Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

Abstract

Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [I]-1-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([I]IIQP) and [I]-N-3-iodobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [I]IIQP and [I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [I]IIQP was significantly higher than that after the injection of [I]IB-IQP. These results indicated that [I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio.

Comparison of Radioiodine- or Radiobromine-Labeled RGD Peptides between Direct and Indirect Labeling Methods

“…SIB was synthesized according to a previous report with a slight modification. 26) Namely, 3-iodobenzoic acid (719 mg, 2.90 mmol) was dissolved in 10 mL of acetonitrile. NHydroxysuccinimide (NHS) (401 mg, 3.48 mmol) was added to the solution, and 50 mL of acetonitrile containing N,N′-dicyclohexylcarbodiimide (DCC) (718 mg, 3.48 mmol) was added dropwise at 0°C.…”

Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRβ) imaging probes

“…In these reports, using the same corresponding precursors, the radiochemical yields for radiobromine labeling were lower than those for radioiodine labeling. In this study, we obtained [ 77 Br] 2 and [ 77 Br] 3 with prominently high radiochemical yields (95% and 83%, respectively), and the radiochemical yields were comparable to those of the corresponding radioiodinated compounds at 95% for [ 125 I] 4 and 85% for [ 125 I] 5 24 .…”

“…Intermediate, reference compounds, 1 , and corresponding tin precursors were synthesized according to the reported studies, with a slight modification 24 .…”

“…The cell viability assay of brominated compounds, 2 and 3 , was evaluated as described previously 24 , 27 . Namely, TR-PCT1 cells were seeded on 96-well plates (5 × 10 3 cells/well) and cultured at 33 °C in DMEM medium with 20 ng/mL PDGF-BB and 2% FBS in a 5% CO 2 incubator.…”

“…Partition coefficients of [ 77 Br] 2 and [ 77 Br] 3 into n-octanol and 0.1 M phosphate buffer (PB) pH 7.4 were determined using the method described previously 24 . The measurement was performed in quadruplicate.…”