39. Development of an Automated System for the Quick Production of ¹³N-labeled Compo- unds with High Specific Activity Using Anhydrous [¹³N]NH₃

Kazutoshi Suzuki and Yuichiro Yoshida

N-13 (half-life: 9.965 min; 100% ⁺decay) is one of the most important of all positron emitters. It has been used mostly in the chemical form [¹³N]NH₃ or as enzymatically synthesized ¹³N-labeled amino acids in the field of nuclear medicine. However, in clinical applications, N-13 is of limited use compared to other positron emitters such as C-11 and F-18, mainly due to its short half-life which causes difficulties both in the synthesis of ¹³N-labeled compounds and in their clinical applications. N-13 may be used more widely if more ¹³N-labeled compounds are made available. High specific activity may also increase the applicability of ¹³N-labeled compounds for receptor studies with PET.

We developed an automated system (Fig.13) to realize: 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. A 10 mM ethanol solution was saturated with pure O₂ gas and then loaded into the target chamber (1.9 ml). The solution was irradiated at 17 A for 25 minutes with 18 MeV protons (15.7 MeV on target). The [¹³N]NH₃ generated directly in the target chamber by the ¹⁶O(p,)¹³N reaction was concentrated on the preconditioned cation exchange column and then eluted with 30 l of 2N KOH under a He gas flow and desiccated through the small column filled with 250 mg of CaO (3 mm i.d. X 30 mm, kept at 150 ^oC), and introduced into a cooled reaction vessel (-20^oC) containing substrate and Na₂CO₃ in 0.6 ml THF. The mixture was allowed to react for 30 seconds under a hot air flow (70 ^oC). The reaction mixture was then purified with a Sep PAK silica cartridge. The effluent was introduced into the flask of a specially designed rotary evaporator and evaporated to dryness by heating with hot air (80 ^oC) under reduced pressure. An i.v. injectable solution of [¹³N]p-nitrophenyl carbamate (as a model compound) was obtained by dissolving it in 8 ml of physiological saline solution and by filtrating the solution through a 0.22 m Millex filter into a sterilized vial. The product was analyzed by radio-HPLC using a Finepak SIL C₁₈ column with CH₃CN/0.1M-CH₃COONH₄/CH₃COOH= 100/300/5.

In summary, we established an automated production method for the quick synthesis of ¹³N-labeled compounds with ultra-high specific activity using anhydrous [¹³N]NH₃ as a synthetic precursor for practical use in PET studies. Using this system, we could obtain [¹³N]p-nitrophenyl carbamate ([¹³N]NPC) ready for i.v. injection in 5.1 + 0.1 minutes at the yield of 3.5 + 0.4 GBq, specific activity 1800 + 200 GBq/mol, and radiochemical purity >99 % ( n = 3 ).

Publications:
1) Suzuki, K., Yoshida, Y., Shikano, N. and Kubodera, Y.: Applied Radiation and Isotopes, 50, 1033 - 1038, 1999.
2) Suzuki, K. and Yoshida, Y.: Applied Radiation and Isotopes, 50, 497-503, 1999.
3) Sasaki, M., Haradahira, T. and Suzuki, K.: Radiochimica Acta. 88, 217-220, 2000.

Fig.13. System diagram for the automatic production of i.v. injectable 13N-labeled compounds. (Suzuki K. et al.)

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