The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer ¹¹C-BMT-136088 (1-(4′-(3-methyl-4-(((1(R)-(3-¹¹C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test–retest scans; self-saturation to estimate the tracer’s in vivo dissociation constant, nondisplaceable volume of distribution (V_ND), and nondisplaceable binding potential (BP_ND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (V_T) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results: ¹¹C-BMT-136088 baseline V_T was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test–retest variability of −6% (MA1, n = 1) or −1% ± 14% (EA, n = 2). For the self-saturation study, ¹¹C-BMT-136088 V_ND and BP_ND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of ¹¹C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer’s in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 μSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 μSv/MBq, respectively. Conclusion: Specific binding of ¹¹C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.

1型溶血磷脂酸受体（LPA1）是细胞外信号分子溶血磷脂酸的6种已知受体中的1种。它介导细胞增殖，迁移和分化等效应。在肺中，LPA1通过介导成纤维细胞募集和血管渗漏而参与导致肺组织损伤后导致肺纤维化而非正常愈合的途径。因此，LPA1 PET放射性示踪剂可用于研究肺纤维化或开发靶向LPA1的药物。我们开发并评估了放射性示踪剂¹¹ C-BMT-136088（1-（4'-（3-甲基-4-（（（（R）-（3- ¹¹ C-甲基苯基）乙氧基）羰基）氨基）异恶唑-恒河猴中的5-yl）-[1,1'-联苯] -4-yl）环丙烷-1-羧酸以体内的PET成像肺中的LPA1。方法：该研究包括3个部分：重测扫描；重测扫描。自饱和，以估计示踪剂的体内解离常数，不可替代的分布体积（V _ND）和不可替代的结合电位（BP _ND）；和剂量学。在前两个部分中，使用大剂量加输注方案施用放射性示踪剂，测量动脉输入功能，每天对动物进行两次扫描，间隔约4小时。从CT图像中分割出感兴趣的肺区域，并估计组织密度。应用固定的血容量校正。使用多线性分析1（MA1）或平衡分析（EA）估算示踪剂的分布体积（V _T）。结果： ¹¹ C-BMT-136088基线V _T为1.83±0.16（MA1，n = 5）或2.1±0.55（EA，n = 7）mL血浆/每克感兴趣的左右肺区域组织，其中a重新测试的变异性为−6％（MA1，n = 1）或−1％±14％（EA，n = 2）。对于自饱和研究，估计¹¹ C-BMT-136088 V _ND和BP _ND分别为每克组织0.9±0.08 mL血浆和1.1±0.14。未标记的药物剂量和血浆浓度导致50％降低¹¹C-BMT-136088的特异性结合分别为73±30 nmol / kg和28±12 nM。平均无血浆分数为0.2％；因此，示踪剂的体内解离常数估计为55 pM。对于剂量学研究，最高的器官剂量是在肝脏中（参考人的男性和女性幻影分别为43.1±4.9和68.9±9.4μSv/ MBq），等效等效剂量为6.9±0.6和8.7±0.6μSv/ MBq。 MBq，分别。结论：可以可靠地测量¹¹ C-BMT-136088的特异性结合，以定量体内恒河猴肺中的LPA1。