Verena Arsyangela, Kuo Hsiou-Ting, Merkens Helen, Zeisler Jutta, Bendre Shreya, Wong Antonio A W L, Bénard François, Lin Kuo-Shyan
Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Pharmaceuticals (Basel). 2023 Mar 16;16(3):449. doi: 10.3390/ph16030449.
Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC(FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [Ga]Ga-AV02053 and [Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [Ga]Ga-AV02070 and [Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast.
与基于喹啉的成纤维细胞活化蛋白（FAP）靶向放射性示踪剂相比，基于吡啶的FAP靶向示踪剂由于其较小的分子尺寸和更高的亲水性，预计具有更快的药代动力学，我们推测这将改善肿瘤与背景的图像对比度。我们旨在开发用于正电子发射断层扫描（PET）癌症成像的镓标记的基于吡啶的FAP靶向示踪剂，并将其成像潜力与临床验证的[镓]Ga-FAPI-04进行比较。通过多步有机合成制备了两种与DOTA共轭的基于吡啶的AV02053和AV02070。通过酶法测定，Ga-AV02053和Ga-AV02070的IC（FAP）值分别为187±52.0和17.1±4.60 nM。在注射后1小时，对携带HEK293T:hFAP肿瘤的小鼠进行PET成像和生物分布研究。[镓]Ga-AV02053和[镓]Ga-AV02070在PET图像上能清晰地显示出HEK293T:hFAP肿瘤异种移植，对比度良好，且两种示踪剂主要通过肾脏途径排泄。[镓]Ga-AV02070（7.93±1.88%ID/g）和[镓]Ga-AV02053（5.6±1.12%ID/g）的肿瘤摄取值低于先前报道的[镓]Ga-FAPI-04（12.5±2.00%ID/g）。然而，[镓]Ga-AV02070和[镓]Ga-AV02053的肿瘤与背景（血液、肌肉和骨骼）摄取比均高于[镓]Ga-FAPI-04。我们的数据表明，基于吡啶的药效基团在设计FAP靶向示踪剂方面具有前景。未来将探索连接子选择的进一步优化，以增加肿瘤摄取，同时保持甚至进一步提高高肿瘤与背景对比度。
