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An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[18F]Fluorobenzyl-Triphenylphosphonium ([18F]FBnTP).

ABSTRACT: PURPOSE:The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients. PROCEDURES:A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as well as chemical purity during several production runs (n = 24). The compound was purified by solid-phase extraction (SPE) with a Sep-Pak Plus Accell CM cartridge, thereby avoiding HPLC purification. RESULTS:Under optimized conditions, AY of 1.4-2.2 GBq of [18F]FBnTP were obtained from 9.4 to 12.0 GBq [18F]fluoride in 90-92 min (RCY = 28.6 ± 5.1 % with n = 3). Molar activities ranged from 80 to 99 GBq/?mol at the end of synthesis. RCP of final formulations was >?99 % at the end of synthesis and >?95 % after 8 h. With starting activities of 23.2-33.0 GBq, RCY decreased to 16.1 ± 0.4 % (n = 3). The main cause of the decline in RCY when high amounts of [18F]fluoride are used is radiolytic decomposition of [18F]FBnTP during SPE purification. CONCLUSIONS:In initial attempts, the probe was synthesized with RCY

SUBMITTER: Waldmann CM

PROVIDER: S-EPMC6054454 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[<sup>18</sup>F]Fluorobenzyl-Triphenylphosphonium ([<sup>18</sup>F]FBnTP).

Waldmann Christopher M CM Gomez Adrian A Marchis Phillip P Bailey Sean T ST Momcilovic Milica M Jones Anthony E AE Shackelford David B DB Sadeghi Saman S

Molecular imaging and biology 20180401 2

<h4>Purpose</h4>The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[<sup>18</sup>F]fluorobenzyl-triphenylphosphonium ([<sup>18</sup>F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients.<h4>Procedures</h4>A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as ...[more]

PMID: 28905308

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Project description:PurposePreviously, we showed successful imaging of xenografts that express the prostate-specific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18.Experimental designN-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-l-cysteine ([18F]DCFBC) was prepared by reacting 4-[18F]fluorobenzyl bromide with the precursor (S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid in ammonia-saturated methanol at 60 degrees C for 10 min followed by purification using C-18 reverse-phase semipreparative high-performance liquid chromatography. Severe combined immunodeficient mice bearing a s.c. PSMA+ PC-3 PIP tumor behind one shoulder and a PSMA(-) PC-3 FLU tumor behind the other shoulder were injected via the tail vein with either 1.85 MBq (50 microCi) of [18F]DCFBC for ex vivo biodistribution or 7.4 MBq (200 microCi) for imaging. For biodistribution, mice were sacrificed at 5, 15, 30, 60, and 120 min. Tumor, blood, and major organs were harvested and weighed, and radioactivity was counted. Imaging was done on the GE eXplore Vista small-animal PET scanner by collecting 12 consecutive 10-min frames.ResultsRadiochemical yield for [18F]DCFBC averaged 16 +/- 6% (n = 8) from 4-[18F]fluorobenzyl bromide. Specific radioactivities ranged from 13 to 133 GBq/micromol (350-3,600 Ci/mmol) with an average of 52 GBq/micromol (1,392 Ci/mmol; n = 6). Biodistribution and imaging studies showed high uptake of [18F]DCFBC in the PIP tumors with little to no uptake in FLU tumors. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 +/- 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 +/- 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi).Conclusion[18F]DCFBC localizes to PSMA+-expressing tumors in mice, permitting imaging by small-animal PET. This new radiopharmaceutical is an attractive candidate for further studies of PET imaging of prostate cancer.

Project description:Radiofluorinated benzamide and nicotinamide analogues are promising molecular probes for the positron emission tomography (PET) imaging of melanoma. Compounds containing aromatic (benzene or pyridine) and N,N-diethylethylenediamine groups have been successfully used for development of melanin targeted PET and single-photon emission computed tomography (SPECT) imaging agents for melanoma. The objective of this study was to determine the feasibility of using aliphatic compounds as a molecular platform for the development of a new generation of PET probes for melanoma detection. An aliphatic N,N-diethylethylenediamine precursor was directly coupled to a radiofluorination synthon, p-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP), to produce the probe N-(2-(diethylamino)ethyl)-2-(18)F-fluoropropanamide ((18)F-FPDA). The melanoma-targeting ability of (18)F-FPDA was further evaluated both in vitro and in vivo through cell uptake assays, biodistribution studies, and small animal PET imaging in C57BL/6 mice bearing B16F10 murine melanoma tumors. Beginning with the precursor (18)F-NFP, the total preparation time for (18)F-FPDA, including the final high-performance liquid chromatography purification step, was approximately 30 min, with a decay-corrected radiochemical yield of 79.8%. The melanin-targeting specificity of (18)F-FPDA was demonstrated by significantly different uptake rates in tyrosine-treated and untreated B16F10 cells in vitro. The tumor uptake of (18)F-FPDA in vivo reached 2.65 ± 0.48 %ID/g at 2 h postinjection (p.i.) in pigment-enriched B16F10 xenografts, whereas the tumor uptake of (18)F-FPDA was close to the background levels, with rates of only 0.37 ± 0.07 %ID/g at 2 h p.i. in the nonpigmented U87MG tumor mouse model. Furthermore, small animal PET imaging studies revealed that (18)F-FPDA specifically targeted the melanotic B16F10 tumor, yielding a tumor-to-muscle ratio of approximately 4:1 at 1 h p.i. and 7:1 at 2 h p.i. In summary, we report the development of a novel (18)F-labeled aliphatic compound for melanoma imaging that can be easily synthesized in high yields using the radiosynthon (18)F-NFP. The PET probe (18)F-FPDA exhibits high B16F10 tumor-targeting efficacy and favorable in vivo pharmacokinetics. Our study demonstrates that aliphatic compounds can be used as a new generation molecular platform for the development of novel melanoma targeting agents. Further evaluation and optimization of (18)F-FPDA for melanin targeted molecular imaging are therefore warranted.

Project description:BACKGROUND:To facilitate hypoxia imaging in a clinical setting, we developed 1-(2,2-dihydroxymethyl-3-[18F]-fluoropropyl)-2-nitroimidazole ([18F]DiFA) as a new tracer that targets tumor hypoxia with its lower lipophilicity and efficient radiosynthesis. Here, we evaluated the radiation dosage, biodistribution, human safety, tolerability, and early elimination after the injection of [18F]DiFA in healthy subjects, and we performed a preliminary clinical study of patients with malignant tumors in a comparison with [18F]fluoromisonidazole ([18F]FMISO). RESULTS:The single administration of [18F]DiFA in 8 healthy male adults caused neither adverse events nor abnormal clinical findings. Dynamic and sequential whole-body scans showed that [18F]DiFA was rapidly cleared from all of the organs via the hepatobiliary and urinary systems. The whole-body mean effective dose of [18F]DiFA estimated by using the medical internal radiation dose (MIRD) schema with organ level internal dose assessment/exponential modeling (OLINDA/EXM) computer software 1.1 was 14.4 ± 0.7 μSv/MBq. Among the organs, the urinary bladder received the largest absorbed dose (94.7 ± 13.6 μSv/MBq). The mean absorbed doses of the other organs were equal to or less than those from other hypoxia tracers. The excretion of radioactivity via the urinary system was very rapid, reaching 86.4 ± 7.1% of the administered dose. For the preliminary clinical study, seven patients were subjected to [18F]FMISO and [18F]DiFA positron emission tomography (PET) at 48-h intervals to compare the two tracers' diagnostic ability for tumor hypoxia. The results of the tumor hypoxia evaluation by [18F]DiFA PET at 1 h and 2 h were not significantly different from those obtained with [18F]FMISO PET at 4 h ([18F]DiFA at 1 h, p = 0.32; [18F]DiFA at 2 h, p = 0.08). Moreover, [18F]DiFA PET at both 1 h (k = 0.68) and 2 h (k = 1.00) showed better inter-observer reproducibility than [18F]FMISO PET at 4 h (k = 0.59). CONCLUSION:[18F]DiFA is well tolerated, and its radiation dose is comparable to those of other hypoxia tracers. [18F]DiFA is very rapidly cleared via the urinary system. [18F]DiFA PET generated comparable images to [18F]FMISO PET in hypoxia imaging with shorter waiting time, demonstrating the promising potential of [18F]DiFA PET for hypoxia imaging and for a multicenter trial.

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Dataset Information

An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[18F]Fluorobenzyl-Triphenylphosphonium ([18F]FBnTP).

Publications

An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[<sup>18</sup>F]Fluorobenzyl-Triphenylphosphonium ([<sup>18</sup>F]FBnTP).

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