Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled [Nle14,Lys40]exendin-4 analog, shows promise for clinical imaging

Abstract

BackgroundSeveral radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. 18F-labeled [Nle14,Lys40]exendin-4 analog ([18F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [18F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of 18F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats.Results[18F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [18F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [18F]exendin-4.Conclusions[18F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.

Exendin‐4 analogs in insulinoma theranostics

“…Fluorine‐18 is a favorable radionuclide for PET imaging because of the low positron emission energy, which provides a short tissue range and thus the potential for achieving a high resolution. As the conditions typically required for 18 F‐fluorination are very harsh (eg, high temperatures and strong bases), prosthetic groups that can be labeled and conjugated to functional moieties of the exendin‐4 have been developed . Interestingly, kidney uptake of these tracers is high at first, but clearance from the kidneys is more rapid compared with radiometal‐labeled exendin.…”

“…Some dosimetry studies have been performed with exendin‐4–based tracers. Absorbed kidney doses that were found in case of exendin‐4–based imaging tracers ranged from 0.1 to 4.5 mGy/MBq; these data were mostly derived from animal studies . Furthermore, two studies investigated the potential of PRRT with 177 Lu‐labeled exendin‐4 using dosimetric calculations either extrapolated from biodistribution data of 177 Lu‐labeled exendin‐4 in rats or with a macro‐ and small‐scale‐dosimetry model applied to 111 In‐labeled exendin‐4 SPECT/CT scans in humans .…”

“…As the conditions typically required for 18 F-fluorination are very harsh (eg, high temperatures and strong bases), prosthetic groups that can be labeled and conjugated to functional moieties of the exendin-4 have been developed. [30][31][32][33][34][35] Interestingly, kidney uptake of these tracers is high at first, but clearance from the kidneys is more rapid compared with radiometal-labeled exendin. To overcome the time-consuming synthesis of prosthetic groups, other strategies such as aluminum complexation were applied and showed high tracer uptake by the tumor as well.…”

Synthesis of an Alkyne‐Modified Bleomycin Disaccharide Precursor, Conversion to a 18F‐Labeled Radiotracer, and Preliminary in vivo‐PET Imaging Studies

“…Prior to the 18 F‐labeling, precursor 11 (as an anomeric mixture) was quantitatively converted into the alkyne modified BLM disaccharide 12 using 6 N ammonia in dry methanol, followed by filtration through a C‐18 RP column. The prosthetic agent 15 ([ 18 F]FATG) was prepared by reacting 2‐{2‐[2‐(2‐azidoethoxy)ethoxy]ethoxy}ethyl p ‐toluenesulfonate with [ 18 F]fluoride‐Kryptofix complex in anhydrous DMSO . The obtained 1‐azido‐2‐(2‐{2‐[2‐( 18 F)fluoroethoxy]ethoxy}ethoxy)ethane ([ 18 F]FATG 15 , about 2 GBq), with a radiochemical purity of at least 90 %, was allowed to react with 12 in the presence of pre‐activated copper sulfate/sodium ascorbate.…”

“…for C 19 H 31 NO 12 Na [M + Na] + , found 488.1725). Radiosynthesis was performed following previously described protocols with slight modifications . In brief, 18 F‐fluoride was produced using the 18 O(p,n) 18 F nuclear reaction on 18 O‐enriched water (98 % isotopic pure, Rotem Industries Ltd, Israel).…”