Production of [13N]ammonia from [13C]methanol on a 7.5 MeV cyclotron using 13C(p, n)13N reaction: Detection of myocardial infarction in a mouse model.

[13N]Ammonia is commonly produced using 16O(p, α)13N reaction but one of the limiting factor of this reaction is the relatively small nuclear cross-section at proton energies of <10 MeV. An alternative production method using 13C(p, n)13N reaction, which has a higher nuclear cross-section at low proton energies, is more suitable for a preclinical PET imaging facility equipped with a <10 MeV cyclotron. Here, we report a novel method to produce [13N]ammonia from [13C]methanol for preclinical use on a 7.5 MeV cyclotron. A tantalum solution target (80 µl) consisting of a havar window supplied by the cyclotron manufacturer for the production of [18F]fluoride was used without any modifications. The final bombardment parameters were optimized as follow: [13C]methanol concentration in target solution - 10%, bombardment time - 8 min, and beam current - 2.2 µA. These parameters provided doses of [13N]ammonia which were sufficient to conduct preclinical PET imaging studies in a mouse model of myocardial infarction. Under optimized conditions, the operational lifetime of the target was approximately 150 µAmin. Radionuclide identity of the product as 13N was confirmed by measuring the decay half-life and its radionuclide purity was confirmed by γ-ray spectroscopic analysis. Gas chromatography revealed that the final [13N]ammonia dose was not distinguishable from water, showing no traces of methanol. As expected, PET/CT imaging in healthy CD-1 mice indicated the accumulation of [13N]ammonia in myocardial tissue; mice with myocardial infarction created by left ascending coronary ligation showed clear perfusion deficit in affected tissue. This work demonstrates the proof-of-concept of using 13C(p, n)13N reaction to produce [13N]ammonia from [13C]methanol with a <10 MeV cyclotron, and its diagnostic application in imaging cardiac perfusion.

Imaging of isoproterenol-induced myocardial injury with 18F labeled fluoroglucaric acid in a rat model.

Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize 18F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model. METHODS: We synthesized 18F-FGA by controlled oxidation of 18F-fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions. After ascertaining preferential uptake of 18F-FGA in necrotic as compared to normal H9c2 myoblasts, the biodistribution and circulation kinetics of 18F-FGA was assessed in mice. Moreover, the potential of 18F-FGA to image myocardial damage was investigated in a rat model of isoproterenol-induced cardiomyopathy. Isoproterenol-induced myocardial injury was verified at necropsy by tissue staining and plasma cardiac troponin levels. RESULTS: Synthesis of radiochemically pure 18F-FGA was accomplished by a 5 min, one step oxidation of 18F-FDG. Reaction yield was quantitative and no side-products were detected. Biodistribution studies showed rapid elimination from the body (ke = 0.83 h-1); the major organ of 18F-FGA accumulation was kidney. In the rat model, isoproterenol-treatment resulted in significant increase in cardiac troponin. PET images showed that the hearts of isoproterenol-treated rats accumulated significant amounts of 18F-FGA, whereas healthy hearts showed negligible uptake of 18F-FGA. Target-to-nontarget contrast for 18F-FGA accumulation became significantly more pronounced in 4 h images as compared to images acquired 1 h post-injection. CONCLUSION: 18F-FGA can be easily and quantitatively synthesized from ubiquitously available 18F-FDG as a precursor. The resultant 18F-FGA has a potential to serve as an infarct-avid agent for PET imaging of MI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FGA/PET will complement existing perfusion imaging protocols in therapeutic decision making, determination of revascularization candidacy and success, differentiation of ischemia from necrosis in MI, discrimination of myocarditis from infarction, and surveillance of heart transplant rejection.

Facile synthesis of para-[(18)F]fluorohippurate via iodonium ylide-mediated radiofluorination for PET renography.

para-[(18)F]fluorohippurate ([(18)F]PFH) is a renal tubular agent suitable for conducting positron emission tomography (PET) renography. [(18)F]PFH is currently synthesized by a four-step two-pot procedure utilizing a classical prosthetic group, N-succinimidyl-4-[(18)F]fluorobenzoate, followed by glycine conjugation. Considering the short half-life of fluorine-18 (110min), it is important to reduce the number of synthetic steps and overall production time for successful translation of any fluorine-18 radiopharmaceutical in to clinical practice. Here, we report a new two-step one-pot procedure using a novel spirocyclic iodonium ylide precursor for producing a dose of [(18)F]PFH suitable for human use in 45min including HPLC purification with an overall decay-corrected radiochemical yield of 46.4±2.9% (n=3) and radiochemical purity of >99%.