In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with ⁶⁸Ga-Labeled DO3A-Exendin-4

Abstract

The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on b-cells in the islets of Langerhans and is therefore an attractive target for imaging of the b-cell mass. In the present study, 68 Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. Methods: Dose escalation studies of 68 Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. Results: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P , 0.0001) by coadministration of DO3A-exendin-4 at 100 mg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P , 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 mg/kg ranged from 49% to 97%, as estimated by compartment modeling. Conclusion: These results strongly support the notion that 68 Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of b-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native b-cells.

Positron Emission Tomography Ligand [11C]5-Hydroxy-Tryptophan Can Be Used as a Surrogate Marker for the Human Endocrine Pancreas

“…[ The ability to repeatedly quantify the amount of remaining b-cells by noninvasive methods would be of significant importance to obtain further insights into the pathophysiology of diabetes, as well as a tool to evaluate new therapies aiming to prevent b-cell loss. Significant efforts have been made in order to develop such a method (1)(2)(3)(4)(5), but so far no clinically validated technique has been described. Despite originating from different germinal layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain (6,7).…”

Development of 68Ga- and 89Zr-Labeled Exendin-4 as Potential Radiotracers for the Imaging of Insulinomas by PET

“…The A s achieved for the individual exendin-4 radiotracers described herein are in the range of those described in the literature (13-700 GBq/mmol) for preclinical (2,7,8,11,28) and clinical investigations (9,18,19,29).…”

“…These derivatives were functionalized with different chelators (diethylenetriaminepentaacetic acid [DTPA], hydrazinonicotinic acid, DOTA, and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) suitable for radiolabeling with 111 In (2,7,8), 99m Tc (8,9), 68 Ga (7,8,(10)(11)(12), and 64 Cu (10,12,13), respectively. More recently, examples of 18 F-labeled exendins have also been described (14)(15)(16)(17).…”

PET Imaging for Endocrine Malignancies: From Woe to Go

“…Recent studies have shown that radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting, and there are several ongoing studies across various NETs. Glucagon-like peptide-1 receptor imaging using 68 Ga-exendin-4 PET/CT (15) and 18 F-radiolabeled analogs of exendin-4 PET/CT has emerged and is highly sensitive for detecting benign insulinomas that might be missed by other imaging studies (16). Studies have also shown a high expression of C-X-C chemokine receptor type 4 in normal adrenal cortex and adrenocortical tumors, opening new avenues for imaging these tumors with peptides targeting C-X-C chemokine receptor type 4 ( 68 Ga-pentixafor) and theranostic approaches (17,18).…”