Multi-pot radiosynthesizer capable of high-pressure reactions for production of [18F]FAC and analogs

Objectives Recently, a family of PET probes based on the fluorinated nucleoside analog 1-(2’-deoxy-2’-[18F]fluoroarabinofuranosyl)cytosine ([18F]FAC) has been developed that measures activity of deoxycytidine kinase (dCK) [1]. The probes show promise for use in oncology as predictors of tumor response to dCK-dependent drugs [2], and in immunology to measure activation of the immune system in response to pathogens or cancer [3]. Research interest is high, but supply of [18F]FAC is limited due to its difficult and lengthy synthesis and lack of a commercial synthesizer for it.

Methods Similar to the 4-step synthesis of [18F]FMAU and analogs pioneered by Mangner et al. [4], the synthesis of [18F]FAC involves highly corrosive and moisture-sensitive reagents and high-pressure reactions to obtain good yields. Attempts to use commercial synthesizers for these syntheses have generally led to low yields due to adverse effects of exposing valves or tubing to high pressures, or due to reduction of reaction temperatures to avoid high pressures [5,6]. We have developed a reactor for our modular, macroscale radiosynthesizer plaform that avoids these issues by using motion actuators to automatically seal reaction vessels with an inert stopper for high-pressure reactions.

Results Our reactor can robustly maintain temperatures up to 200°C and sealed conditions at pressures above 150 psi, sufficient for all steps of the synthesis. Using a first-generation prototype system constructed from 3 of these reactors, we have successfully synthesized [18F]FAC. Based on this proof of concept, additional engineering was carried out in collaboration with Sofie Biosciences to develop a commercial prototype.

Conclusions This prototype addresses limitations of available synthesizers for successful synthesis of [18F]FAC. It could be used for the routine, semi-automated production of cGMP-compliant [18F]FAC for use in preclinical and clinical environments