Imaging cardiac SCN5A using the novel F-18 radiotracer radiocaine

Abstract

The key function of the heart, a well-orchestrated series of contractions, is controlled by cardiac action potentials. These action potentials are initiated and propagated by a single isoform of voltage gated sodium channels – SCN5A. However, linking changes in SCN5A expression levels to human disease in vivo has not yet been possible. Radiocaine, an F-18 radiotracer for positron emission tomography (PET), is the first SCN5A imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart has ~30% lower SCN5A levels - the first evidence of changes in SCN5A expression in humans as a function of disease. Paving the way for translational imaging, radiocaine proved to exhibit high in vivo specific binding to the myocardium of non-human primates. We envision that SCN5A measurements using PET imaging may serve as a novel diagnostic tool to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.

In Vivo [18F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates

“…[ 18 F]­GE-179 was synthesized using a thiophenol precursor purchased from GE Healthcare (Amersham, UK) for [ 18 F]­fluoroethylation as previously described . Briefly, the radionuclide 18 F and the common alkylation building block [ 18 F]­fluoroethyl tosylate (FETs) were synthesized as described earlier in our lab . Freshly prepared FETs was added to 0.8 mg of precursor and 0.5 mg of K 2 CO 3 as a solution in 0.5 mL of acetonitrile.…”

Response to Comment on “In Vivo [18F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”

“…In both cases, specific binding could be characterized successfully by traditional in vivo competition experiments. 13 These experimental data demonstrate that PET imaging probes that act as activity-dependent ion channel pore blockers, as is the case for [ 18 F]GE-179, are amenable to presaturation, competition, and chase-experiments.…”

“…However, it is important to point out that other activity-dependent binders, e.g., a local anesthetic and a dihydropyridine, have been used as PET imaging probes for voltage gated sodium and calcium channels, respectively. , The respective binding sites of these probes are structurally related to NMDA receptors. In both cases, specific binding could be characterized successfully by traditional in vivo competition experiments . These experimental data demonstrate that PET imaging probes that act as activity-dependent ion channel pore blockers, as is the case for [ 18 F]­GE-179, are amenable to presaturation, competition, and chase-experiments.…”

Sequential Ir/Cu-Mediated Method for the Meta-Selective C–H Radiofluorination of (Hetero)Arenes

“…Notably, this radiolabeling approach is complementary to Hooker's synthesis of the 18 F-fluoroethyl analogue [ 18 F]radiocaine. 54 Protected aromatic amino acid derivatives undergo high yielding radiofluorination to afford products such as 18-18 F and 19-18 F. These have potential applications for imaging dopaminergic metabolism and tumor proliferation. 55 Automated labeling was followed by semipreparative HPLC purification to afford 18-18 F in 25% isolated RCY, 99% RCP, and 0.52 Ci/μmol (19.24 GBq/μmol) A m (n = 2).…”

“…Under the standard C–H borylation/CMRF conditions, the anesthetic lidocaine reacts to furnish 17- 18 F in 15 ± 8% RCY. Notably, this radiolabeling approach is complementary to Hooker’s synthesis of the 18 F-fluoroethyl analogue [ 18 F]­radiocaine …”