Franziska Wagner

Three-Step, “One-Pot” Radiosynthesis of 6-Fluoro-3,4-Dihydroxy-l-Phenylalanine by Isotopic Exchange

The 18F-labeled aromatic amino acid 6-fluoro-3,4-dihydroxy-l-phenylalanine (6-18F-fluoro-l-DOPA) is widely used as a radiopharmaceutical in neurologic and oncologic PET. In this study, a novel approach to the preparation of carrier-added (CA) 6-18F-fluoro-l-DOPA in 3 radiosynthesis steps was developed and evaluated; in this approach, direct nucleophilic 18F fluorination of a protected amino acid derivative was used. The method currently used for the routine preparation of 6-18F-fluoro-l-DOPA by electrophilic labeling is limited to the production of small amounts of activity at high costs. Alternative syntheses based on the advantage of large-scale production of nucleophilic 18F-fluoride, however, either have resulted in insufficient enantiomeric purity or are difficult to automate because of the complexity of the necessary multiple steps. Methods: An isotopic exchange reaction on the precursor (2S,5S)-tert-butyl-5-(4-benzyloxy-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate was used. The formyl group served as the activating group in the 18F-for-19F exchange with tetrabutylammonium bicarbonate for anion activation in N,N-dimethylformamide. The intermediate was converted to a hydroxy group by Baeyer–Villiger oxidation with meta-chloroperbenzoic acid. After final deprotection with hydrobromic acid, CA 6-18F-fluoro-l-DOPA was isolated by high-performance liquid chromatography. Results: The precursor was obtained by an 11-step organic synthesis. The optimized isotopic 18F exchange proceeded with a radiochemical yield of about 50%. The complete preparation and isolation of CA 6-18F-fluoro-l-DOPA thus far are possible with a radiochemical yield of about 22%, within a synthesis time of 105 min, and at a much higher specific activity than with the electrophilic method. The enantiomeric excess of the desired l-isomer was greater than 96%.Conclusion: The pathway to 6-18F-fluoro-l-DOPA by isotopic exchange not only is more efficient but also is suited to automation as a “one-pot” procedure.

(S)-4-(3-18F-Fluoropropyl)-l-Glutamic Acid: An 18F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

The glutamic acid derivative (S)-4-(3-18F-Fluoropropyl)-l-glutamic acid (18F-FSPG, alias BAY 94-9392), a new PET tracer for the detection of malignant diseases, displayed promising results in non–small cell lung cancer patients. The aim of this study was to provide dosimetry estimates for 18F-FSPG based on human whole-body PET/CT measurements. Methods: 18F-FSPG was prepared by a fully automated 2-step procedure and purified by a solid-phase extraction method. PET/CT scans were obtained for 5 healthy volunteers (mean age, 59 y; age range, 51–64 y; 2 men, 3 women). Human subjects were imaged for up to 240 min using a PET/CT scanner after intravenous injection of 299 ± 22.5 MBq of 18F-FSPG. Image quantification, time–activity data modeling, estimation of normalized number of disintegrations, and production of dosimetry estimates were performed using the RADAR (RAdiation Dose Assessment Resource) method for internal dosimetry and in general concordance with the methodology and principles as presented in the MIRD 16 document. Results: Because of the renal excretion of the tracer, the absorbed dose was highest in the urinary bladder wall and kidneys, followed by the pancreas and uterus. The individual organ doses (mSv/MBq) were 0.40 ± 0.058 for the urinary bladder wall, 0.11 ± 0.011 for the kidneys, 0.077 ± 0.020 for the pancreas, and 0.030 ± 0.0034 for the uterus. The calculated effective dose was 0.032 ± 0.0034 mSv/MBq. Absorbed dose to the bladder and the effective dose can be reduced significantly by frequent bladder-voiding intervals. For a 0.75-h voiding interval, the bladder dose was reduced to 0.10 ± 0.012 mSv/MBq, and the effective dose was reduced to 0.015 ± 0.0010 mSv/MBq. Conclusion: On the basis of the distribution and biokinetic data, the determined radiation dose for 18F-FSPG was calculated to be 9.5 ± 1.0 mSv at a patient dose of 300 MBq, which is of similar magnitude to that of 18F-FDG (5.7 mSv). The effective dose can be reduced to 4.5 ± 0.30 mSv (at 300 MBq), with a bladder-voiding interval of 0.75 h.