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 ¹¹C-acetate, and ¹⁸F-FAC (2-¹⁸F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed ¹⁸F-fluoropivalate (¹⁸F-FPIA; 3-¹⁸F-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 ¹⁸F-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 ¹⁸F-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 ¹⁸F-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 ¹⁸F-FPIA a promising candidate radiotracer for tracing SCFA metabolism.

中文翻译：

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18F-氟新戊酸盐的临床转化——一种用于成像短链脂肪酸代谢的 PET 示踪剂：在进食和禁食健康志愿者中的安全性、生物分布和剂量测定。

背景

从头衍生或从细胞外空间吸收的脂肪酸是细胞生长和增殖的重要营养来源。^包括11 C-乙酸盐和¹⁸ F-FAC（2- ¹⁸ F-氟乙酸盐）在内的放射性药物先前已用于研究短链脂肪酸 (SCFA) 代谢。我们开发了带有gem-二甲基取代基的¹⁸ F-氟新戊酸酯（¹⁸ F-FPIA；3- ¹⁸ F-氟-2,2-二甲基丙酸），以保证用于研究SCFA代谢的代谢稳定性。^{我们报告了 24 名健康志愿者中18} F-FPIA的安全性、生物分布和内部辐射剂量学特征以及饮食条件的影响。

材料和方法

招募健康志愿者男性和女性受试者（n  = 24），并分为 12 名进食和 12 名禁食。评估了非酯化脂肪酸 (NEFA) 和肉碱血液测量值。受试者接受了 159.48 MBq（范围，47.31–164.66 MBq）的¹⁸ F-FPIA。放射化学纯度> 99%。在放射性示踪剂给药期间和给药后 24 小时获得安全性数据。受试者接受了详细的全身 PET/CT 扫描，并采集静脉血进行放射性和放射性代谢物量化。定义感兴趣区域以得出个体和平均器官停留时间；使用 OLINDA 1.1 计算有效剂量。

结果

所有受试者均耐受¹⁸ F-FPIA，没有不良事件。注射后 60 分钟时血浆中存在超过 90% 的放射性示踪剂。接受最高吸收剂量（mGy/MBq）的器官是肝脏（0.070±0.023）、肾脏（0.043±0.013）、胆囊壁（0.026±0.003）和膀胱（0.021±0.004）；否则组织吸收率低。使用所有 24 名受试者的平均器官停留时间计算的有效剂量为 0.0154 mSv/MBq (SD ± 0.0010)。尽管全身 NEFA 和肉碱水平反映了禁食和进食状态，但在进食和禁食受试者中没有观察到生物分布或剂量测定的差异。

结论

良好的安全性、成像和剂量学特征使¹⁸ F-FPIA 成为追踪 SCFA 代谢的有希望的候选放射性示踪剂。