Over the past decade, porphyrin derivatives have emerged as invaluable synthetic building blocks and theranostic kits for the delivery of cellular fluorescence imaging and photodynamic therapy. Tetraphenylporphyrin (TPP), its metal complexes, and related derivatives have been investigated for their use as dyes in histology and as components of multimodal imaging probes. The photophysical properties of porphyrin–metal complexes featuring radiometals have been a focus of our attention for the realization of fluorescence imaging probes coupled with radioimaging capabilities and therapeutic potential having “true” theranostic promise. We report hereby on the synthesis, radiochemistry, structural investigations, and preliminary in vitro and in vivo uptake studies on a range of functionalized porphyrin-based derivatives. In pursuit of developing new porphyrin-based probes for multimodality imaging applications, we report new functionalized neutral, polycationic, and polyanionic porphyrins incorporating nitroimidazole and sulfonamide moieties, which were used as targeting groups to improve the notoriously poor pharmacokinetics of porphyrin tags. The resulting functional metalloporphyrin species were stable under serum challenges and the nitroimidazole and sulfonamide derivatives remained fluorescent, allowing in vitro confocal studies and visualization of the lysosomal uptake in a gallium(III) sulfonamide derivative. The molecular structures of selected porphyrin derivatives were determined by single crystal X-ray diffraction using synchrotron radiation. We also investigated the nature of the emission/excitation behavior of model functional porphyrins using in silico approaches such as TD DFT in simple solvation models. The conjugation of porphyrins with the [7-13] and [7-14] fragments of bombesin was also achieved, to provide targeting of the gastrin releasing peptide receptor (GRPR). Depending on the metal, probe conjugates of relevance for single photon emission computed tomography (SPECT) or positron emission tomography (PET) probes have been designed and tested hereby, using TPP and related functional free base porphyrins as the bifunctional chelator synthetic scaffold and ¹¹¹In[In] or ⁶⁸Ga[Ga], respectively, as the central metal ions. Interestingly, for simple porphyrin conjugates good radiochemical incorporation was obtained for both radiometals, but the presence of peptides significantly diminished the radio-incorporation yields. Although the gallium-68 radiochemistry of the bombesin conjugates did not show radiochemical incorporation suitable for in vivo studies, likely because the presence of the peptide changed the behavior of the TPP-NH₂ synthon taken alone, the optical imaging assays indicated that the conjugated peptide tags do mediate uptake of the porphyrin units into cells.

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中性、聚阳离子和聚阴离子功能金属卟啉偶联物的结构研究、细胞成像和放射性标记

在过去的十年中，卟啉衍生物已成为提供细胞荧光成像和光动力治疗的宝贵合成构件和治疗诊断试剂盒。四苯基卟啉 (TPP)、其金属配合物和相关衍生物已被研究用作组织学中的染料和多模态成像探针的组分。具有放射性金属的卟啉-金属配合物的光物理性质一直是我们关注的焦点，因为荧光成像探针的实现与放射成像能力和治疗潜力相结合，具有“真正的”治疗诊断前景。我们在此报告合成、放射化学、结构研究和初步的体外和体内对一系列功能化卟啉衍生物的吸收研究。为了开发用于多模态成像应用的新的基于卟啉的探针，我们报告了新的功能化中性、聚阳离子和聚阴离子卟啉，它们结合了硝基咪唑和磺酰胺部分，用作靶向基团以改善众所周知的卟啉标签的不良药代动力学。由此产生的功能性金属卟啉在血清挑战下是稳定的，硝基咪唑和磺胺衍生物保持荧光，允许在体外镓 (III) 磺酰胺衍生物中溶酶体摄取的共聚焦研究和可视化。选定的卟啉衍生物的分子结构是通过使用同步辐射的单晶 X 射线衍射确定的。我们还研究了使用in silico模型功能卟啉的发射/激发行为的性质简单溶剂化模型中的 TD DFT 等方法。还实现了卟啉与铃蟾肽的 [7-13] 和 [7-14] 片段的结合，以提供对胃泌素释放肽受体 (GRPR) 的靶向。根据金属的不同，与单光子发射计算机断层扫描 (SPECT) 或正电子发射断层扫描 (PET) 探针相关的探针共轭物已被设计和测试，使用 TPP 和相关的功能性游离碱卟啉作为双功能螯合剂合成支架和¹¹¹ In [在] 或⁶⁸Ga[Ga]分别作为中心金属离子。有趣的是，对于简单的卟啉缀合物，两种放射性金属都获得了良好的放射化学掺入，但肽的存在显着降低了放射性掺入的产率。尽管铃蟾肽偶联物的镓 68 放射化学未显示适合体内研究的放射化学掺入，可能是因为肽的存在改变了单独使用的 TPP-NH ₂合成子的行为，但光学成像分析表明偶联肽标签确实介导卟啉单位被细胞吸收。