Euy Sung Moon, Sanjana Ballal, Madhav Prasad Yadav, Chandrasekhar Bal, Yentl Van Rymenant, Sarah Stephan, An Bracke, Pieter Van der Veken, Ingrid De Meester, Frank Roesch
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The homodimers with two squaramide coupled FAP inhibitor conjugates DOTA.(SA.FAPi)<sub>2</sub> and DOTAGA.(SA.FAPi)<sub>2</sub> were synthesized and radiochemically evaluated with gallium-68. [<sup>68</sup>Ga]Ga-DOTAGA.(SA.FAPi)<sub>2</sub> was tested for its <i>in vitro</i> stability, lipophilicity and affinity properties. In addition, human PET/CT scans were performed for [<sup>68</sup>Ga]Ga-DOTAGA.(SA.FAPi)<sub>2</sub> with a head-to-head comparison with [<sup>68</sup>Ga]Ga-DOTA.SA.FAPi and [<sup>18</sup>F]FDG. Labeling with gallium-68 demonstrated high radiochemical yields. Inhibition measurements revealed excellent affinity and selectivity with low nanomolar IC<sub>50</sub> values for FAP. In PET/CT human studies, significantly higher tumor uptake as well as longer tumor retention could be observed for [<sup>68</sup>Ga]Ga-DOTAGA.(SA.FAPi)<sub>2</sub> compared to [<sup>68</sup>Ga]Ga-DOTA.SA.FAPi. Therefore, the introduction of the dimer led to an advance in human PET imaging indicated by increased tumor accumulation and prolonged retention times <i>in vivo</i> and thus, the use of dimeric structures could be the next step towards prolonged uptake of FAP inhibitors resulting in radiotherapeutic analogs of FAP inhibitors.</p>","PeriodicalId":7572,"journal":{"name":"American journal of nuclear medicine and molecular imaging","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2021-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727881/pdf/ajnmmi0011-0476.pdf","citationCount":"0","resultStr":"{\"title\":\"Fibroblast Activation Protein (FAP) targeting homodimeric FAP inhibitor radiotheranostics: a step to improve tumor uptake and retention time.\",\"authors\":\"Euy Sung Moon, Sanjana Ballal, Madhav Prasad Yadav, Chandrasekhar Bal, Yentl Van Rymenant, Sarah Stephan, An Bracke, Pieter Van der Veken, Ingrid De Meester, Frank Roesch\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Several radiopharmaceuticals targeting fibroblast activation protein (FAP) based on the highly potent FAP inhibitor UAMC1110 are currently under investigation. 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Inhibition measurements revealed excellent affinity and selectivity with low nanomolar IC<sub>50</sub> values for FAP. In PET/CT human studies, significantly higher tumor uptake as well as longer tumor retention could be observed for [<sup>68</sup>Ga]Ga-DOTAGA.(SA.FAPi)<sub>2</sub> compared to [<sup>68</sup>Ga]Ga-DOTA.SA.FAPi. 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引用次数: 0
摘要
几种基于高效FAP抑制剂UAMC1110靶向成纤维细胞活化蛋白(FAP)的放射性药物目前正在研究中。临床前和临床研究显示了这些显像剂的潜力。然而,单分子小分子似乎在肿瘤中保留时间短,并且肾脏清除速度快。因此,我们的策略是开发具有两种FAP抑制剂的同二聚体系统,以改善停留时间和肿瘤积累。合成了具有两种方酰胺偶联FAP抑制剂偶联物DOTA.(SA.FAPi)2和DOTAGA.(SA.FAPi)2的同型二聚体,并用镓-68进行了放射化学评价。[68Ga]Ga-DOTAGA.(SA.FAPi)2的体外稳定性、亲脂性和亲和力进行了测试。此外,对[68Ga] ga - dota .(SA.FAPi)2进行了人体PET/CT扫描,并与[68Ga]Ga-DOTA.SA进行了头部比较。[18F]FDG。用镓-68标记显示出很高的放射化学产率。抑制实验显示FAP具有良好的亲和性和选择性,IC50值较低。在PET/CT人体研究中,与[68Ga]Ga-DOTA.SA.FAPi相比,[68Ga]Ga-DOTAGA.(SA.FAPi)2的肿瘤摄取率明显更高,肿瘤滞留时间也更长。因此,二聚体的引入导致了人体PET成像的进步,这表明肿瘤积累增加,体内滞留时间延长,因此,二聚体结构的使用可能是延长FAP抑制剂摄取的下一步,从而产生FAP抑制剂的放射治疗类似物。
Fibroblast Activation Protein (FAP) targeting homodimeric FAP inhibitor radiotheranostics: a step to improve tumor uptake and retention time.
Several radiopharmaceuticals targeting fibroblast activation protein (FAP) based on the highly potent FAP inhibitor UAMC1110 are currently under investigation. Pre-clinical as well as clinical research exhibited the potential of these imaging agents. However, the monomeric small molecules seemed to have a short retention time in the tumor in combination with fast renal clearance. Therefore, our strategy was to develop homodimeric systems having two FAP inhibitors to improve residence time and tumor accumulation. The homodimers with two squaramide coupled FAP inhibitor conjugates DOTA.(SA.FAPi)2 and DOTAGA.(SA.FAPi)2 were synthesized and radiochemically evaluated with gallium-68. [68Ga]Ga-DOTAGA.(SA.FAPi)2 was tested for its in vitro stability, lipophilicity and affinity properties. In addition, human PET/CT scans were performed for [68Ga]Ga-DOTAGA.(SA.FAPi)2 with a head-to-head comparison with [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG. Labeling with gallium-68 demonstrated high radiochemical yields. Inhibition measurements revealed excellent affinity and selectivity with low nanomolar IC50 values for FAP. In PET/CT human studies, significantly higher tumor uptake as well as longer tumor retention could be observed for [68Ga]Ga-DOTAGA.(SA.FAPi)2 compared to [68Ga]Ga-DOTA.SA.FAPi. Therefore, the introduction of the dimer led to an advance in human PET imaging indicated by increased tumor accumulation and prolonged retention times in vivo and thus, the use of dimeric structures could be the next step towards prolonged uptake of FAP inhibitors resulting in radiotherapeutic analogs of FAP inhibitors.
期刊介绍:
The scope of AJNMMI encompasses all areas of molecular imaging, including but not limited to: positron emission tomography (PET), single-photon emission computed tomography (SPECT), molecular magnetic resonance imaging, magnetic resonance spectroscopy, optical bioluminescence, optical fluorescence, targeted ultrasound, photoacoustic imaging, etc. AJNMMI welcomes original and review articles on both clinical investigation and preclinical research. Occasionally, special topic issues, short communications, editorials, and invited perspectives will also be published. Manuscripts, including figures and tables, must be original and not under consideration by another journal.