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-氟新戊酸的临床转化——一种用于对短链脂肪酸代谢进行成像的 PET 示踪剂：在进食和禁食的健康志愿者中的安全性、生物分布和剂量测定。

 背景

从头产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。我们开发了带有偕二甲基取代基的¹⁸ F-氟新戊酸（ ¹⁸ F-FPIA；3- ¹⁸ F-氟-2,2-二甲基丙酸），以维持研究 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测定情况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 名进食者和 12 名禁食者。评估了非酯化脂肪酸（NEFA）和肉碱血液测量结果。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%。安全性数据是在放射性示踪剂施用期间和施用后 24 小时获得的。受试者接受了详细的多次全身 PET/CT 扫描，并采集静脉血样本进行放射性和放射性代谢物定量。定义感兴趣区域以获得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，未出现不良事件。注射后 60 分钟，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）；否则组织摄取较低。使用所有 24 名受试者的平均器官停留时间计算出的有效剂量为 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，但进食和禁食受试者的生物分布或剂量测定没有差异。

 结论

良好的安全性、成像和剂量特征使¹⁸ F-FPIA 成为追踪 SCFA 代谢的有前途的候选放射性示踪剂。