Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand ¹¹C-ER176 can successfully image 18-kDa translocator protein (TSPO), a biomarker of inflammation, in the human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an ¹⁸F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic ¹¹C labeling and in vivo performance in the monkey brain to select the most promising among 6 fluorine-containing analogs of ER176 for subsequent labeling with longer-lived ¹⁸F. Methods: Six fluorine-containing analogs of ER176—3 fluoro and 3 trifluoromethyl isomers—were synthesized and labeled by ¹¹C methylation at the secondary amide group of the respective N-desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide (PK11195). Uptake was quantified using radiometabolite-corrected arterial input function. The 6 candidate radioligands were ranked for performance on the basis of 2 in vivo criteria: the ratio of specific to nondisplaceable uptake (i.e., nondisplaceable binding potential [BP_ND]) and the time stability of total distribution volume (V_T), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as V_T corrected for plasma free fraction (V_T/f_P) using Logan graphical analysis for all 6 radioligands. V_T/f_P was generally high at baseline (222 ± 178 mL·cm^–3) and decreased by 70%–90% after preblocking with PK11195. BP_ND calculated using the Lassen plot was 9.6 ± 3.8; the o-fluoro radioligand exhibited the highest BP_ND (12.1), followed by the m-trifluoromethyl (11.7) and m-fluoro (8.1) radioligands. For all 6 radioligands, V_T reached 90% of the terminal 120-min values by 70 min and remained relatively stable thereafter, with excellent identifiability (SEs < 5%), suggesting that no significant radiometabolites accumulated in the brain. Conclusion: All 6 radioligands had good BP_ND and good time stability of V_T. Among them, the o-fluoro, m-trifluoromethyl, and m-fluoro compounds were the 3 best candidates for development as radioligands with an ¹⁸F label.

由于其特异性摄取与不可置换摄取的出色比率，放射性配体¹¹ C-ER176 可以成功地在人脑中成像 18-kDa 易位蛋白 (TSPO)，一种炎症的生物标志物，并准确量化纯合低亲和力粘合剂中的目标密度。我们的实验室试图开发一种基于 ER176的^{18 F 标记的 TSPO PET 放射性配体，具有更广泛分布的潜力。}本研究使用通用¹¹ C 标记和猴脑中的体内性能，从 ER176 的 6 种含氟类似物中选择最有希望的用于随后用寿命更长的¹⁸ F进行标记。方法：ER176 的六种含氟类似物——3 个氟和 3 个三氟甲基异构体——被合成并通过在各自N-去甲基前体的仲酰胺基团上进行¹¹ C 甲基化来标记。在基线和被N -butan-2-yl-1-(2-chlorophenyl) -N -methylisoquinoline-3-carboxamide (PK11195) 阻断后对猴脑进行 PET 成像。使用放射性代谢物校正的动脉输入函数对摄取进行量化。根据 2 个体内标准对 6 种候选放射性配体的性能进行排名：特异性与不可置换吸收的比率（即不可置换结合电位 [ BP _ND ]）和总分布体积的时间稳定性（V_T )，一种间接测量大脑中缺乏放射性代谢物积累的方法。结果：使用所有 6 种放射性配体的 Logan 图形分析，将总 TSPO 结合量化为针对血浆游离分数 ( V _T / f _{P ) 校正的}V _{T 。}V _T / f _P在基线时普遍较高（222 ± 178 mL·cm ^–3），在使用 PK11195 预封闭后下降了 70%–90%。使用拉森图计算的BP _{ND为 9.6 ± 3.8；}邻氟放射性配体表现出最高的BP ND ₍ 12.1)，其次是m-三氟甲基 (11.7) 和间-氟 (8.1) 放射性配体。对于所有 6 种放射性配体，V _T在 70 分钟时达到 90% 的最终 120 分钟值，此后保持相对稳定，具有出色的可识别性（SEs < 5%），表明大脑中没有显着的放射性代谢物积累。结论： 6种放射性配体均具有良好的BP _{ND和良好的}V _T时间稳定性。其中，邻氟、间三氟甲基和间氟化合物是开发¹⁸ F 标记的放射性配体的 3 种最佳候选物。