Key result
The 125I-labeled iminodihydroquinoline tracer was rapidly metabolized in vivo with low brain uptake and high intestinal accumulation, making it poorly suited for tracer development.
Iminodihydroquinolines are poorly suited for tracer development for imaging voltage-gated sodium channels due to rapid in vivo metabolism and low brain uptake.
Iminodihydroquinolines should not be pursued for NaV imaging tracers; leaves open alternative scaffolds for preclinical evaluation.
In vivo imaging of voltage-gated sodium channels (VGSCs) can potentially provide insights into the activation of neuronal pathways and aid the diagnosis of a number of neurological diseases. The iminodihydroquinoline WIN17317-3 is one of the most potent sodium channel blockers reported to date and binds with high affinity to VGSCs throughout the rat brain. We have synthesized a (125)I-labeled analogue of WIN17317-3 and evaluated the potential of the tracer for imaging of VGSCs with SPECT. Automated patch clamp studies with CHO cells expressing the Nav1.2 isoform and displacement studies with [(3)H]BTX yielded comparable results for the non-radioactive iodinated iminodihydroquinoline and WIN17317-3. However, the (125)I-labeled tracer was rapidly metabolized in vivo, and suffered from low brain uptake and high accumulation of radioactivity in the intestines. The results suggest that iminodihydroquinolines are poorly suited for tracer development.
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Pérez‐Medina et al. (2013) studied this question. 125I-labeled analogue of WIN17317-3 was evaluated on Tracer potential for imaging of VGSCs with SPECT. The 125I-labeled iminodihydroquinoline tracer was rapidly metabolized in vivo with low brain uptake and high intestinal accumulation, making it poorly suited for tracer development.
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