Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging

Abstract

Measuring changes in β-cell mass in vivo during progression of diabetes mellitus is important for understanding the pathogenesis, facilitating early diagnosis, and developing novel therapeutics for this disease. However, a non-invasive method has not been developed. A novel series of mitiglinide derivatives (o-FMIT, m-FMIT and p-FMIT; FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. (+)-(S)-o-FMIT had the highest affinity of our synthesized FMITs (IC50=1.8μM). (+)-(S)-o-[(18)F]FMIT was obtained with radiochemical yield of 18% by radiofluorination of racemic precursor 7, hydrolysis, and optical resolution with chiral HPLC; its radiochemical purity was >99%. In biodistribution experiments using normal mice, (+)-(S)-o-[(18)F]FMIT showed 1.94±0.42% ID/g of pancreatic uptake at 5min p.i., and decreases in radioactivity in the liver (located close to the pancreas) was relatively rapid. Ex vivo autoradiography experiments using pancreatic sections confirmed accumulation of (+)-(S)-o-[(18)F]FMIT in pancreatic β-cells. These results suggest that (+)-(S)-o-[(18)F]FMIT meets the basic requirements for an radiotracer, and could be a candidate positron emission tomography tracer for in vivo imaging of pancreatic β-cells.

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

“…Therefore, the various molecules whose expression is observed specifically in b cells have been explored, and those ligands, substrates, and antibodies have been investigated as putative probes for b-cell imaging. To date, sulfonylurea receptor 1 (SUR1) (40,41), glucose transporter 2 (42), voltage-dependent calcium channel (43), G protein-coupled receptor 44 (GPR44) (44,45), D2 and D3 dopamine receptors (46,47), serotonergic system (48-51), vesicular monoamine transporter 2 (VMAT2) (52,53), and GLP-1 receptor (GLP-1R) (54, 55) have been reported as potential probe targets (Figure 2) (56).…”

“…However, these probes have failed to achieve sufficient specificity to b cells; low accumulations in the pancreas and high background signals (57,58). Although a mitiglinide derivative has been reported as a potential b-cell imaging probe with higher specificity (40), none of the available probes targeting SUR1 are currently feasible.…”

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

“…GLP-1R has been a promising target for a b-cell-specific probe. For the purpose of visualization and quantification of b-cells, GLP-1R-targeted imaging methods, such as single-photon emission computed tomography (SPECT) and positron emission tomography have recently emerged [8][9][10][11] . These methods were developed for the detection of insulinoma and transplanted islets, and the evaluation of b-cell mass [12][13][14] , and they have not been used for clinical prediction of drug efficacy in diabetes treatment.…”

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

“…Thus, 18 F can be incorporated into small molecules with little to no change in biological activity. Several 18 F-tracers have been evaluated for their ability to quantify beta cell mass including 18 F-exendin analogs [ 140 ], 5-(2-[ 18 F]-fluoroethoxy)-L-tryptophan [ 141 ], [ 18 F]fluoropropyl-(+)-DTBZ [ 71 ], 18 F-mitiglinide derivatives [ 142 ], and 18 F-repaglinide derivatives [ 143 ].…”