Analysis of [18F]exendin-4 PET data
Exendin-4 is a subcutaneously administered peptide drug, used in the treatment of type 2 diabetes. [18F]exendin-4 and its analogue tracers, also labeled with other radionuclides than 18F, are specific to glucagon-like peptide 1 receptor (GLP-1R), and have been used for imaging pancreatic β-cell mass, insulinoma (Kiesewetter et al., 2012; Xu et al., 2015), transplanted islets (Wu et al., 2013), and myocardial ischemia (Gao et al., 2012). 18F-labelled exendin tracers have faster renal clearance and lower uptake than the widely used SPECT tracers, leading to lower radiation dose to the kidneys (Mikkola et al., 2016; Dialer et al., 2018).
Pancreatic uptake of exendin-4 tracers has noticeable species variations, caused by differences in β-cell mass and GLP-1R expression in β-cells and exocrine pancreas (Eriksson et al., 2017).
Majority of [18F]exendin-4 is internalized into cells after binding to GLP-1R receptors (Kiesewetter et al., 2012a). True efflux rate is expected to be slow, and if any tracer efflux from the internalized compartment is seen during the PET study, it may be an artifact caused by tissue heterogeneity inside the volume of interest, or errors in measurement of plasma parent fraction. However, total radioactivity concentration in tissues can decrease, at rates dependent on the organ and tracer (Kiesewetter et al., 2012a; Wu et al., 2013).
Low amount of GLP-1 receptors requires that only low amount of peptide (high specific activity) can be administered, especially in small animals, to avoid pharmacological and receptor blocking effects (Brom et al., 2010; Mikkola et al., 2016). Although 18F is an optimal isotope for labelling exendin-4 in high specific activity, the binding results should be verified to not show any correlation with the injected mass.
Plasma vs blood
Exendin-4 is a relatively large peptide, and it does not pass the membranes of red blood cells. Since that applies also to the radioactive metabolites, the image-derived input function, blood time-activity curve (TAC), of an exendin-4 tracer is easy to convert to plasma TAC. Conversion is based on haematocrit value, preferably measured individually.
Exendin-4 has an in vivo halflife of about 2.4 h. Fraction of radiolabelled metabolite(s) in plasma and tissues is relatively low even at 60 min p.i., except for kidneys and liver (Kiesewetter et al., 2012a).
Kiesewetter et al. (2012a) suggest that co-precipitation with plasma proteins may be a confounding factor for determining parent fraction in plasma.
Exendin-4 tracer data has so far been analyzed mainly qualitatively and by calculation of regional SUV or %ID/g, and with tumour-to-muscle ratio. Depending on the tracer, target organ, and scan time, Logan plot or one-tissue compartmental model may be suitable for quantitative analysis.
Antwi K, Fani M, Nicolas G, Rottenburger C, Heye T, Reubi JC, Gloor B, Christ E, Wild D. Localization of hidden insulinomas with 68Ga-DOTA-Exendin-4 PET/CT: a pilot study. J Nucl Med. 2015; 56(7): 1075-1078.
Gao H, Kiesewetter DO, Zhang X, Huang X, Guo N, Lang L, Hida N, Wang H, Wang H, Cao F, Niu G, Chen X. PET of glucagonlike peptide receptor upregulation after myocardial ischemia or reperfusion injury. J Nucl Med. 2012; 53: 1960-1968.
Jodal A, Lankat-Buttgereit B, Brom M, Schibli R, Béhé M. A comparison of three 67/68Ga-labelled exendin-4 derivatives for β-cell imaging on the GLP-1 receptor: the influence of the conjugation site of NODAGA as chelator. EJNMMI Res. 2014; 4:31.
Kiesewetter DO, Gao H, Ma Y, Niu G, Quan Q, Guo N, Chen X. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging. 2012a; 39(3): 463-473.
Kiesewetter DO, Guo N, Guo J, Gao H, Zhu L, Ma Y, Niu G, Chen X. Evaluation of an [18F]AIF-NOTA analog of exendin-4 for imaging of GLP-1 receptor in insulinoma. Theranostics 2012b; 2(10): 999-1009.
Mikkola K, Yim C-B, Fagerholm V, Ishizu T, Elomaa V-V, Rajander J, Jurttila J, Saanijoki T, Tolvanen T, Tirri M, Gourni E, Béhé M, Gotthardt M, Reubi JC, Mäcke H, Roivainen A, Solin O, Nuutila P. 64Cu- and 68Ga-labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats. Mol Imaging Biol. 2014; 16: 255-263. doi: 10.1007/s11307-013-0691-2.
Mikkola K, Yim C-B, Lehtiniemi P, Kauhanen S, Tarkia M, Tolvanen T, Nuutila P, Solin O. Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled [Nl114,Lys40]-exendin-4 analog, shows promise for clinical imaging. EJNMMI Res. 2016; 6:91. doi: 10.1186/s13550-016-0243-2.
Nalin L, Selvaraju RK, Velikyan I, Berglund M, Andréasson S, Wikstrand A, Rydén A, Lubberink M, Kandeel F, Nyman G, Korsgren O, Eriksson O, Jensen-Waern M. Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs. Eur J Nucl Med. 2014; 41: 1800-1810.
Selvaraju RK, Velikyan I, Johansson L, Wu Z, Todorov I, Shively J, Kandeel F, Korsgren O, Eriksson O. In vivo imaging of the glucagonlike peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4. J Nucl Med. 2013; 54: 1458-1463.
Wang Y, Lim K, Normandin M, Zhao X, Cline GW, Ding Y-S. Synthesis and evaluation of [18F]exendin (9-39) as a potential biomarker to measure pancreatic β-cell mass. Nucl Med Biol. 2012; 39: 167-176.
Wild D, Béhé M, Wicki A, Storch D, Waser B, Gotthardt M, Keil B, Christofori G, Reubi JC, Mäcke HR. [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.
Wu H, Liang S, Liu S, Pan Y, Cheng D, Zhang Y. 18F-radiolabeled GLP-1 analog exendin-4 for PET/CT imaging of insulinoma in small animals. Nucl Med Commun. 2013; 34(7): 701-708.
Wu Z, Liu S, Hassink M, Nair I, Park R, Li L, Todorov I, Fox JM, Li Z, Shively JE, Conti PS, Kandeel F. Development and evaluation of 18F-TTCO-Cys40-Exendin-4: a PET probe for imaging transplanted islets. J Nucl Med. 2013; 54(2): 244-251.
Updated at: 2018-08-16
Created at: 2013-10-23
Written by: Vesa Oikonen