Nicht-invasive Visualisierung und Quantifizierung der Betazellmasse des humanen Pankreas - Aktueller Stand

Zusammenfassung

Die genaue Bestimmung der Betazellmasse (BZM) bei Patienten mit Diabetes mellitus ist bisher nicht möglich, da Pankreasbiopsien ein nicht vertretbares Risiko mit sich bringen. Die Entwicklung eines nicht-invasiven Verfahrens wäre deshalb sehr wertvoll, um die BZM im Laufe der Diabeteserkrankung oder im Rahmen von Interventionsstudien longitudinal zu erfassen. Dieser Artikel diskutiert die prinzipiellen theoretischen Anforderungen um dieses Ziel zu erreichen. Zusätzlich gibt er einen Überblick über Radiopharmazeutika, die in den letzten Jahren als mögliche Tracer evaluiert worden sind, um die BZM nicht-invasiv in vivo zu bestimmen. Der Artikel diskutiert darüber hinaus mögliche Perspektiven.

Abstract

Accurate assessment of the beta cell mass in humans is hampered by the inaccessibility of the pancreas for biopsy sampling. Thus, the development of non-invasive means of beta cell mass measurement would be invaluable in the study of the natural course of diabetes and the ongoing trials to preserve beta cell mass in patients with diabetes. This article discusses the principle theoretical requirements for reaching this goal and provides an overview of radiopharmaceuticals which have been examined as possible tracers for non-invasive imaging of the beta cell mass. In addition, some key points for further developments in this field are discussed.

Schlüsselwörter

Betazellmasse - PET - nicht-invasiv - SUR 1

Key words

beta-cell mass - PET - non-invasive - SUR 1

Literatur

• 1 Weir G C, Bonner-Weir S, Leahy J L. Islet mass and function in diabetes and transplantation.  Diabetes. 1990;  39 401-415
• 2 Butler A E, Janson J, Bonner-Weir S, Ritzel R, Rizza R A, Butler P C. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes.  Diabetes. 2003;  52 102-110
• 3 Stoffers D A, Kieffer T J, Hussain M A et al. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.  Diabetes. 2000;  49 741-748
• 4 Mu J, Woods J, Zhou Y P et al. Chronic inhibition of dipeptidyl peptidase-4 with sitagliptin analog preserves pancreatic cell mass and function in a rodent model of type 2 diabetes.  Diabetes. 2006;  55 1695-1704
• 5 Sweet I R, Cook D L, Lernmark A, Greenbaum C J, Wallen A R, Marcum E S, Stekhova S A, Krohn K A. Systematic screening of potential β-cell imaging agents.  Biochem Biophys Res Commun. 2004;  314 976-983
• 6 Sweet I R, Cook D L, Lernmark A, Greenbaum C J, Krohn K A. Non-invasive imaging of β-cell mass: A quantitative analysis.  Diabetes Technology & Therapeutics. 2004;  6 652-659
• 7 Hampe C S, Wallen A R, Schlosser M, Ziegler, Sweet I R. Quantitative evaluation of a monoclonal antibody and its fragment as potential markers for pancreatic β-cell mass.  Exp Clin Endocrinol Diabetes. 2005;  113 381-387
• 8 Guiot Y, Stevens M, Marhfour I et al. Morphological localisation of sulfonylurea receptor 1 in endocrine cells of human, mouse and rat pancreas.  Diabetologia. 2007;  50 1889-1899
• 9 Dubowchik G M, Walker M A. Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs.  Pharmcol Ther. 1999;  83 67-123
• 10 Moore A, Bonner-Weir S, Weissleder R. Non-invasive in vivo measurement of β-cell mass in mouse model of diabetes.  Diabetes. 2001;  50 2231-2236
• 11 Ladriere L, Malaisse-Lagae F, Alejandro R, Malaisse W J. Pancreatic fate of a (¹²⁵)I-labelled mouse monoclonal antibody directed against pancreatic β-cell surface ganglioside(s) in control and diabetic rats.  Cell Biochem Funct. 2001;  19 107-115
• 12 Colcher D, Pavlinkova G, Beresford G, Booth B J, Choudhury A, Batra S K. Pharmacokinetics and biodistribution of genetically-engineered antibodies.  Q J Nucl Med. 1998;  42 225-241
• 13 Malaisse W J. On the track to the β-cell.  Diabetologia. 2001;  44 393-406
• 14 Malaisse W J, Ladrière L, Cancelas J, Acitores A, Villanueva-Peñacarrillo M L, Valverde I. Pancreatic and hepatic glycogen content in normoglycemic and hyperglycemic rats.  Mol Cell Biochem. 2001;  219 45-49
• 15 Drucker D J, Nauck M A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.  Lancet. 2006;  368 1696-1705
• 16 Reubli J C, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting.  Eur J Nucl Med Mol Imaging. 2003;  30 781-793
• 17 Wild D, Béhé M, Wicki A et al. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting.  J Nucl Med. 2006;  47 2025-2033
• 18 Gotthardt M, Lalyko G, van Eerd-Vismale J et al. A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents.  Regul Pept. 2004;  137 162-167
• 19 Ran C, Pantazopoulos P, Medarova Z, Moore A. Synthesis and testing of β-cell-specific streptozotocin-derived near-infrared imaging probes.  Angew Chem Int Ed Engl. 2007;  46 8998-9001
• 20 Malaisse W J, Doherty M, Ladrière L, Malaisse-Lagae F. Pancreatic uptake of [2-(14)C]alloxan.  Int J Mol Med. 2001;  7 311-315
• 21 Malaisse W J, Doherty M, Kadiata M M, Ladriere L, Malaisse-Lagae F. Pancreatic fate of D-[³H] mannoheptulose.  Cell Biochem Funct. 2001;  19 171-179
• 22 Crenier L, Courtois P, Malaisse W J. Uptake of tritiated D-mannoheptulose by liver, pancreatic exocrine and endocrine cells.  Int J Mol Med. 2001;  8 155-157
• 23 Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes.  Diabetologia. 2008;  51 216-226
• 24 Ladriere L, Malaisse-Lagae F, Malaisse W J. Pancreatic uptake of ⁶⁵Zn in control and streptozotocin diabetic rats.  Med Sci Res. 2000;  28 43-44
• 25 Schirrmacher R, Weber M, Schmitz A et al. Radiosyntheses of 1-(4-(2-[¹⁸F]fluoroethoxy)benzenesulfonyl)-3-butyl urea: A potential β-cell imaging agent.  J Label Compd Radiopharm. 2002;  45 763-774
• 26 Schneider S, Feilen P J, Schreckenberger M 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;  113 388-395
• 27 Schneider S, Ueberberg S, Korobeynikov A 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;  139 122-127
• 28 Wängler B, Schneider S, Thews O et al. Synthesis and evaluation of [¹⁸F]repaglinide): a promising radioligand for quantification of pancreatic β-cell mass with positron emission tomography (PET).  Nucl Med Biol. 2004;  31 639-647
• 29 Wängler B, Shiue C Y, Schneider S et al. Synthesis and in vitro evaluation of (S)-2-([¹¹C]methoxy)-4-([3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([¹¹C]methyl-Repaglinide): a potential β-cell imaging agent.  Bioorg Med Chem Lett. 2004;  14 5205-5209
• 30 Maffei A, Liu Z, Witkowski P et al. Identification of tissue-restricted transcripts in human islets.  Endocrinology. 2004;  145 4513-4521
• 31 Souza F, Simpson N, Raffo A et al. Longitudinal non-invasive PET-based β-cell mass estimates in a spontaneous diabetes rat model.  J Clin Invest. 2006;  116 1506-1513
• 32 Liu E H, Herscovitch P, Barker C et al. C-11-DTBZ PET scanning: Its potential for measuring β-cell mass in vivo.  Diabetes. 2007;  56 Suppl. 1 A 83
• 33 Sweet I R. Obstacles to achieve adaequate imaging.  Diabetologia. 2007;  50 Suppl. 1 1
• 34 Trepel M, Arap W, Pasqualini R. In vivo phage display and vascular heterogeneity: implications for targeted medicine.  Curr Opin Chem Biol. 2002;  6 399-404
• 35 Arap W, Kolonin M G, Trepel M et al. Steps toward mapping the human vasculature by phage display.  Nat Med. 2002;  8 121-127
• 36 Rajotte D, Arap W, Hagerdorn M, Koivunen E, Pasqualini R, Ruoslahti E. Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display.  J Clin Invest. 1998;  102 430-437
• 37 Samli K N, McGuire M J, Newgard C B, Johnston S A, Brown K C. Peptide-mediated targeting of the islets of Langerhans.  Diabetes. 2005;  54 2103-2108