Molecular Imaging and Biology

, Volume 17, Issue 1, pp 58–66 | Cite as

A Standardized Method for In Vivo Mouse Pancreas Imaging and Semiquantitative β Cell Mass Measurement by Dual Isotope SPECT

  • Iris Mathijs
  • Catarina Xavier
  • Cindy Peleman
  • Vicky Caveliers
  • Maarten Brom
  • Martin Gotthardt
  • Pedro L. Herrera
  • Tony Lahoutte
  • Luc BouwensEmail author
Research Article



In order to evaluate future β cell tracers in vivo, we aimed to develop a standardized in vivo method allowing semiquantitative measurement of a prospective β cell tracer within the pancreas.


2-[123I]Iodo-l-phenylalanine ([123I]IPA) and [Lys40([111In]DTPA)]exendin-3 ([111In]Ex3) pancreatic uptake and biodistribution were evaluated using SPECT, autoradiography, and an ex vivo biodistribution study in a controlled unilaterally nephrectomized mouse β cell depletion model. Semiquantitative measurement of the imaging results was performed using [123I]IPA to delineate the pancreas and [111In]Ex3 as a β cell tracer.


The uptake of [123I]IPA was highest in the pancreas. Aside from the kidneys, the uptake of [111In]Ex3 was highest in the pancreas and lungs. Autoradiography showed only uptake of [111In]Ex3 in insulin-expressing cells. Semiquantitative measurement of [111In]Ex3 in the SPECT images based on the delineation of the pancreas with [123I]IPA showed a high correlation with the [111In]Ex3 uptake data of the pancreas obtained by dissection. A strong positive correlation was observed between the relative insulin positive area and the pancreas-to-blood ratios of [111In]Ex3 uptake as determined by counting with a gamma counter and the semiquantitative analysis of the SPECT images.


[123I]IPA is a promising tracer to delineate pancreatic tissue on SPECT images. It shows a high uptake in the pancreas as compared to other abdominal tissues. This study also demonstrates the feasibility and accuracy to measure the β cell mass in vivo in an animal model of diabetes.

Key words

Exendin l-phenylalanine Dual isotope SPECT Beta cell mass Pancreas imaging 



Our work was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013), project BetaImage, under grant agreement n° 222980. We thank William Rabiot, Emmy De Blay, and Chéraz Mehiri for technical support.

Conflict of Interest

The authors report no conflicts of interest.

Supplementary material


(MOV 6798 kb)


  1. 1.
    Bouwens L, Rooman I (2005) Regulation of pancreatic beta-cell mass. Physiol Rev 85:1255–1270PubMedCrossRefGoogle Scholar
  2. 2.
    Pipeleers D, Chintinne M, Denys B et al (2008) Restoring a functional beta-cell mass in diabetes. Diabetes Obes Metab 10(Suppl 4):54–62PubMedCrossRefGoogle Scholar
  3. 3.
    Bacha F, Gungor N, Arslanian SA (2008) Measures of beta-cell function during the oral glucose tolerance test, liquid mixed-meal test, and hyperglycemic clamp test. J Pediatr 152:618–621PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Henquin JC, Cerasi E, Efendic S et al (2008) Pancreatic beta-cell mass or beta-cell function? That is the question! Diabetes Obes Metab 10(Suppl 4):1–4PubMedGoogle Scholar
  5. 5.
    Porter JR, Barrett TG (2005) Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and beta cell failure. J Med Genet 42:893–902PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Peyot ML, Pepin E, Lamontagne J et al (2010) Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass. Diabetes 59:2178–2187PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Larsen MO, Rolin B, Gotfredsen CF et al (2004) Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide-streptozotocin Gottingen minipig after oral glucose in vivo and in the perfused pancreas. Diabetologia 47:1873–1878PubMedCrossRefGoogle Scholar
  8. 8.
    Brom M, Andralojc K, Oyen WJ et al (2010) Development of radiotracers for the determination of the beta-cell mass in vivo. Curr Pharm Des 16:1561–1567PubMedCrossRefGoogle Scholar
  9. 9.
    Schneider S (2008) Efforts to develop methods for in vivo evaluation of the native beta-cell mass. Diabetes Obes Metab 10(Suppl 4):109–118PubMedCrossRefGoogle Scholar
  10. 10.
    Bouckenooghe T, Flamez D, Ortis F et al (2010) Identification of new pancreatic beta cell targets for in vivo imaging by a systems biology approach. Curr Pharm Des 16:1609–1618PubMedCrossRefGoogle Scholar
  11. 11.
    Flamez D, Roland I, Berton A et al (2010) A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2) gamma as a pancreatic beta cell-specific biomarker. Diabetologia 53:1372–1383PubMedCrossRefGoogle Scholar
  12. 12.
    Kersemans V, Cornelissen B, Kersemans K et al (2006) 123/125I-labelled 2-iodo-L-phenylalanine and 2-iodo-D-phenylalanine: comparative uptake in various tumour types and biodistribution in mice. Eur J Nucl Med Mol Imaging 33:919–927PubMedCrossRefGoogle Scholar
  13. 13.
    Varma VM, Beierwaltes WH, Lieberman LM, Counsell RE (1969) Pancreatic concentration of 125-I-labeled phenylalanine in mice. J Nucl Med 10:219–223PubMedGoogle Scholar
  14. 14.
    Brom M, Oyen WJ, Joosten L et al (2010) 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. Eur J Nucl Med Mol Imaging 37:1345–1355PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Brom M, Woliner-van der Weg W, Joosten L et al (2014) Non-invasive quantification of the beta cell mass by SPECT with In-labelled exendin. DiabetologiaGoogle Scholar
  16. 16.
    Mertens J, Gysemans M (1991) New trends in radiopharmaceutical synthesis, quality assurance and regulatory control. In: Emran AM (ed) New trends in radiopharmaceutical synthesis, quality assurance and regulatory control. Plenum Press, New YorkGoogle Scholar
  17. 17.
    Mertens J, Kersemans V, Bauwens M et al (2004) Synthesis, radiosynthesis, and in vitro characterization of [125I]-2-iodo-L-phenylalanine in a R1M rhabdomyosarcoma cell model as a new potential tumor tracer for SPECT. Nucl Med Biol 31:739–746PubMedCrossRefGoogle Scholar
  18. 18.
    Thorel F, Nepote V, Avril I et al (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464:1149–1154PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gainkam LO, Keyaerts M, Caveliers V et al (2011) Correlation between epidermal growth factor receptor-specific nanobody uptake and tumor burden: a tool for noninvasive monitoring of tumor response to therapy. Mol Imaging Biol 13:940–948PubMedCrossRefGoogle Scholar
  20. 20.
    Vanhove C, Defrise M, Bossuyt A, Lahoutte T (2009) Improved quantification in single-pinhole and multiple-pinhole SPECT using micro-CT information. Eur J Nucl Med Mol Imaging 36:1049–1063PubMedCrossRefGoogle Scholar
  21. 21.
    Gotthardt M, Lalyko G, van Eerd-Vismale J et al (2006) A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents. Regul Pept 137:162–167PubMedCrossRefGoogle Scholar
  22. 22.
    Wild D, Behe M, Wicki A et al (2006) [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 47:2025–2033PubMedGoogle Scholar
  23. 23.
    Christ E, Wild D, Forrer F et al (2009) Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab 94:4398–4405PubMedCrossRefGoogle Scholar
  24. 24.
    Connolly BM, Vanko A, McQuade P et al (2011) Ex vivo imaging of pancreatic beta cells using a radiolabeled GLP-1 receptor agonist. Mol Imaging Biol 14:79–87Google Scholar
  25. 25.
    Mukai E, Toyoda K, Kimura H et al (2009) GLP-1 receptor antagonist as a potential probe for pancreatic beta-cell imaging. Biochem Biophys Res Commun 389:523–526PubMedCrossRefGoogle Scholar
  26. 26.
    Selvaraju RK, Velikyan I, Johansson L et al (2013) In vivo imaging of the glucagon-like peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4. J Nucl Med 54:1458–1463PubMedCrossRefGoogle Scholar
  27. 27.
    Nalin L, Selvaraju RK, Velikyan I et al (2014) Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs. Eur J Nucl Med Mol ImagingGoogle Scholar
  28. 28.
    Kirsi M, Cheng-Bin Y, Veronica F et al (2014) (64)Cu- and (68)Ga-labelled [Nle (14), Lys (40)(Ahx-NODAGA)NH 2]-exendin-4 for pancreatic beta cell imaging in rats. Mol Imaging Biol 16:255–263PubMedCrossRefGoogle Scholar
  29. 29.
    Virostko J, Henske J, Vinet L et al (2011) Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands. Proc Natl Acad Sci USA 108:20719–20724PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Segawa H, Fukasawa Y, Miyamoto K et al (1999) Identification and functional characterization of a Na+−independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751PubMedCrossRefGoogle Scholar
  31. 31.
    Babu E, Kanai Y, Chairoungdua A et al (2003) Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 278:43838–43845PubMedCrossRefGoogle Scholar
  32. 32.
    Rooman I, Lutz C, Pinho AV et al (2013) Amino acid transporters expression in acinar cells is changed during acute pancreatitis. Pancreatology 13:475–485PubMedCrossRefGoogle Scholar
  33. 33.
    Mariotta L, Ramadan T, Singer D et al (2012) T-type amino acid transporter TAT1 (Slc16a10) is essential for extracellular aromatic amino acid homeostasis control. J Physiol 590:6413–6424PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2014

Authors and Affiliations

  • Iris Mathijs
    • 1
  • Catarina Xavier
    • 2
  • Cindy Peleman
    • 2
  • Vicky Caveliers
    • 2
  • Maarten Brom
    • 3
  • Martin Gotthardt
    • 3
  • Pedro L. Herrera
    • 4
  • Tony Lahoutte
    • 2
  • Luc Bouwens
    • 1
    Email author
  1. 1.Cell Differentiation UnitVrije Universiteit BrusselBrusselsBelgium
  2. 2.In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
  3. 3.Department of Nuclear MedicineRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  4. 4.Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical SchoolGeneva 4Switzerland

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