Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine.

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value < 0.0001) and higher permeability to an artificial brain membrane (Pe = 88.1 ± 18.3 vs. 31.1 ± 2.9 nm/s, P-value = 0.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (IC50 = 36.2 ± 2.5 vs. 15.4 ± 5.1, P-value = 0.0003); the enzyme responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties as a candidate for PET imaging warranting additional investigation.

Oxygen quenching of structurally characterized [5,10,15,20-tetrakis(4-fluoro-2,6-dimethylphenyl)porphyrinato]platinum(II).

The compound [5,10,15,20-tetrakis(4-fluoro-2,6-dimethylphenyl)porphyrinato]platinum(II), [Pt(C52H40F4N4)] or Pt(II)TFP, has been synthesized and structurally characterized by single-crystal X-ray crystallography. The Pt porphyrin exhibits a long-lived phosphorescent excited state (τ0 = 66 µs), which has been characterized by transient absorption and emission spectroscopy. The phosphorescence is extremely sensitive to oxygen, as reflected by a quenching rate constant of 5.0 × 108 M-1 s-1, and as measured by Stern-Volmer quenching analysis.

Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine.

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). Here, we describe 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP), a novel K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP is more lipophilic (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002) and slightly more basic (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07). In addition, 5Me3F4AP appears to be more permeable to an artificial brain membrane and more stable towards oxidation by the cytochrome P450 enzyme family 2 subfamily E member 1 (CYP2E1), responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties for PET imaging warranting additional investigation.