Improved small scale production of iodine-124 for radiolabeling and clinical applications.

AIM: This work describes a small-scale production of iodine-124 using a 16.5 MeV cyclotron, and a subsequent validation of the formulated sodium [124I]iodide solution for routinely clinical applications. METHODS: Iodine-124 (124I) was produced via the 124Te(p, n)124I reaction using a 16.5 MeV GE PETtrace® cyclotron. Irradiation was performed with a pre-prepared solid target consisting of [124Te]TeO2 (99.93%) and Al2O3. Different layer thicknesses, irradiation and extraction parameters were tested. After irradiation at the cyclotron, the shuttle with irradiated material was transferred fully automatically via a tube system to the Comecer ALCEO® Halogen 2.0 extraction unit. Iodine-124 was subsequently extracted in form of sodium [124I]iodide ([124I]NaI) in 0.05 N aqueous NaOH solution, followed by reconstitution and validation for preclinical and clinical uses. RESULTS: Good result was achieved using a beam degradation foil of 500 µm thickness in combination with beam currents between 10 and 15 µA. Under these conditions, up to 150 MBq no-carrier-added [124I]NaI was obtained after a 2 h irradiation time in less than 500 µl 0.05 N NaOH. Isolation of [124I]NaI, including evaporation and extraction at the ALCEO® Halogen EVP unit was accomplished in 90 min 24 h after production (irradiation), the amount of iodine-123 as assessed by gamma-ray spectroscopy was less than 1.5%. The undesirable iodine-125 was not detectable by gamma spectroscopy. The extracted [124I]NaI could be used directly for radiolabeling purposes, and after buffering with phosphate buffered saline (PBS) and sterile filtration for clinical applications. CONCLUSIONS: Through the optimized conditions for irradiation and extraction, iodine-124 was produced in good radiochemical yields and high radionuclide purity. The generated injectable [124I]NaI solution was sterile, non-pyrogenic and ready for preclinical and clinical applications after a sterile filtration through a 0.22 µm membrane filter.

[18F]Fluoro-azomycin-2´-deoxy-ß-d-ribofuranoside - A new imaging agent for tumor hypoxia in comparison with [18F]FAZA.

INTRODUCTION: Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [18F]Fluoro-azomycin-α-arabinoside ([18F]FAZA) - already in clinical use - may be seen as α-configuration nucleoside, but enters cells only via diffusion and is not transported by cellular nucleoside transporters. To enhance image contrast in comparison to [18F]FAZA our objective was to 18F-radiolabel an azomycin-2´-deoxyriboside with ß-configuration ([18F]FAZDR, [18F]-ß-8) to mimic nucleosides more closely and comparatively evaluate it versus [18F]FAZA. METHODS: Precursor and cold standards for [18F]FAZDR were synthesized from methyl 2-deoxy-d-ribofuranosides α- and ß-1 in 6 steps yielding precursors α- and ß-5. ß-5 was radiolabeled in a GE TRACERlab FXF-N synthesizer in DMSO and deprotected with NH4OH to give [18F]FAZDR ([18F]-ß-8). [18F]FAZA or [18F]FAZDR was injected in BALB/c mice bearing CT26 colon carcinoma xenografts, PET scans (10min) were performed after 1, 2 and 3h post injection (p.i.). On a subset of mice injected with [18F]FAZDR, we analyzed biodistribution. RESULTS: [18F]FAZDR was obtained in non-corrected yields of 10.9±2.4% (9.1±2.2GBq, n=4) 60min EOB, with radiochemical purity >98% and specific activity >50GBq/µmol. Small animal PET imaging showed a decrease in uptake over time for both [18F]FAZDR (1h p.i.: 0.56±0.22% ID/cc, 3h: 0.17±0.08% ID/cc, n=9) and [18F]FAZA (1h: 1.95±0.59% ID/cc, 3h: 0.87±0.55% ID/cc), whereas T/M ratios were significantly higher for [18F]FAZDR at 1h (2.76) compared to [18F]FAZA (1.69, P<0.001), 3h p.i. ratios showed no significant difference. Moreover, [18F]FAZDR showed an inverse correlation between tracer uptake in carcinomas and oxygen breathing, while muscle tissue uptake was not affected by switching from air to oxygen. CONCLUSIONS: First PET imaging results with [18F]FAZDR showed advantages over [18F]FAZA regarding higher tumor contrast at earlier time points p.i. Availability of precursor and cold fluoro standard together with high output radiosynthesis will allow for a more detailed quantitative evaluation of [18F]FAZDR, especially with regard to mechanistic studies whether active transport processes are involved, compared to passive diffusion as observed for [18F]FAZA.

Development and Successful Validation of Simple and Fast TLC Spot Tests for Determination of Kryptofix® 2.2.2 and Tetrabutylammonium in 18F-Labeled Radiopharmaceuticals.

Kryptofix® 2.2.2 (Kry) or tetrabutylammonium (TBA) are commonly used as phase transfer catalysts in 18F-radiopharmaceutical productions for positron emission tomography (PET). Due to their toxicity, quality control has to be performed before administration of the tracer to assure that limit concentration of residual reagent is not reached. Here, we describe the successful development and pharmaceutical validation (for specificity, accuracy and detection limit) of a simplified color spot test on TLC plates. We were able to prove its applicability as a general, time and resources saving, easy to handle and reliable method in daily routine analyzing 18F-tracer formulations for Kry (in [18F]FDG or [18F]FECh) or TBA contaminations (in [18F]FLT) with special regard to complex matrix compositions.

In vivo imaging of cell proliferation enables the detection of the extent of experimental rheumatoid arthritis by 3'-deoxy-3'-18f-fluorothymidine and small-animal PET.

UNLABELLED: The aim of this work was to study the feasibility of measuring cell proliferation noninvasively in vivo during different stages of experimental arthritis using the PET proliferation tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). METHODS: We injected mice with serum containing glucose-6-phosphate-isomerase-specific antibodies to induce experimental arthritis, and we injected control mice with control serum. Animals injected with (18)F-FLT 1, 3, 6, and 8 d after the onset of disease were analyzed in vivo by PET, PET/CT, or PET/MR imaging followed by autoradiography analysis. The (18)F-FLT uptake in the ankles and forepaws was quantified on the basis of the PET images by drawing standardized regions of interest. To correlate the in vivo PET data with cell proliferation, we performed Ki-67 immunohistochemistry of diseased and healthy joints at the corresponding time points. RESULTS: Analysis of the different stages of arthritic joint disease revealed enhanced (18)F-FLT uptake in arthritic ankles (2.2 ± 0.2 percentage injected dose per gram [%ID/g]) and forepaws (2.1 ± 0.3 %ID/g), compared with healthy ankles (1.4 ± 0.3 %ID/g) and forepaws (1.5 ± 0.5 %ID/g), as early as 1 d after the glucose-6-phosphate-isomerase serum injection, a time point characterized by clear histologic signs of arthritis but only slight ankle swelling. The (18)F-FLT uptake in the ankles (3.5 ± 0.3 %ID/g) reached the maximum observed level at day 8. Ki-67 immunohistochemical staining of the arthritic ankles and forepaws revealed a strong correlation with the in vivo (18)F-FLT PET data. PET/CT and PET/MR imaging measurements enabled us to identify whether the (18)F-FLT uptake was located in the bone or the soft tissue. CONCLUSION: Noninvasive in vivo measurement of cell proliferation in experimental arthritis using (18)F-FLT PET is a promising tool to investigate the extent of arthritic joint inflammation.