LMI1195 PET imaging in evaluation of regional cardiac sympathetic denervation and its potential role in antiarrhythmic drug treatment.

PURPOSE: Regional cardiac sympathetic denervation (RCSD) associated with reduced noradrenaline transporter (NAT) function has been linked to cardiac arrhythmia. This study examined the association of LMI1195, an (18)F-labeled NAT substrate developed for positron emission tomography (PET) imaging, with NAT in vitro, and its imaging to detect RCSD and guide antiarrhythmic drug treatment in vivo. METHODS: LMI1195 association with NAT was assessed in comparison with other substrates, noradrenaline (NA) and (123)I-metaiodobenzylguanidine (MIBG), in NAT-expressing cells. LMI1195 cardiac imaging was performed for evaluation of RCSD in a rabbit model surgically developed by regional phenol application on the left ventricular (LV) wall. The normal LV areas in images were quantified as regions with radioactivity ≥50 % maximum. Potential impact of RCSD on dofetilide, an antiarrhythmic drug, induced ECG changes was assessed. RESULTS: NAT blockade with desipramine reduced LMI1195 cell uptake by 90 ± 3 %, similar to NA and MIBG. NA, MIBG, or self inhibited LMI1195 cell uptake concentration-dependently with comparable IC(50) values (1.09, 0.21, and 0.90 µM). LMI1195 cardiac imaging differentiated innervated and denervated areas in RCSD rabbits. The surgery resulted in a large denervated LV area at 2 weeks which was partially recovered at 12 weeks. Myocardial perfusion imaging with flurpiridaz F 18 showed normal perfusion in RCSD areas. Dofetilide induced more prominent QTc prolongation in RCSD than control animals. However, changes in heart rate were comparable. CONCLUSION: LMI1195 exhibits high association with NAT and can be used for imaging RCSD. The detected RCSD increases cardiac risks to the antiarrhythmic drug, dofetilide, by inducing more QTc prolongation.

Metal-ligand charge-transfer-promoted photoelectronic Bergman cyclization of copper metalloenediynes: photochemical DNA cleavage via C-4' H-atom abstraction.

Metal-to-ligand charge-transfer (MLCT) photolyses (lambda > or = 395 nm) of copper complexes of cis-1,8-bis(pyridin-3-oxy)oct-4-ene-2,6-diyne (bpod, 1), [Cu(bpod)(2)]PF(6) (2), and [Cu(bpod)(2)](NO(3))(2) (3) yield Bergman cyclization of the bound ligands. In contrast, the uncomplexed ligand 1 and Zn(bpod)(2)(CH(3)COO)(2) compound (4) are photochemically inert under the same conditions. In the case of 4, sensitized photochemical generation of the lowest energy (3)pi-pi state, which is localized on the enediyne unit, leads to production of the trans-bpod ligand bound to the Zn(II) cation by photoisomerization. Electrochemical studies show that 1, both the uncomplexed and complexed, exhibits two irreversible waves between E(p) values of -1.75 and -1.93 V (vs SCE), corresponding to reductions of the alkyne units. Irreversible, ligand-based one-electron oxidation waves are also observed at +1.94 and +2.15 V (vs SCE) for 1 and 3. Copper-centered oxidation of 2 and reduction of 3 occur at E(1/2) = +0.15 and +0.38 V, respectively. Combined with the observed Cu(I)-to-pyridine(pi) MLCT and pyridine(pi)-to-Cu(II) ligand-to-metal charge transfer (LMCT) absorption centered near approximately 315 nm, the results suggest a mechanism for photo-Bergman cyclization that is derived from energy transfer to the enediyne unit upon charge-transfer excitation. The intermediates produced upon photolysis degrade both pUC19 bacterial plasmid DNA, as well as a 25-base-pair, double-stranded oligonucleotide. Detailed analyses of the cleavage reactions reveal 5'-phosphate and 3'-phosphoglycolate termini that are derived from H-atom abstraction from the 4'-position of the deoxyribose ring rather than redox-induced base oxidation.