Abstract
AimsRadiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.MethodsIn vitro and ex vivo autoradiography studies of pancreas were performed using [177Lu]Lu-DO3A-VS-Cys40-Exendin4, in order to investigate the mechanism of uptake as well as the islet uptake contrast in mouse, rat, pig, and non-human primate. The autoradiography results were compared to the in vivo pancreatic uptake as assessed by [68Ga]Ga-DO3A-VS-Cys40-Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.Results[177Lu]Lu-DO3A-VS-Cys40-Exendin4 displayed the highest islet-to-exocrine pancreas ratio (IPR) in rat (IPR 45) followed by non-human primate and mouse at similar levels (IPR approximately 5) while pigs exhibited negligible IPR (1.1). In vivo pancreas uptake was mainly GLP-1R mediated in all species, but the magnitude of uptake under basal physiology varied significantly in decreasing order: non-human primate, mouse, pig, and rat. The theoretical calculation of islet contribution to the total pancreatic PET signal predicted the in vivo observation of differences in pancreatic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin4.ConclusionsIPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.
Highlights
In vivo imaging of the endocrine pancreas requires labeled probes with high affinity for a molecular target expressed in the beta cells [1, 2]
The sections were exposed against a phosphorimager screen together with a reference droplets of known activity of [177Lu]Lu-DO3A-VS-Cys40-Exendin4 overnight and scanned using a Cyclone Plus Phosphorimager (Perkin Elmer) at 600 dpi. [68Ga]Ga-DO3A-VSCys40-Exendin4 was used as radioligand the frozen section autoradiography of human insulinoma sections
Ex vivo autoradiography of [177Lu] Lu‐DO3A‐VS‐Cys40‐Exendin4 binding in the pancreas
Summary
In vivo imaging of the endocrine pancreas requires labeled probes with high affinity for a molecular target expressed in the beta cells [1, 2]. Glucagonlike peptide-1 receptor (GLP-1R) is an important pharmaceutical target in the treatment of type 2 diabetes (T2D) and has been proposed as a surrogate imaging biomarker for beta cell mass [1]. Several radiolabeled analogues of Exendin-4 have been evaluated for critical parameters such as affinity to GLP-1R and beta cell selectivity in vivo. Rats display a strong contrast between beta cell uptake compared to that of the exocrine pancreatic background uptake (isletto-exocrine pancreas ratio, IPR). It has been feasible to detect decreased beta cell mass in rat models of diabetes [3, 4]
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