Marike Drexler, Ioannis Kanavos, Daniela Krauss, Guillermo Moreno-Alcántar, Lydia M. Smith, Madeleine E. George, Timothy H. Witney, Ryszard Lobinski, Luisa Ronga and Angela Casini
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Ligands (<strong>L1</strong>, <strong>L2</strong>) and the respective homoleptic cages (<strong>C1<small><sub>hom</sub></small></strong> [Pd<small><sub>2</sub></small>(<strong>L1</strong>)<small><sub>4</sub></small>]<small><sup>4+</sup></small>, <strong>C2<small><sub>hom</sub></small></strong> [Pd<small><sub>2</sub></small>(<strong>L2</strong>)<small><sub>4</sub></small>]<small><sup>4+</sup></small>) were fully characterized by NMR spectroscopy, liquid chromatography and high-resolution electrospray mass spectrometry (HR-ESI-MS). Cage stability was assessed in different solvents and concentrations by HPLC. <small><sup>18</sup></small>F-labelled cages were obtained by radiolabeling the ligands pre-assembly under mild conditions within four hours <em>via</em> [<small><sup>19</sup></small>F]-to-[<small><sup>18</sup></small>F] isotopic exchange. The high lipophilicity of the ligands was also assessed <em>in vitro</em> (log <em>D</em><small><sub>pH7.4</sub></small>) and <em>in ovo</em>, using the chick chorioallantoic membrane (CAM) model. Furthermore, formation of host–guest complexes between the metallacages and perrhenate (ReO<small><sub>4</sub></small><small><sup>−</sup></small>), the ‘cold’ surrogate of radioactive <small><sup>99m</sup></small>TcO<small><sub>4</sub></small><small><sup>−</sup></small> (used for single photon computed tomography, SPECT), could be detected by mass spectrometry, although the adduct did not sustain chromatographic separation. To improve stability of the supramolecular system, heteroleptic cages of general formula [Pd<small><sub>2</sub></small>(L)<small><sub><em>m</em></sub></small>(<strong>L0</strong>)<small><sub><em>n</em></sub></small>]<small><sup>4+</sup></small> (<em>m</em> = 1, 2, <em>n</em> = 4 − <em>m</em>) were synthesized by statistical self-assembly and separated by liquid chromatography in good yield. 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Ligands (<strong>L1</strong>, <strong>L2</strong>) and the respective homoleptic cages (<strong>C1<small><sub>hom</sub></small></strong> [Pd<small><sub>2</sub></small>(<strong>L1</strong>)<small><sub>4</sub></small>]<small><sup>4+</sup></small>, <strong>C2<small><sub>hom</sub></small></strong> [Pd<small><sub>2</sub></small>(<strong>L2</strong>)<small><sub>4</sub></small>]<small><sup>4+</sup></small>) were fully characterized by NMR spectroscopy, liquid chromatography and high-resolution electrospray mass spectrometry (HR-ESI-MS). Cage stability was assessed in different solvents and concentrations by HPLC. <small><sup>18</sup></small>F-labelled cages were obtained by radiolabeling the ligands pre-assembly under mild conditions within four hours <em>via</em> [<small><sup>19</sup></small>F]-to-[<small><sup>18</sup></small>F] isotopic exchange. The high lipophilicity of the ligands was also assessed <em>in vitro</em> (log <em>D</em><small><sub>pH7.4</sub></small>) and <em>in ovo</em>, using the chick chorioallantoic membrane (CAM) model. Furthermore, formation of host–guest complexes between the metallacages and perrhenate (ReO<small><sub>4</sub></small><small><sup>−</sup></small>), the ‘cold’ surrogate of radioactive <small><sup>99m</sup></small>TcO<small><sub>4</sub></small><small><sup>−</sup></small> (used for single photon computed tomography, SPECT), could be detected by mass spectrometry, although the adduct did not sustain chromatographic separation. 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引用次数: 0
摘要
超分子自组装是开发多功能治疗剂的一种很有前途的工具,近年来已进入放射化学领域。在这项工作中,设计了具有血脑屏障穿透肽的灯笼形[Pd2L4]4+金属膜,用于双模态成像。在笼形配体中加入了两个硅基氟化物受体,用氟- 18(一种用于正电子发射断层扫描(PET)的同位素)进行放射性标记。通过核磁共振光谱、液相色谱和高分辨率电喷雾质谱(HR-ESI-MS)对配体(L1、L2)和各自的同色笼(C1hom [Pd2(L1)4]4+、C2hom [Pd2(L2)4]4+)进行了全面表征。采用高效液相色谱法测定不同溶剂和浓度下笼型稳定性。通过[19F]到-[18F]同位素交换,在温和条件下4小时内对配体预组装进行放射性标记,得到18F标记的笼。在体外(LogDpH7.4)和鸡蛋中,利用鸡绒毛膜尿囊膜(CAM)模型评估了配体的高亲脂性。此外,虽然加合物不能维持色谱分离,但在金属和高透酸盐(ReO4-)(放射性99mTcO4-(用于单光子计算机断层扫描,SPECT)的“冷”替代品)之间形成的主客体配合物可以通过质谱检测到。为提高超分子体系的稳定性,采用统计自组装方法合成了通式[Pd2(L)m(L0)n]4+ (m = 1,2, n = 4-m)的异亲笼,并采用液相色谱分离,收率较高。总的来说,本研究证明了超分子原理在实现创新治疗药物方面的可行性。
Design of porous self-assembled homoleptic and heteroleptic Pd2+ cages incorporating silicon-based fluoride acceptors: the way towards nuclear imaging applications†
Supramolecular self-assembly is a promising tool to develop multifunctional theranostic agents and has recently entered the field of radiochemistry. In this work, lantern-shaped [Pd2L4]4+ metallacages featuring a blood–brain barrier-penetrating peptide were designed for dual-modality imaging. Two silicon-based fluoride acceptors were incorporated in the cage ligand for radiolabeling with fluorine-18, an isotope used in positron emission tomography (PET). Ligands (L1, L2) and the respective homoleptic cages (C1hom [Pd2(L1)4]4+, C2hom [Pd2(L2)4]4+) were fully characterized by NMR spectroscopy, liquid chromatography and high-resolution electrospray mass spectrometry (HR-ESI-MS). Cage stability was assessed in different solvents and concentrations by HPLC. 18F-labelled cages were obtained by radiolabeling the ligands pre-assembly under mild conditions within four hours via [19F]-to-[18F] isotopic exchange. The high lipophilicity of the ligands was also assessed in vitro (log DpH7.4) and in ovo, using the chick chorioallantoic membrane (CAM) model. Furthermore, formation of host–guest complexes between the metallacages and perrhenate (ReO4−), the ‘cold’ surrogate of radioactive 99mTcO4− (used for single photon computed tomography, SPECT), could be detected by mass spectrometry, although the adduct did not sustain chromatographic separation. To improve stability of the supramolecular system, heteroleptic cages of general formula [Pd2(L)m(L0)n]4+ (m = 1, 2, n = 4 − m) were synthesized by statistical self-assembly and separated by liquid chromatography in good yield. Overall, this study demonstrates the feasible adaptation of supramolecular principles to achieve innovative theranostic agents.