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

Abstract

Platelet-derived growth factor receptor beta (PDGFRβ) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRβ could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRβ ligands and evaluate their effectiveness as PDGFRβ imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRβ. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRβ-positive) than in MCF7 cells (PDGFRβ-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRβ than [76Br]3.

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

“…In this study, to minimize both the number of animals used for experiments and experimental errors, radioiodinated and radiobrominated probes were co-injected into normal mice and tumor-bearing mice. , The biodistribution experiments in normal mice were performed to investigate detailed pharmacokinetics of [ 125 I] 9 and [ 77 Br] 15 before studies with tumor-bearing mice. The biodistribution after co-injection of [ 125 I] 9 and [ 77 Br] 15 in normal mice is shown in Figure (Tables S1 and S2, respectively).…”

“…In this study, to minimize both the number of animals used for experiments and experimental errors, radioiodinated and radiobrominated probes were co-injected into normal mice and tumor-bearing mice. 33,34 The biodistribution experiments in normal mice were performed to investigate detailed pharmacokinetics of S3. The blood clearance of [ 77 Br]Br − is slow.…”

Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents

“…Partition coefficients of [ 67 Ga] 5 , [ 67 Ga] 6 , [ 67 Ga] 7 , and [ 67 Ga] 8 into n -octanol and 0.1 M phosphate buffered saline (PBS) pH 7.4 were determined according to previously described procedures [ 17 ]. The partition coefficient was calculated by the ratio of cpm/mL in n -octanol to that in PBS, and expressed as a common logarithm (log P ).…”

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

“…For other preclinical studies with PDGFR imaging agents for non-GB tumors, see Table S1 . These include the mAb [ 64 Cu]Cu-D13C6, the affibody conjugate [ 89 Zr]Zr-ZPDGFRβ, the radioiodinated 1-[ 303 ]piperidin-4-amine (IQP) and radiobrominated PDGFRβ ligands [ 306 , 307 , 308 ]. Recently, radiogallium-labeled peptides for PDGFRβ were developed and the effects of several linkers were studied, concluding that further probe modification is required [ 309 ].…”