Simplifying “SiFA”: A High-Yielding, Automated Protocol for the One-Step Radiosynthesis of the Neuroendocrine Tumor Imaging Agent [ ¹⁸ F]SiTATE <i>via</i> a Merging of “Silicon-Fluoride Acceptor” (SiFA) and “Nonanhydrous, Minimally Basic” (NAMB) Chemistries

Developing radiochemical strategies that enable the simple, rapid, and high-yielding incorporation of radioisotopes into bioactive targeting vectors using sterile, cassette-based kits is critical to sustaining clinical practice and advancing radiopharmaceutical research. 18 F-bearing positron emission tomography (PET) imaging radiopharmaceuticals that use functionally-complex biomolecules as targeting vectors are particularly challenging to synthesize because they are sensitive to the elevated temperatures and basic conditions traditionally used to incorporate [ 18 F]fluoride, necessitating complex, low-yielding multistep radiolabeling strategies using 18 F-prosthetic groups. Direct 18 F-labeling of bioactive peptides can be achieved through 19 F-for- 18 F exchange of di- tert -butylphenylfluorosilane pendant groups (a.k.a. “SiFA” chemistry). However, the translation of such protocols to automated synthesis units, which are required for the clinical production of 18 F-radiopharmaceuticals, has been hampered by the incompatibility of SiFAylated 19 F-peptide precursors with current methods to isolate [ 18 F]F – on anion exchange sorbents, including azeotropic distillation of aqueous eluates containing (bi)carbonate base, or the extraction of [ 18 F]F – via strongly-basic Kryptofix-222/KOH complex. Nonbasic tetraalkylammonium salts can be used to release [ 18 F]F – from anion exchange cartridges in small volumes of water directly into vessels containing radiolabeling precursors in MeCN or DMSO [a.k.a. nonanhydrous, minimally basic (‘NAMB’) 18 F chemistry]; these “damp” reaction mixtures (1–6% water) can be heated to achieve traditional nucleophilic 18 F-fluorinations, or, as we report here, high-yielding SiFA reactions. This merging of SiFA and NAMB is reported here first for the one-step, manual radiosynthesis of [ 18 F]SiTATE, a clinically-validated neuroendocrine tumor imaging agent, and then later translated to the FASTlab 1 automated synthesis platform. An exceptionally high non-decay-corrected radiochemical yield (NDC-RCY; 50 ± 6%, n = 4) was obtained after admixing of 19 F-precursor (50 nmol) with tetrabutylammonium dihydrogen phosphate/tetrabutylammonium [ 18 F]fluoride in 44:50:6 MeCN:DMSO:H 2 O (1 mL) for 10 min at ambient temperature. Radiochemical purity was 95% after the purification of 18 F-peptide by solid-phase extraction. The highest activity yield produced from a single cyclotron bombardment was 594 mCi (52% NDC-RCY; 440 GBq/μmol), suggesting that this ultrasimple and efficient automated protocol is amenable to the production of multiple patient doses from a single batch of [ 18 F]fluoride.

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