Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas

Abstract

Purpose: In diabetes, pancreatic beta cell mass declines significantly prior to onset of fasting hyperglycemia. This decline may be due to endoplasmic reticulum (ER) stress, and the system L amino acid transporter LAT1 may be a biomarker of this process. In this study, we used 5-(2- 18F-fluoroethoxy)-L-tryptophan ( 18F-L-FEHTP) to target LAT1 as a potential biomarker of beta cell function in diabetes. Procedures: Uptake of 18F-L-FEHTP was determined in wild-type C57BL/6 mice by ex vivo biodistribution. Both dynamic and static positron emission tomography (PET) images were acquired in wild-type and Akita mice, a model of ER stress-induced diabetes, as well as in mice treated with streptozotocin (STZ). LAT1 expression in both groups of mice was evaluated by immunofluorescence microscopy. Results: Uptake of 18F-L-FEHTP was highest in the pancreas, and static PET images showed highly specific pancreatic signal. Time-activity curves showed significantly reduced 18F-L-FEHTP uptake in Akita mice, and LAT1 expression was also reduced. However, mice treated with STZ, in which beta cell mass was reduced by 62%, showed no differences in 18F-L-FEHTP uptake in the pancreas, and there was no significant correlation of 18F-L-FEHTP uptake with beta cell mass. Conclusions: 18F-L-FEHTP is highly specific for the pancreas with little background uptake in kidney or liver. We were able to detect changes in LAT1 in a mouse model of diabetes, but these changes did not correlate with beta cell function or mass. Therefore, 18F-L-FEHTP PET is not a suitable method for the noninvasive imaging of changes in beta cell function during the progression of diabetes.

Development of [18F]F-5-OMe-Tryptophans through Photoredox Radiofluorination: A New Method to Access Tryptophan-Based PET Agents

“…For example, kidney uptake of l -[ 18 F]­T 13 was 11.30 ± 0.09%ID/g at 0.5 h and quickly decreased by 83% at the 3.0 h time point. Due to LAT1 expression in pancreatic beta cells, we observed substantial pancreas uptake of all four tracers. In addition to the B16F10 model, we also performed a preliminary pilot study of [ 18 F]­T 13 using MCF-7, H358, LnCap, and UPPL tumor-bearing animal models.…”

L-type Amino Acid Transporter 1 Utilizing Ferulic Acid Derivatives Show Increased Drug Delivery in the Mouse Pancreas Along with Decreased Lipid Peroxidation and Prostaglandin Production

“…The pancreas showed the highest accumulation of LAT1-utilizing derivatives D1 and D2, with AUCs increasing 129.2- and 203.8-times higher in comparison to the original FA, respectively. We have previously reported similar pancreatic accumulation with the LAT1-utilizing prodrugs of perforin inhibitors, which showed increased delivery into the pancreas along the brain. , In addition to our prodrugs, a LAT1-targeting positron emission tomography-probe, 5-(2- 18 F-fluoroethoxy)- l -tryptophan, has been reported to accumulate significantly in wild-type mouse pancreas . Furthermore, the LAT1-utilizing drug levodopa has been observed to accumulate into both mouse and human pancreas, supporting the common LAT1-mediated delivery between species .…”

“… 24 , 30 In addition to our prodrugs, a LAT1-targeting positron emission tomography-probe, 5-(2- 18 F-fluoroethoxy)- l -tryptophan, has been reported to accumulate significantly in wild-type mouse pancreas. 39 Furthermore, the LAT1-utilizing drug levodopa has been observed to accumulate into both mouse and human pancreas, supporting the common LAT1-mediated delivery between species. 40 These findings with multiple LAT1-targeted compounds combined with pharmacoproteomics suggest that the LAT1-mediated drug targeting also increases pancreatic drug delivery greatly.…”