Automated radiosynthesis of 18F-fluoromethylated tracers using the simplified one-pot 18F-fluoromethylation via [18F]fluoromethyl tosylate.

Background/Aims: [18F]Fluoroalkyl groups are essential labeling units because they are considered as surrogates for [11C]methyl moieties, and are coupled to the same functional units as the [11C]methyl group. Many [18F]fluoroalkyated PET tracers have been developed. In general, 18F-fluoroalkylation using [18F]fluoroalkyl reagents requires multi-step radiosynthesis procedures and a multi-pot 18F-labeling synthesizer. To overcome these limitations, a straightforward one-pot method for 18F-fluoroethylation without azeotropic drying of [18F]F- was developed [1]. We have used an improved one-pot 18F-fluoroethylaion method to synthesize 18F-fluoroethylated tracers [2]. In this study, we further modified this one-pot method suitable for 18F-fluoromethylation, and simplified the automated radiosynthesis of two [18F]fluoromethylated tracers using this method. Methods: We synthesized [18F]fluoromethyl tosylate in a mixture of 18F- in K222/K2CO3 acetonitrile solution including 2% water, bis(tosyloxy)methane and cesium carbonate. Without purification of [18F]fluoromethyl tosylate, we directly added a labeling precursor to this mixture for the simplified one-pot 18F-fluoromethylation. Using this procedure equipped to a 18F-labeling synthesizer, [18F]FCho (a PET tracer for imaging tumor) and [18F]FMeNER-D2 (a PET tracer for imaging norepinephrine transporter) were automatically synthesized by the reactions of their corresponding labeling precursors with [18F]fluoromethyl tosylate, respectively. Results: Using the simplified one-pot 18F-fluoromethylation procedure in the automated radiosynthesis, we achieved [18F]FCho and [18F]FMeNER-D2 in approximately 10% of radiochemical yield from 18F- at the end of irradiation (EOI). Radiosynthesis times and radiochemical purities of two 18F-labeled tracers were approximately 60 min after EOI and over 95%, respectively. Conclusions: We have successively synthesized [18F]FCho and [18F]FMeNER-D2 using the simplified one-pot 18F-fluoromethylation method, and achieved automation for all radiosynthesis processes using an 18F-labeling synthesizer. The present method provides a shorter synthesis time and automated procedures with one-pot for the 18F-fluoromethylation strategy.第13回世界核医学会(13th Congress of the World Federation of Nuclear Medicine and Biology

Automated radiosynthesis and in vivo evaluation of 18F-labeled analog of the photosensitizer ADPM06 for planning photodynamic therapy

Abstract Background A family of BF2-chelated tetraaryl-azadipyrromethenes was developed as non-porphyrin photosensitizers for photodynamic therapy. Among the developed photosensitizers, ADPM06 exhibited excellent photochemical and photophysical properties. Molecular imaging is a useful tool for photodynamic therapy planning and monitoring. Radiolabeled photosensitizers can efficiently address photosensitizer biodistribution, providing helpful information for photodynamic therapy planning. To evaluate the biodistribution of ADPM06 and predict its pharmacokinetics on photodynamic therapy with light irradiation immediately after administration, we synthesized [18F]ADPM06 and evaluated its in vivo properties. Results [18F]ADPM06 was automatically synthesized by Lewis acid-assisted isotopic 18F-19F exchange using ADPM06 and tin (IV) chloride at room temperature for 10 min. Radiolabeling was carried out using 0.4 μmol of ADPM06 and 200 μmol of tin (IV) chloride. The radiosynthesis time was approximately 60 min, and the radiochemical purity was > 95% at the end of the synthesis. The decay-corrected radiochemical yield from [18F]F− at the start of synthesis was 13 ± 2.7% (n = 5). In the biodistribution study of male ddY mice, radioactivity levels in the heart, lungs, liver, pancreas, spleen, kidney, small intestine, muscle, and brain gradually decreased over 120 min after the initial uptake. The mean radioactivity level in the thighbone was the highest among all organs investigated and increased for 120 min after injection. Upon co-injection with ADPM06, the radioactivity levels in the blood and brain significantly increased, whereas those in the heart, lung, liver, pancreas, kidney, small intestine, muscle, and thighbone of male ddY mice were not affected. In the metabolite analysis of the plasma at 30 min post-injection in female BALB/c-nu/nu mice, the percentage of radioactivity corresponding to [18F]ADPM06 was 76.3 ± 1.6% (n = 3). In a positron emission tomography study using MDA-MB-231-HTB-26 tumor-bearing mice (female BALB/c-nu/nu), radioactivity accumulated in the bone at a relatively high level and in the tumor at a moderate level for 60 min after injection. Conclusions We synthesized [18F]ADPM06 using an automated 18F-labeling synthesizer and evaluated the initial uptake and pharmacokinetics of ADPM06 using biodistribution of [18F]ADPM06 in mice to guide photodynamic therapy with light irradiation

Automated radiosynthesis of the 18F-labeled BF2-chelated tetraaryl-azadipyrromethenes photosensitizer using isotopic exchange

Objectives: A family of the BF2-chelated tetraaryl-azadipyrromethenes (ADPMs) was developed as a nonporphyrin photosensitizer (PS) for photodynamic therapy (PDT) [1]. Among ADPMs, ADPM06 displayed excellent photochemical and photophysical properties [1]. In addition, PDT using ADPM06 elicited impressive complete response rates in various tumor models when a short drug-light interval was applied [2]. Molecular imaging is a promising PDT planning and monitoring tool, and the PS biodistribution is a relevant issue for PDT planning that radiolabeled PSs may address efficiently. To evaluate efficiency for PDT using ADPM06 and also side effects of ADPM, we synthesized [18F]ADPM06 using an automated 18F-labeling synthesizer, and evaluated its in vivo properties.Methods: [18F]ADPM06 was synthesized using an automated 18F-labeling synthesizer by Lewis acid-assisted isotopic 18F-19F exchange [3]. The [18F]F– was extracted from a Sep-Pak Accell Plus QMA Carbonate Plus Light cartridge with a mixture of tetrabutylanmmonium bicarbonate aqueous solution and acetonitrile. The solution was concentrated by evaporation at 100 °C for 10 min under nitrogen gas flow. After the reaction vessel was cooled, the mixture of ADPM06 in acetonitrile and tin(IV) chloride (SnCl4) solution was added to the reaction vessel, and then was agitated using magnetic stirrer at room temperature for 10 min. After the reaction, the mixture was diluted with water for injection, and transferred to the injector for semi-preparative radio-HPLC. The HPLC fractions were collected in a flask, to which Tween 80 in ethanol was added prior to radiosynthesis. The solution was subsequently evaporated to dryness and the residue was dissolved in physiological saline. The product was analyzed by HPLC with radioactivity and UV-VIS detection. The in vivo biodistribution study was performed using mice.Results:To radio-synthesize efficiently [18F]ADPM06, we performed semi-automated radiosynthesis. By increasing the concentration of SnCl4 from 100 to 400 μmol, the radiochemical conversion (RCC) of [18F]ADPM06 from [18F]TBAF was increased until 60%. Also, the RCC using 0.8 μmol of ADPM06 was 1.2-fold higher than that using 0.4 μmol of ADPM06. In the radiosynthesis using an automated 18F-labeling synthesizer, we successfully synthesized [18F]ADPM06 for in vivo applications. The radiochemical yield (RCY) from [18F]F- was 13 ± 2.7 % (n = 5; 0.4 μmol of ADPM06, 200 μmol of SnCl4) at the end of irradiation. The radiosynthesis time was within 60 min, and radiochemical purity remained >95% after maintaining it for 1 hour after the end of synthesis. In the biodistribution study within 120 min after the injection, radioactivity levels in heart, lung, liver, pancreas, spleen, kidney, small intestine, muscle, and brain gradually decreased after initial uptake.Conclusions: We enabled to synthesize [18F]ADPM06 using an automated 18F-labeling synthesizer, and to evaluate biodistribution of [18F]ADPM06 in mice