This study aimed to develop a novel radiotracer using trastuzumab and the long-lived [⁵²Mn]Mn isotope for HER2-targeted therapy selection and monitoring. A new Mn(II) chelator, BPPA, synthesized from a rigid bispyclen platform possessing a picolinate pendant arm, formed a stable and inert Mn(II) complex with favorable relaxation properties. BPPA was converted into a bifunctional chelator (BFC), conjugated to trastuzumab, and labeled with [⁵²Mn]Mn isotope. In comparison to DOTA-GA-trastuzumab, the BPPA-trastuzumab conjugate exhibits a labeling efficiency with [⁵²Mn]Mn approximately 2 orders of magnitude higher. In female CB17 SCID mice bearing 4T1 (HER2−) and MDA-MB-HER2+ (HER2+) xenografts, [⁵²Mn]Mn-BPPA-trastuzumab demonstrated superior uptake in HER2+ cells on day 3, with a 3–4 fold difference observed on day 7. Overall, the hexadentate BPPA chelator proves to be exceptional in binding Mn(II). Upon coupling with trastuzumab as a BFC ligand, it becomes an excellent imaging probe for HER2-positive tumors. [⁵²Mn]Mn-BPPA-trastuzumab enables an extended imaging time window and earlier detection of HER2-positive tumors with superior tumor-to-background contrast.

中文翻译：

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[52Mn]Mn-BPPA-曲妥珠单抗：一种有前途的 HER2 特异性 PET 放射性示踪剂

本研究旨在开发一种使用曲妥珠单抗和长寿命 [ ⁵² Mn]Mn 同位素的新型放射性示踪剂，用于 HER2 靶向治疗的选择和监测。一种新型 Mn(II) 螯合剂 BPPA，由具有吡啶甲酸悬臂的刚性 Bipyclen 平台合成，形成稳定且惰性的 Mn(II) 配合物，具有良好的弛豫性能。 BPPA 转化为双功能螯合剂 (BFC)，与曲妥珠单抗缀合，并用 [ ⁵² Mn]Mn 同位素标记。与 DOTA-GA-曲妥珠单抗相比，BPPA-曲妥珠单抗缀合物的 [ ⁵² Mn]Mn 标记效率高出约 2 个数量级。在携带 4T1 (HER2−) 和 MDA-MB-HER2+ (HER2+) 异种移植物的雌性 CB17 SCID 小鼠中，[ ⁵² Mn]Mn-BPPA-曲妥珠单抗在第 3 天在 HER2+ 细胞中表现出优异的摄取，在第 3 天观察到 3-4 倍的差异第 7 天。总体而言，六齿 BPPA 螯合剂在结合 Mn(II) 方面表现出色。与曲妥珠单抗作为 BFC 配体偶联后，它成为 HER2 阳性肿瘤的出色成像探针。 [ ⁵² Mn]Mn-BPPA-曲妥珠单抗能够延长成像时间窗口，并以优异的肿瘤背景对比度更早地检测 HER2 阳性肿瘤。