Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meißner-Strasse 3, 85748, Garching, Germany.
Department of Nuclear Medicine, Technische Universität München, Germany.
Chemistry. 2018 Jan 12;24(3):547-550. doi: 10.1002/chem.201702335. Epub 2017 Sep 14.
Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., Lu, Y, or Bi) and PET (e.g., Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as Ga ). Such DOTPI-TRAP conjugates were decorated with 3 Gly-urea-Lys (KuE) motifs for targeting prostate-specific membrane antigen (PSMA), employing Cu-catalyzed (CuAAC) as well as strain-promoted (SPAAC) click chemistry. These were labeled with Lu or Bi and Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept.
提高放射性核素治疗中的剂量测定准确性有可能提高患者安全性和治疗效果。虽然正电子发射断层扫描（PET）非常适合获取剂量学数据，因为 PET 本身是定量的，并且具有高灵敏度和空间分辨率，但它不能直接用于此目的，因为常见的治疗性放射性核素缺乏必要的正电子发射。本工作报道了具有治疗和 PET 功能的双放射性核素标记放射性药物的合成，这些放射性药物基于常见且广泛可用的金属放射性核素。双螯合剂缀合物，具有相互连接的环戊二烯和三氮杂环壬烷基聚膦酸盐 DOTPI 和 TRAP，通过利用这些螯合剂的正交金属离子选择性（DOTPI：大阳离子，如镧系元素（III）离子；TRAP：小三价离子，如 Ga），允许在同一分子框架中严格区域选择性地络合治疗性（例如 Lu、Y 或 Bi）和 PET（例如 Ga）放射性金属。这些 DOTPI-TRAP 缀合物用 3Gly-urea-Lys（KuE）基序进行了针对前列腺特异性膜抗原（PSMA）的修饰，采用 Cu 催化（CuAAC）和应变促进（SPAAC）点击化学。这些放射性核素标记了 Lu 或 Bi 和 Ga，并用于通过 PET 对 SCID 小鼠中的 LNCaP（人前列腺癌）肿瘤异种移植物进行体内成像，从而证明了该概念的实际适用性。
