Organic Cation Transporter-Mediated Accumulation of Quinolinium Salts in the LV Myocardium of Rodents.

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.

Multiparametric Evaluation of Post-MI Small Animal Models Using Metabolic ([18F]FDG) and Perfusion-Based (SYN1) Heart Viability Tracers.

Cardiovascular diseases (CVD), with myocardial infarction (MI) being one of the crucial components, wreak havoc in developed countries. Advanced imaging technologies are required to obtain quick and widely available diagnostic data. This paper describes a multimodal approach to in vivo perfusion imaging using the novel SYN1 tracer based on the fluorine-18 isotope. The NOD-SCID mice were injected intravenously with SYN1 or [18F] fluorodeoxyglucose ([18F]-FDG) radiotracers after induction of the MI. In all studies, the positron emission tomography-computed tomography (PET/CT) technique was used. To obtain hemodynamic data, mice were subjected to magnetic resonance imaging (MRI). Finally, the biodistribution of the SYN1 compound was performed using Wistar rat model. SYN1 showed normal accumulation in mouse and rat hearts, and MI hearts correctly indicated impaired cardiac segments when compared to [18F]-FDG uptake. In vivo PET/CT and MRI studies showed statistical convergence in terms of the size of the necrotic zone and cardiac function. This was further supported with RNAseq molecular analyses to correlate the candidate function genes' expression, with Serpinb1c, Tnc and Nupr1, with Trem2 and Aldolase B functional correlations showing statistical significance in both SYN1 and [18F]-FDG. Our manuscript presents a new fluorine-18-based perfusion radiotracer for PET/CT imaging that may have importance in clinical applications. Future research should focus on confirmation of the data elucidated here to prepare SYN1 for first-in-human trials.

Development and preclinical evaluation of novel fluorinated ammonium salts for PET myocardial perfusion 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.

Cyclotron production of (43)Sc for PET imaging.

BACKGROUND: Recently, significant interest in (44)Sc as a tracer for positron emission tomography (PET) imaging has been observed. Unfortunately, the co-emission by (44)Sc of high-energy γ rays (E γ = 1157, 1499 keV) causes a dangerous increase of the radiation dose to the patients and clinical staff. However, it is possible to produce another radionuclide of scandium-(43)Sc-having properties similar to (44)Sc but is characterized by much lower energy of the concurrent gamma emissions. This work presents the production route of (43)Sc by α irradiation of natural calcium, its separation and purification processes, and the labeling of [DOTA,Tyr3] octreotate (DOTATATE) bioconjugate. METHODS: Natural CaCO3 and enriched [(40)Ca]CaCO3 were irradiated with alpha particles for 1 h in an energy range of 14.8-30 MeV at a beam current of 0.5 or 0.25 µA. In order to find the optimum method for the separation of (43)Sc from irradiated calcium targets, three processes previously developed for (44)Sc were tested. Radiolabeling experiments were performed with DOTATATE radiobioconjugate, and the stability of the obtained (43)Sc-DOTATATE was tested in human serum. RESULTS: Studies of (nat)CaCO3 target irradiation by alpha particles show that the optimum alpha particle energies are in the range of 24-27 MeV, giving 102 MBq/µA/h of (43)Sc radioactivity which creates the opportunity to produce several GBq of (43)Sc. The separation experiments performed indicate that, as with (44)Sc, due to the simplicity of the operations and because of the chemical purity of the (43)Sc obtained, the best separation process is when UTEVA resin is used. The DOTATATE conjugate was labeled by the obtained (43)Sc with a yield >98 % at elevated temperature. CONCLUSIONS: Tens of GBq activities of (43)Sc of high radionuclidic purity can be obtainable for clinical applications by irradiation of natural calcium with an alpha beam.

Adsorption of 137Cs on titanate nanostructures.

Various types of sodium and potassium titanate nanostructures (nanotubes, nanofibers, nanoribbons, nanwires) were synthesized and characterized by X-ray diffraction, SEM and TEM, as well BET and BJH methods. Adsorption of radiotracer 137Cs+ ions from aqueous solutions on synthesized titanate nanostructures was investigated in batch technique as a function of contact time, concentration of sodium ions and pH of the solutions. It was found that among the studied nanostructures nanotubes shows the highest selectivity for 137Cs, which is related to a zeolitic character of Cs+ adsorption. The efficient adsorption of 137Cs was obtained in Na+ solutions with concentration below 10-2 M, at pH 7-9 and in contact time above 2 h. Moreover, nanotubes have the higher specific surface area than other nanostructures, which results in better availability of ion exchange groups and high ion exchange capacity. These properties of nanotubes indicate that they may be used for adsorption of 137Cs from various types of nuclear wastes.

Search of ligands suitable for 212Pb/212Bi in vivo generators.

The short half-life of 212Bi and 213Bi limits the application of these radionuclides in α radionuclide therapy. The labeling of biomolecules with 212Pb (mother nuclide of 212Bi) instead of 212Bi or 213Bi has the advantage of obtaining a conjugate with a half-life of 10.6 h, compared with of 60 min for 212Bi or 46 min for 213Bi. Previous attempts to prepare a potential in vivo generator with 212Pb complexed by the DOTA chelator failed, because about 36 % of Bi was reported to escape as a result of the radioactive decay [Formula: see text]. Herein, we report studies on the stability of the 212Pb complexes with eight selected polydentate ligands, which demonstrate high affinity for 3+ metal cations. From the ligand studied DOTP and BAPTA show a sufficient 212Pb labeling yields but only 212Pb-DOTP complex is stable in isotonic solution of sodium chloride making this way radioactivity level of released 212Bi is below the limit of detection. It should be emphasized that the DOTP complex is stable only in the case when the concentration of free DOTP exceeds 10-4 M.

Stability of 47Sc-complexes with acyclic polyamino-polycarboxylate ligands.

The aim of this study was to evaluate acyclic ligands which can be applied for labeling proteins such as monoclonal antibodies and their fragments with scandium radionuclides. Recently, scandium isotopes (47Sc, 44Sc) are more available and their properties are convenient for radiotherapy or PET imaging. They can be used together as "matched pair" in theranostic approach. Because proteins denaturize at temperature above 42 °C, ligands which efficiently form complexes at room temperature, are necessary for labelling such biomolecules. For complexation of scandium radionuclides open chain ligands DTPA, HBED, BAPTA, EGTA, TTHA and deferoxamine have been chosen. We found that the ligands studied (except HBED) form strong complexes within 10 min and that the radiolabelling yield varies between 96 and 99 %. The complexes were stable in isotonic NaCl, but stability of 46Sc-TTHA, 46Sc-BAPTA and 46Sc-HBED in PBS buffer was low, due to formation by Sc3+stronger complexes with phosphates than with the studied ligands. From the radiolabelling studies with n.c.a. 47Sc we can conclude that the most stable complexes are formed by the 8-dentate DTPA and EGTA ligands.

Separation of fission produced 106Ru from simulated high level nuclear wastes for production of brachytherapy sources.

An effective and simple process for the isolation of 106Ru from high-level liquid wastes was developed. Radioactive ruthenium was oxidized by H5IO6 in HNO3 solution and was extracted to CCl4 phase in the form of RuO4. In order to obtain ruthenium in the suitable form for production of brachytherapy sources, RuO4 in organic phase was reduced and re-extracted to aqueous phase. The efficiency of extraction of 103Ru to organic phase was 86 %, re-extraction to aqueous solution was near 100 %, so the overall recovery of 103Ru is estimated at more than 80 %.