Automated radiosynthesis of [18 F]CETO, a PET radiotracer for imaging adrenal glands, on Synthra RNplus.

Primary aldosteronism (PA) is the leading secondary cause of hypertension. Determining whether one (unilateral) or both (bilateral) adrenal glands are the source of PA in a patient remains challenging, and yet it is a critical step in the decision whether to recommend potentially curative surgery (adrenalectomy) or lifelong medical therapy (typically requiring multiple drugs). Recently, we have developed a fluorine-18 radiopharmaceutical [18 F]CETO to permit greater access to PA molecular imaging. Herein, we report an automated synthesis of this radiotracer. To manufacture the radiopharmaceutical routinely for clinical PET studies, we implemented an automated radiosynthesis method on a Synthra RNplus© synthesiser for which Cl-tosyletomidate was used as the precursor for radiolabelling via nucleophilic [18 F]fluorination. [18 F]CETO was produced with 35 ± 1% (n = 7), decay corrected and 25 ± 4% (n = 7) non-decay corrected radiochemical yield with molar activities ranging from 150 to 400 GBq/µmol. The GMP compliant manufacturing process produces a sterile formulated [18 F]CETO injectable solution for human use as demonstrated by the results of quality control. Automation of the radiosynthesis of [18 F]CETO should facilitate uptake by other adrenal centres and increase access to molecular imaging in PA.

Improved Radiosynthesis and Automation of [11C]2-(2,6-Difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2) for Positron Emission Tomography of the Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptor.

A new automated radiosynthesis of [11C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use.

Light-Driven Radiochemistry with Fluorine-18, Carbon-11 and Zirconium-89.

This review discusses recent advances in light-driven radiochemistry for three key isotopes: fluorine-18, carbon-11, and zirconium-89, and their applications in positron emission tomography (PET). In the case of fluorine-18, the predominant approach involves the use of cyclotron-produced [18F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine-18 labeled reagent. Advancements in carbon-11 photo-mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11C-methylation, 11C-carboxylation, 11C-carbonylation, and 11C-cyanation. Contrastingly, zirconium-89 photo-mediated radiochemistry differs from fluorine-18 and carbon-11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo-mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers.

Fully automated dual-run manufacturing of [11C]PIB on FASTlab.

This report describes an updated, fully automated method for the production of [11C]PIB on a cassette-based automated synthesis module. The method allows for two separate productions of [11C]PIB, both of which meet all specification for use in clinical studies. The GE FASTlab developer system was used to create the cassette design as well as the controlling tracer package. The method takes 16 min from the delivery of [11C]MeOTf to the FASTlab, or 35 min from the End of Bombardment; and reliably produces 3547 ± 586 MBq of [11C]PIB in high radiochemical purity (> 98 %). This methodology increases the production capacity of radiopharmaceutical facilities for [11C]PIB, and can easily produce 4 batches in a single day with limited infrastructure footprint.

Design and radiosynthesis of class-IIa HDAC inhibitor with high molar activity via repositioning the 18F-radiolabel.

The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.

Development of 225Ac/213Bi generator based on α-ZrP-PAN composite for targeted alpha therapy.

BACKGROUND: Radioligand therapy using alpha emitters has gained more and more prominence in the last decade. Despite continued efforts to identify new appropriate radionuclides, the combination of 225Ac/213Bi remains among the most promising. Bismuth-213 has been employed in clinical trials in combination with appropriate vectors to treat patients with various forms of cancer, such as leukaemia, bladder cancer, neuroendocrine tumours, melanomas, gliomas, or lymphomas. However, the half-life of 213Bi (T½ = 46 min) implies that its availability for clinical use is limited to hospitals possessing a 225Ac/213Bi radionuclide generator, which is still predominantly scarce. We investigated a new Ac/Bi generator system based on using the composite sorbent α-ZrP-PAN (zirconium(IV) phosphate as active component and polyacrylonitrile as matrix). The developed 225Ac/213Bi generator was subjected to long-term testing after its development. The elution profile was determined and the elution yield, the contamination of the eluate with the parent 225Ac and the contamination of the eluate with the column material were monitored over time. RESULTS: The high activity (75 MBq of parent 225Ac) generator with a length of 75 mm and a diameter of 4 mm containing the composite sorbent α-ZrP-PAN with a particle size of 0.8 to 1.0 mm as the stationary phase, eluted with a mixture of 10 mM DTPA in 5 mM nitric acid, provided 213Bi with yields ranging from 77 % to 96 % in 2.8 mL of eluate, with parent 225Ac contamination in the order of 10-3 %, up to twenty days of use. CONCLUSION: All the results of the monitored parameters indicate that the composite sorbent α-ZrP-PAN based separation system for the elution of 213Bi is a very promising and functional solution.

Current Approach in Radiochemical Quality Control of the 99mTc-Radiopharmaceuticals: a mini-review

Abstract To present optimized chromatographic systems for radiochemical purity (RCP) evaluation of 99mTc-eluate and 99mTc-radiopharmaceuticals, as well as to assess doses calibrator reliability for routine purposes in hospital radiopharmacies. RCP was determined by different systems and radioactivity was quantified by TLC-scanner, doses calibrator and gamma-counter. Suitable and optimized systems were presented for RCP analyses. No significant differences were observed between radioactivity counting devices and, thus, doses calibrator showed reliability for RCP determination in hospital radiopharmacies.

Technetium-99m-alendronate: a new radiopharmaceutical for bone scanning

The purpose of this paper is to report the preparation of a new technetium-99m-radiopharmaceutical for bone scanning. The chelating agent for99mTc is a new bisphosphonate, alendronate, 4-amino-1-hydroxy-butylidene-1,1-bisphosphonate (ABP) used as a treatment for osteoporosis. ABP, because of its amino group, seems to be better suited to form a strong and stable complex with technetium-99m and therefore might be better than 99mTc-etidronate (HEDP) or 99mTc-medronate (MDP) for bone scanning. A sterile dry kit containing APB, a reducing agent and a stabilizer was prepared. The parameters studied were molar concentrations, pH, shelf life, labeling efficiency and radiochemical purity. the oven dried sterile kit was formulated with 5 mg ABP, 0.25 mg stannous fluoride and 0.025 mg gentisic acid at pH2.5-3.5. The labeling efficiency with 20 - 1500 MBq of pertechnetate (99mTcO4-) was over 95 percent at room temperature and was stable for 5 h. Technetium-99m-alendronate was tested in two rabbits and it proved to be a promising new radiopharmaceutical for bone scanning. Work is underway to study underway to study 99m-Tc-ABP biodistribution in a statistically significant number of laboratory animals and, later on, to determine radiopharmacokinetic parameters in normal volunteers