Pre-clinical evaluation of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 for imaging of insulinoma

Selvaraju, Ram Kumar; Velikyan, Irina; Asplund, Veronika; Johansson, Lars; Wu, Zhanhong; Todorov, Ivan; Shively, J. E.; Kandeel, Fouad; Eriksson, Barbro; Korsgren, Olle; Eriksson, Olof

doi:10.1016/j.nucmedbio.2014.03.017

Cited by 28 publications

(20 citation statements)

References 22 publications

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“…68 Ga-Exendin-4 has previously shown strong specific binding to the GLP-1R 37 . Competition studies in mouse demonstrated that the 68 Ga-Exendin-4 uptake in lung and pancreas was GLP-1R mediated 38 . However, the high accumulation and retention of the tracer in kidneys make the accurate quantification of the tracer uptake in the pancreas of a mouse challenging.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 /PET

Monazzam

Lau

Velikyan

et al. 2018

Sci Rep

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Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

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Section: Discussionmentioning

confidence: 99%

Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 /PET

Monazzam

Lau

Velikyan

et al. 2018

Sci Rep

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“…Pancreatic tissue was collected from non-diabetic rat, pigs, and non-human primate. Explanted INS-1 (rat beta cell origin) xenograft tumors were collected from immunodeficient mice [ 11 ]. Biopsies from resected human pancreatic insulinoma ( n = 3) were obtained by the section for Endocrine Oncology, Uppsala University Hospital and its use was approved by EPN 2013/460 according to the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4

et al. 2017

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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.

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“…27 The [ 68 Ga]Ga-DO3A-VS-Cys40-exendin-4 tracer could be labeled with six times higher specific activity compared with Lys 40 (Ahx-DOTA-[ 68 Ga]Ga)NH2]-exendin-4, thereby enabling injection of lower peptide dose, and this tracer also showed good tumor uptake in INS-1 xenografts. 39 During the recent years, multiple case reports have been published in which 68 Ga-labeled exendin-4 tracers enabled successful detection of insulinomas with PET/CT, while other imaging methods were negative 11,[40][41][42][43][44] (for an overview of clinical PET tracers, see Table 4).…”

Section: Tracer Development and Clinical Implementationmentioning

confidence: 99%

Exendin‐4 analogs in insulinoma theranostics

Jansen

Lith

Boss

et al. 2019

Labelled Comp Radiopharmac

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Insulinomas are neuroendocrine tumors arising from the pancreatic beta cells. Currently, surgical resection is the therapy of choice, and therefore, preoperative localization of insulinomas is essential. Nearly all insulinomas show overexpression of the glucagon‐like peptide‐1 receptor (GLP‐1R), and therefore, radiolabeled GLP‐1 peptide analog exendin‐4 can be used for diagnosis and preoperative localization with nuclear imaging. Here, we present an overview of the development and clinical implementation of exendin‐4–based tracers for single‐photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging of insulinomas, and we address the potential use of this molecule for optical imaging. At last, we discuss the possibilities and pitfalls of the use of exendin‐4–based tracers for therapeutic applications such as peptide receptor radionuclide therapy (PRRT) or targeted photodynamic therapy (tPDT), giving a future outlook on the use of exendin‐4 in insulinoma theranostics.

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Pre-clinical evaluation of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 for imaging of insulinoma

Cited by 28 publications

References 22 publications

Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 /PET

Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 /PET

Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4

Exendin‐4 analogs in insulinoma theranostics

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