Toward Brain Na_V1.8 Imaging with [¹¹C]Suzetrigine.

Area of Science:

• Neuroscience
• Radiochemistry
• Pharmacology

Background:

• Millions suffer from acute and chronic pain, lacking molecular imaging tools for central nervous system (CNS) pain mechanisms.
• Voltage-gated sodium channel NaV1.8 is crucial in neuropathic pain by enhancing nociceptive neuron excitability.
• Developing a PET tracer for NaV1.8 could noninvasively quantify this target in the CNS, advancing pain neurobiology understanding.

Purpose of the Study:

• To develop a novel positron emission tomography (PET) imaging probe targeting the NaV1.8 channel.
• To assess the suitability of [11C]suzetrigine as a PET tracer for in vivo quantification of NaV1.8 in the CNS.
• To investigate the factors influencing the in vivo performance of [11C]suzetrigine.

Main Methods:

• In silico docking and CNS multiparameter optimization (MPO) analysis of suzetrigine.
• Radiolabeling of suzetrigine with [11C]methyl iodide to produce [11C]suzetrigine.
• In vitro binding assays (autoradiography, saturation binding) and in vivo PET imaging in rats.
• Evaluation of tracer behavior under baseline and pretreatment conditions (unlabeled suzetrigine, verapamil, A-803467).

Main Results:

• In silico analysis predicted favorable binding and adequate brain penetration for suzetrigine.
• [11C]Suzetrigine was synthesized with high radiochemical yield and purity.
• In vitro assays confirmed saturable and selective binding of [11C]suzetrigine to NaV1.8 (K_D = 0.1 nM).
• In vivo PET imaging revealed rapid brain uptake but unexpected signal increases after pretreatment, primarily due to P-gp efflux.

Conclusions:

• [11C]Suzetrigine demonstrates potential as a first-in-class NaV1.8-PET tracer due to high affinity and selectivity in vitro.
• In vivo performance is hindered by P-glycoprotein (P-gp)-mediated efflux, complicating accurate quantification of NaV1.8 in the brain.
• Efflux transporters significantly impact CNS radiotracer development, necessitating strategies to mitigate P-gp interactions for ion channel imaging.