Clinical translation of (18)F-fluoropivalate – a PET tracer for imaging short-chain fatty acid metabolism: safety, biodistribution, and dosimetry in fed and fasted healthy volunteers

BACKGROUND: Fatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including (11)C-acetate, and (18)F-FAC (2-(18)F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed (18)F-fluoropivalate ((18)F-FPIA; 3-(18)F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of (18)F-FPIA in 24 healthy volunteers and the effect of dietary conditions. MATERIALS AND METHODS: Healthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31–164.66 MBq) of (18)F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1. RESULTS: All subjects tolerated (18)F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects, though systemic NEFA and carnitine levels reflected fasted and fed states. CONCLUSION: The favourable safety, imaging, and dosimetric profile makes (18)F-FPIA a promising candidate radiotracer for tracing SCFA metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00259-020-04724-y) contains supplementary material, which is available to authorized users.