Implemented one-pot two step fully automated synthesis of [¹⁸F]FPIA for metabolic imaging applications

[¹⁸F]Fluoropivalate ([¹⁸F]FPIA), also known as ¹⁸F-pivalate or ¹⁸F-RAD101, is the fluorinated analogue of pivalic acid and has shown promise in ongoing clinical trials for the detection of brain metastases. The original synthesis of [¹⁸F]FPIA involved a two-step procedure that was not fully automated, limiting its suitability for large-scale or GMP production. A subsequent report described an improved two-step, one-pot synthesis on a cassette-based module, although with certain limitations. Here, we present an optimized two-step, one-pot synthesis of [¹⁸F]FPIA using a vial-based automated synthesizer and demonstrate its successful implementation under GMP conditions. We also report [¹⁸F]FPIA-PET imaging in prostate cancer patient-derived xenograft (PDX) models.

[¹⁸F]FPIA was successfully produced with the optimized synthetic strategy with a total synthesis time of 75 min and a 25.4 ± 3.8% (n = 9) activity yield at end of synthesis (EOS), with >99% radiochemical purity. In a GMP setting, the scale-up synthesis was successful with a 37 ± 9% (n = 37) activity yield at EOS and a > 99% radiochemical purity. In the proof-of-concept PET imaging study of [¹⁸F]FPIA in androgen receptor (AR)-negative and -positive prostate cancer PDX animal models, uptake was observed in both groups when the tumor reached a size of 50-300 mm³. The AR-negative group showed significantly higher [¹⁸F]FPIA uptake compared to the AR-positive group, with average tumor-to-muscle ratios of 1.6 and 1.2, respectively.

In summary, an optimized one-pot, two-step synthesis of [¹⁸F]FPIA on a vial-based automated synthesizer was successful and a seamless transition into a GMP facility is reported, enabling a streamlined transition to clinical production. Furthermore, we have demonstrated the use of [¹⁸F]FPIA for noninvasive metabolic imaging in prostate cancer and its potential to distinguish between different prostate cancer subtypes.