Hilbert Grievink

Purpose: Quaternary ammonium salts have demonstrated marked accumulation in the left ventricular (LV) myocardium of rodents and swine. To investigate the mechanism underlying this uptake, the present study examined the interaction of [¹⁸F]fluoroethylquinolinium ([¹⁸F]FEtQ) with the family of organic cation transporters (OCTs). Procedures: The cellular uptake of [¹⁸F]FEtQ into HEK293 cells, expressing human OCT1, -2, or -3 (HEK293-hOCT), and its inhibition by corticosterone was evaluated in vitro. The inhibitory effect of decynium 22 (D 22) in vivo was also studied, using PET/CT of HEK293-hOCT tumor-bearing mice. Furthermore, the distribution kinetics of [¹⁸F]FEtQ were determined in rats, with and without pre-administration of corticosterone, and following administration to a non-human primate (NHP). Results: The accumulation of [¹⁸F]FEtQ in HEK293-hOCT cells was 15–20-fold higher than in control cells and could be inhibited by corticosterone. in vivo, the uptake of [¹⁸F]FEtQ in the LV myocardium of corticosterone-treated rats was significantly reduced compared to that of untreated animals. Similarly, following administration of D 22 to HEK293-hOCT tumor-bearing mice, the peak tumor uptake of [¹⁸F]FEtQ was reduced by 40–45 % compared to baseline. Contrary to the distinct accumulation of [¹⁸F]FEtQ in the LV myocardium of rats, no cardiac uptake was observed following its administration to a NHP. Conclusions: The quinolinium salt derivative [¹⁸F]FEtQ interacts with the family of OCTs, and this interaction could account, at least in part, for the increased uptake in the LV myocardium of rodents. Nonetheless, its low affinity for hOCT3 and the results of PET/CT imaging in a NHP indicate a limited clinical applicability as a radiopharmaceutical for cardiac and/or OCT imaging.

We previously presented the radiolabeled ammonium salt [¹¹C]-dimethyl diphenylammonium trifluoromethanesulfonate ([¹¹C]DMDPA) as a potential novel PET-MPI agent. The current study aimed to increase the clinical applicability of PET-MPI by designing and synthesizing fluorinated ammonium salt derivatives. Four fluorinated DMDPA derivatives and two quinolinium salt analogs were radiolabeled. The dynamic distribution in vivo, following injection of each derivative into male SD rats, was evaluated using small-animal dedicated PET/CT. Organ uptake after injection of [¹⁸F]fluoroethylquinolinium acetate ([¹⁸F]FEtQ) was examined ex vivo. Four fluorinated DMDPA derivatives were synthesized, two were labeled with fluorine-18: [¹⁸F]fluoroethyl-methyldiphenylammonium trifluoromethanesulfonate ([¹⁸F]FEMDPA) and [¹⁸F]fluorobuthyl-methyldiphenylammonium trifluoromethanesulfonate ([¹⁸F]FBMDPA). The other two were labeled using carbon-11: [¹¹C]methyl-(3-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([¹¹C]3-F-DMDPA) and [¹¹C]methyl-(4-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([¹¹C]4-F-DMDPA). All four DMDPA derivatives exhibited significantly lower heart/liver radioactivity uptake ratios (0.6, 0.4, 0.7 and 0.6, respectively) compared to that of [¹¹C]DMDPA (1.2). Conversely, the two radiolabeled quinolinium salt derivatives, [¹¹C]methylquinolinium iodide ([¹¹C]MeQ) and [¹⁸F]FEtQ demonstrated improved heart/liver ratios (2.0 and 1.3, respectively) with clear visualization of the left ventricle myocardium. Renal clearance was the major route of elimination. Among the fluorinated quaternary ammonium salts tested, [¹⁸F]FEtQ yielded the best images. Further studies are in progress to elucidate the underlying mechanism of its cardiac uptake.

Sevoflurane postconditioning (sevo postC) is an attractive and amenable approach that can protect the myocardium against ischemia/reperfusion (I/R)-injury. Unlike ischemic preconditioning (IPC), sevo postC does not require additional induced ischemic periods to a heart that is already at risk. IPC was previously shown to generate myocardial protection against I/R-injury through regulation of iron homeostasis and de novo ferritin synthesis, a process found to be impaired in the diabetic state. The current study investigated whether alterations in iron homeostasis and ferritin mRNA and protein accumulation are also involved in the cardioprotective effects generated by sevo postC. It was also investigated whether the protective effects of sevo postC in the diabetic state can be salvaged by simvastatin, through inducing nitric oxide (NO) bioavailability/activity, in isolated streptozotocin (STZ)-induced diabetic hearts (DH). Isolated rat hearts from healthy Controls and diabetic animals were retrogradely perfused using the Langendorff configuration and subjected to prolonged ischemia and reperfusion, with and without (2.4 and 3.6%) sevo postC and/or pre-treatment with simvastatin (0.5 mg/kg). Sevo postC significantly reduced infarct size and improved myocardial function in healthy Controls but not in isolated DH. The sevo postC mediated myocardial protection against I/R-injury was not associated with de novo ferrtin synthesis. Furthermore, simvastatin aggravated myocardial injury after sevo postC in STZ-induced DHs, likely due to increasing NO levels. Despite the known mechanistic overlaps between PC and postC stimuli, distinct differences underlie the cardioprotective interventions against myocardial I/R-injury and are impaired in the DH. Sevo postC mediated cardioprotection, unlike IPC, does not involve de novo ferritin accumulation and cannot be rescued by simvastatin in STZ-induced DHs.