The scandium triflate-catalyzed N-[18F]fluoroalkylation of aryl- or heteroaryl-amines with [18F]epifluorohydrin ([18F]2) was investigated. This reaction is mild and provides one-step access to N-[18F]fluoroalkylated aryl- or heteroaryl-amines, which are used for positron emission tomography imaging. The use of 2,2,2-trifluoroethanol as a cosolvent improved the reaction efficiency. The use of (S)- and (R)-[18F]2 produced the corresponding enantiomeric N-[18F]fluoroalkylated anilines.
Abstract Background A family of BF 2 -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 [ 18 F]ADPM06 and evaluated its in vivo properties. Results [ 18 F]ADPM06 was automatically synthesized by Lewis acid-assisted isotopic 18 F- 19 F 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 [ 18 F]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 [ 18 F]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 [ 18 F]ADPM06 using an automated 18 F-labeling synthesizer and evaluated the initial uptake and pharmacokinetics of ADPM06 using biodistribution of [ 18 F]ADPM06 in mice to guide photodynamic therapy with light irradiation.
We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[11 C]carbonitrile ([11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11 C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11 C]MTP38 using [11 C]hydrogen cyanide ([11 C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11 C]MTP38 was performed using an automated 11 C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [11 C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11 C]CO2 at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [11 C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11 C]MTP38 for clinical applications using an 11 C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11 C]MTP38 suitable for clinical applications.
Recently, we produced 11 C‐labeled 2‐((1 E ,3 E )‐4‐(6‐(methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[ d ]thiazol‐6‐ol ([ 11 C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half‐life) of [ 11 C]PBB3, we further synthesized 18 F‐labeled 1‐fluoro‐3‐((2‐((1 E ,3 E )‐4‐(6‐(methylamino)pyridine‐3‐yl)buta‐1,3‐dien‐1‐yl)benzo[ d ]thiazol‐6‐yl)oxy)propan‐2‐ol ([ 18 F]PM‐PBB3). [ 18 F]PM‐PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [ 18 F]PM‐PBB3 for clinical applications. [ 18 F]PM‐PBB3 was synthesized by direct 18 F‐fluorination of the tosylated derivative, followed by removal of the protecting group. [ 18 F]PM‐PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay‐corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [ 18 F]PM‐PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV‐cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [ 18 F]PM‐PBB3 injection complied with our in‐house quality control and quality assurance specifications. We have accomplished >200 production runs of [ 18 F]PM‐PBB3 in our facility for various research purposes.
The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.
Abstract 1-Methyl-tryptophan (1MTrp) is known as a specific inhibitor targeting the immune- checkpoint protein indoleamine-2,3-dioxygenase, in two stereoisomers of levorotary ( l ) and dextrorotary ( d ). A long-standing debate exists in immunology and oncology: which stereoisomer has the potential of antitumor immunotherapy. Herein, we developed two novel radioprobes, 1- N - 11 C-methyl- l - and - d -tryptophan ( 11 C- l -1MTrp and 11 C- d -1MTrp), without modifying the chemical structures of the two isomers and investigated their utility for pharmacokinetic imaging of the whole body. 11 C- l -1MTrp and 11 C- d -1MTrp were synthesized rapidly with radiochemical yields of 47 ± 6.3% (decay-corrected, based on 11 C-CO 2 ), a radiochemical purity of >98%, specific activity of 47–130 GBq/μmol and high enantiomeric purity. PET/CT imaging in rats revealed that for 11 C- l -1MTrp, the highest distribution of radioactivity was observed in the pancreas, while for 11 C- D -1MTrp, it was observed in the kidney. Ex vivo biodistribution confirmed the PET/CT results, indicating the differences in pharmacokinetics between the two isomers. Both 11 C- l -1MTrp and 11 C- d -1MTrp are therefore useful PET probes for delineating the distribution and action of the checkpoint inhibitor 1MTrp in vivo . This study represents the first step toward using whole-body and real-time insight to disentangle the antitumor potential of the two stereoisomers of 1MTrp and it can facilitate the development of 1MTrp immunotherapy.
Two novel radiotracers, namely, N-(4-[18F]fluorobenzyl)-N-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([18F]5) and 2-(5-(4-[18F]fluorophenyl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide ([18F]6), were developed for positron emission tomography (PET) imaging of translocator protein (18 kDa) (TSPO) in ischemic brain in this study. The two radiotracers with a [18F]fluorobenzene ring were derived from the corresponding [18F]fluoroethyl tracers [18F]7 and [18F]8 which underwent [18F]defluoroethylation in vivo easily. [18F]5 or [18F]6 was synthesized by the radiofluorination of the spirocyclic iodonium ylide precursor 10 or 17 with [18F]F- in 23 ± 10% (n = 7) or 56 ± 9% (n = 7) radiochemical yields (decay-corrected, based on [18F]F-). [18F]5 and [18F]6 showed high in vitro binding affinities (Ki = 0.70 nM and 5.9 nM) for TSPO and moderate lipophilicities (log D = 2.9 and 3.4). Low uptake of radioactivity for both radiotracers was observed in mouse bones. Metabolite analysis showed that the in vivo stability of [18F]5 and [18F]6 was improved in comparison to the parent radiotracers [18F]7 and [18F]8. In particular, no radiolabelled metabolite of [18F]5 was found in the mouse brains at 60 min after the radiotracer injection. PET studies with [18F]5 on ischemic rat brains revealed a higher binding potential (BPND = 3.42) and maximum uptake ratio (4.49) between the ipsilateral and contralateral sides. Thus, [18F]5 was shown to be a useful PET radiotracer for visualizing TSPO in neuroinflammation models.
