technical note

The synthesis of ¹³N labeled ammonia, dinitrogen, nitrite, and nitrate using a single cyclotron target system☆

Large volume low-pressure targets were designed for use on the wide-beam Scanditronix MC-17 cyclotron. The design was optimized experimentally by construction of aluminum test targets. Final production targets were constructed of titanium and niobium. The targets tripled the routine production yield of the previous target, giving up to 90 GBq (2.5 Ci) of fluoride and essentially eliminated the need for periodic target maintenance. The final targets represent a considerable improvement. However, they have not performed as well as predicted, indicating that further improvement is possible.

An automated system was developed to synthesize ¹³N-labeled compounds with high specific activity using anhydrous [¹³N]NH₃ as a synthetic precursor. This system enabled (1) production of an aqueous solution of [¹³N]NH₃, (2) concentration and desiccation of the [¹³N]NH₃ solution, (3) reaction of anhydrous [¹³N]NH₃ with substrate, (4) purification and formulation.

By the use of this system, [¹³N]p-nitrophenyl carbamate ([¹³N]NPC) ready for i.v. injection could be obtained in 5.1±0.1 min at the yield of 3.5±0.4 GBq, specific activity 460±55 GBq/μmol, and radiochemical purity >99% (n=3) by irradiating a 10 mM ethanol solution with 18 MeV protons at 17 μA for 25 min. With special precautions, [¹³N]NPC could be obtained at the extremely high specific activity of 1800±200 GBq/μmol.

Methods for producing N-13 ammonia via the ¹⁶O(p,α)¹³N nuclear reaction utilizing a cryogenic target have been investigated. These targets included frozen carbon dioxide and pure frozen water. Results from these targets were compared with the more traditional liquid water target with and without additives. A very dramatic difference was found between the pure water target in the frozen state when compared with the liquid state. When frozen, more than 95% of the nitrogen-13 activity is in the chemical form of ammonia at all radiation doses. In contrast, the liquid water target yielded predominately nitrates and nitrites at high radiation doses. When frozen carbon dioxide was irradiated under these conditions, more than 95% of the nitrogen-13 activity was in the form of nitrate and nitrite. The nitrogen oxides remained on the surface of the target and could be easily removed from the surface with pure water. The wash solution was converted to [¹³N]ammonia using the DeVarda’s alloy method for reduction. It was determined that levels of [¹³N]ammonia sufficient for diagnostic medical procedures could be produced directly using the frozen water targets or from frozen carbon dioxide with a wet chemical reduction. These results have significance particularly in the design of targetry for low-energy, high-beam current accelerators, because targets of this design can be used with either no vacuum isolation window or a very thin window. The substitution of carbon-13-enriched carbon dioxide for natural carbon dioxide gives access to the ¹³C(p,n)¹³N nuclear reaction, which allows protons energies as low as 6 MeV to be used to produce useable quantities of N-13 ammonia. The mechanism of these reactions has been explored to determine why there are such dramatic differences in the product distribution between the frozen state and the liquid or gaseous state.

Aqueous solutions of [¹³N]NH₃ were synthesized according to well-known methods using the ¹⁶O(p, α)¹³N reaction under conditions rendering the smallest possible amount of nitrogen-contaminants. The specific activities and radiochemical yields were measured. Factors, affecting the specific activity of [¹³N]NH₃, were investigated using radio-ionchromatography. The achieved specific activities (GBq/μmol) and radiochemical yields (GBq) of [¹³N]NH₃ were 14±2.8 and 0.3±0.1 (TiCl₃ method)∗, 590±200 and 5.4±1.1 (DeVarda's Alloy method), 5500±500 and 12.7±0.1 (ethanol method), and 6200±2700 and 2.8±0.3 (hydrogen method, 3 bar), respectively at 15 μA for 20 min irradiation (∗; 5 μA, 5 min irradiation). More than 70% of the N-13 generated with the hydrogen method was of the chemical form [¹³N]N₂.

[¹³N]NH₃ prepared by irradiating dilute aqueous ethanol with 10 MeV protons is contaminated with small amounts of [¹⁸F]fluoride and [¹³N]NO₂⁻/NO₃⁻. The content of ¹⁸F is negligible at end of bombardment but increases as a function of time due to the longer half-life of ¹⁸F.

We developed a simple on-line purification method in which the irradiated water directly passes through a small anion exchange column. Both the radionuclidic impurity [¹⁸F]fluoride and the radiochemical impurities [¹³N]NO₃⁻/NO₂⁻ are efficiently removed by this procedure which results in highly pure (>99.9%) [¹³N]NH₃ preparations.

We have developed a technique for the rapid conversion of the nitrogen-13 induced in a graphite target into nitrogen oxides. This was accomplished by heating the graphite target in a stream of pure oxygen at 800 °C. Less than 20% of the radioactivity was found in the form of [¹³N]nitrogen. The rest of the radioactivity was efficiently trapped in a solid-phase medium that consisted of an aqueous solution of 5% NaOH dispersed in silica gel. The radioactivity from this solid-phase medium was eluted with water (94% recovery) and found to be in the form of ¹³NO₂⁻ (99%). This was subsequently converted to [¹³N]ammonia with Raney-nickel, either by a conventional liquid-phase reduction with an overall conversion efficiency to ammonia of 45%, or by an incorporation of the Raney-nickel into the solid-phase medium. The latter system resulted in an overall conversion efficiency to ammonia of 37 ± 9%, with a radiochemical purity of nearly 100% and a synthesis time under 17 min.