The use of ⁸⁹Zr-antibody PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET systems lack the sensitivity needed to study ⁸⁹Zr-labeled antibodies beyond 2–3 isotope half-lives (7–10 d), after which a poor signal-to-noise ratio is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45-cm axial field of view, for total-body imaging of ⁸⁹Zr-labeled antibodies in rhesus monkeys up to 30 d after injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein glycoprotein D (gD) was radiolabeled with ⁸⁹Zr via 1 of 4 chelator-linker combinations (benzyl isothiocyanate-DFO [DFO-Bz-NCS], where DFO is desferrioxamine B; DFO-squaramide; DFO*-Bz-NCS, where DFO* is desferrioxamine*; and DFO*-squaramide). The pharmacokinetics associated with these 4 chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (∼1–2 y old, ∼3 ± 1 kg). Each animal was initially injected intravenously with unlabeled antibody in a peripheral vessel in the right arm (10 mg/kg, providing therapeutic-level antibody concentrations), immediately followed by approximately 40 MBq of one of the ⁸⁹Zr-labeled antibodies injected intravenously in a peripheral vessel in the left arm. All animals were imaged 6 times over a period of 30 d, with an initial 60-min dynamic scan on day 0 (day of injection) followed by static scans of 30–45 min on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using time-of-flight list-mode ordered-subsets expectation maximization. Activity concentrations in various organs were extracted from the PET images using manually defined regions of interest. Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan; later time points showed residual ⁸⁹Zr mainly in the liver. Even at 30 d after injection, representing approximately 9 half-lives of ⁸⁹Zr and with a total residual activity of only 20–40 kBq in the animal, the image quality was sufficient to readily identify activity in the liver, kidneys, and upper and lower limb joints. Significant differences were noted in late time point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, whereas little variation (±10%) was observed within each type. Conclusion: These studies demonstrate the ability to image ⁸⁹Zr-radiolabeled antibodies up to 30 d after injection while maintaining satisfactory image quality, as provided by the primate mini-EXPLORER with high sensitivity and long axial field of view. Quantification demonstrated potentially important differences in the behavior of the 4 chelators. This finding supports further investigation.

使用⁸⁹ Zr抗体PET成像来测量抗体的生物分布和组织药代动力学已经很成熟，但是当前的PET系统缺乏研究⁸⁹ Zr标记的抗体（超过2-3个同位素半衰期（7-10天））所需的灵敏度，之后，较差的信噪比是有问题的。但是，需要进行数周的研究才能更好地匹配人类和非人类灵长类动物的抗体循环半衰期。这些研究调查了使用灵长类动物mini-EXPLORER PET扫描仪的技术可行性，该扫描仪具有高灵敏度和45 cm轴向视场，可在恒河猴术后30 d内对^89种Zr标记抗体进行全身成像注射。方法：人源化单克隆IgG抗体针对单纯疱疹病毒糖蛋白的蛋白质d（GD）与放射性标记的⁸⁹经由1 4的螯合剂-接头组合（异硫氰酸苄酯-DFO [DFO-BZ-NCS]，其中DFO是去铁胺乙锆; DFO- squaramide; DFO * -Bz-NCS，其中DFO *为去铁胺*和DFO * -squaramide）。比较了这12种健康的雄性恒河猴（约1-2岁，约3±1千克）与这4种螯合剂-连接剂组合相关的药代动力学。最初，每只动物在右臂的外周血管中静脉内注射未标记的抗体（10 mg / kg，提供治疗水平的抗体浓度），然后立即注射⁸⁹个动物中的约40 MBqZr标记的抗体静脉注射到左臂的外周血管中。在30天的时间内对所有动物进行6次成像，在第0天（注射日）进行最初的60分钟动态扫描，然后在大约第3、7、14、21和3天进行30-45分钟的静态扫描。 30，所有使用单一床位获取和使用飞行时间列表模式有序子集期望最大化重建的图像。使用手动定义的目标区域从PET图像中提取各种器官中的活性浓度。结果：获得了出色的图像质量，捕获了全身扫描的初始分布阶段；稍后的时间点显示有剩余⁸⁹Zr主要存在于肝脏。即使在注射后第30天，也代表了⁸⁹ Zr的大约9个半衰期，并且在动物中的总残留活性仅为20–40 kBq，图像质量足以识别肝脏，肾脏，上肢和腹部的活动。下肢关节。螯合剂-连接子类型之间在晚期肝脏摄取，骨骼摄取和全身清除率方面存在显着差异，而每种类型之间观察到的差异很小（±10％）。结论：这些研究证明了成像能力⁸⁹灵长类动物mini-EXPLORER提供的具有高灵敏度和长轴视野的Zr放射性标记抗体在注射后长达30 d时仍保持令人满意的图像质量。量化证明这4种螯合剂的行为具有潜在的重要差异。这一发现支持进一步的研究。