K, Kumar N, et al. Synthesis of specific SPECT-radiopharmaceutical for tumor imaging based on methionine: (99m)Tc-DTPA-bis(methionine). Bioconjug Chem. 2010;21(2):229–39.PubMedCrossRefGoogle Scholar
  25. 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
  26. 26.
    Hossain GA, Moinul Islam SM, Mahmood S, Khan N, Chakrabarty RK. Tc-99m DTPA scintigraphy in soft tissue tumor. Mymensingh Med J. 2005;14(2):185–8.PubMedGoogle Scholar
  27. 27.
    Simpson NR, Souza F, Witkowski P, Maffei A, Raffo A, Herron A, et al. Visualizing pancreatic beta-cell mass with [11C]DTBZ. Nucl Med Biol. 2006;33(7):855–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Christ GJ, Day N, Santizo C, Sato Y, Zhao W, Sclafani T, Bakal R, Salman M, Davies K, Melman A. Intracorporal injection of hSlo cDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo. Am J Physiol Heart Circ Physiol. 2004;287(4):H1544–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Goldstein R, Meyer T. Role of everolimus in pancreatic neuroendocrine tumors. Expert Rev Anticancer Ther. 2011;11(11):1653–65.PubMedCrossRefGoogle Scholar
  30. 30.
    Snigur GL, Pisarev VB, Spasov AA, Samokhina MP, Bulanov AE. Mechanisms of toxic effect of streptozotocin on beta-cells in the islets of Langerhans. Bull Exp Biol Med. 2009;148(6):937–9.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2012

Authors and Affiliations

  • Chang-Sok Oh
    • 1
  • Saady Kohanim
    • 1
  • Fan-Lin Kong
    • 1
  • Ho-Chun Song
    • 2
  • Nathan Huynh
    • 1
  • Richard Mendez
    • 1
  • Mithu Chanda
    • 1
  • E. Edmund Kim
    • 1
  • David J. Yang
    • 1
  1. 1.Division of Diagnostic ImagingThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Nuclear MedicineChonnam National University Medical School and HospitalGwangjuSouth Korea

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