FAPI-2   中文名称: FAPI-2

FAP (fibroblast activation protein)

在15种合成的fapi中，FAPI-04被认为是最有临床应用前景的示踪剂。与先前发表的配体FAPI-02相比，FAPI-04在人血清中表现出极好的稳定性，与CD26相比，FAPI-04对FAP具有更高的亲和力，并且在体外排泄较慢。https://pubmed.ncbi.nlm.nih.gov/29626119/

在体内，荷瘤动物达到更高的SUV，导致生物分布实验计算出的曲线下面积更大。最后，用68Ga-FAPI-04对2例转移性乳腺癌患者进行PET/CT扫描，发现转移灶对示踪剂的摄取较高，用相当低剂量的90Y-FAPI-04治疗后疼痛症状减轻。结论：FAPI-04是一种很有前景的示踪剂，可用于诊断成像，并可能用于靶向治疗具有高活性成纤维细胞含量的恶性肿瘤，如乳腺癌。https://pubmed.ncbi.nlm.nih.gov/29626119/

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结果：与18F-FDG， 68Ga-DOTATATE和68Ga-PSMA-11的文献值相似，200 MBq的68Ga-FAPI-2或68Ga-FAPI-4的检测相当于大约3-4 mSv的等效剂量。经肾脏快速清除后，正常器官示踪剂摄取较低，在注射后10分钟至3小时之间变化极小。68Ga-FAPI-2注射后1 ~ 3 h的肿瘤摄取减少75%，而68Ga-FAPI-4注射后肿瘤滞留时间延长（25%洗脱）。关于肿瘤与背景比，注射后1小时，两种68Ga-FAPI示踪剂表现相同。与18F-FDG相比，肿瘤摄取几乎相等(平均SUVmax， 18F-FDG为7.41,68Ga-FAPI-2为7.37；无统计学意义)；68Ga-FAPI在脑（11.01 vs. 0.32）、肝脏（2.77 vs. 1.69）和口腔/咽粘膜（4.88 vs. 2.57）的背景摄取显著降低。其他器官在18F-FDG和68Ga-FAPI之间没有相关性差异。结论：FAPI PET/CT是一种新的肿瘤诊断方法。与18F-FDG相比，在检查前不需要节食或禁食，在使用示踪剂几分钟后就可以开始图像采集。肿瘤与背景对比度等于甚至优于18F-FDG[1]。

基于喹啉结构的fapi被合成，并在表达人类和小鼠FAP以及cd26的细胞中结合、内化和外排进行了表征。https://pubmed.ncbi.nlm.nih.gov/29626119/

Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. https://pubmed.ncbi.nlm.nih.gov/29626119/

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Methods: A preliminary dosimetry estimate for 68Ga-FAPI-2 and 68Ga-FAPI-4 was based on 2 patients examined at 0.2, 1, and 3 h after tracer injection using the QDOSE dosimetry software suit. Further PET/CT scans of tumor patients were acquired 1 h after injection of either 68Ga-FAPI-2 (n = 25) or 68Ga-FAPI-4 (n = 25); for 6 patients an intraindividual related 18F-FDG scan (also acquired 1 h after injection) was available. For the normal tissue of 16 organs, a 2-cm spheric volume of interest was placed in the parenchyma; for tumor lesions, a threshold-segmented volume of interest was used to quantify SUVmean and SUVmax[1]

[1]. 68Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers. J Nucl Med. 2019 Mar;60(3):386-392.

[2]. Fibroblast Activation Protein (FAP) targeting homodimeric FAP inhibitor radiotheranostics: a step to improve tumor uptake and retention time. Am J Nucl Med Mol Imaging. 2021 Dec 15;11(6):476-491.

[3]. Clinical summary of fibroblast activation protein inhibitor-based radiopharmaceuticals: cancer and beyond. Eur J Nucl Med Mol Imaging. 2022 Jul;49(8):2844-2868. doi: 10.1007/s00259-022-05706-y. Epub 2022 Jan 31. Erratum in: Eur J Nucl Med Mol Imaging. 2022 Jul;49(8):3007.

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.[2]

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Fibroblast activation protein (FAP) is a type II membrane-bound glycoprotein which is overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Since the first clinical application of quinoline-based FAP ligands in 2018, FAP inhibitor (FAPI)-based PET imaging and radiotherapy have been investigated for a wide variety of diseases, both cancerous and non-cancerous. As a consequence, promising strides have been made in particular to improve the understanding of FAPI-based PET imaging and the potential value of FAPI-based tumor radiotherapy. Herein, we present a comprehensive review of radiolabeled FAPI, including their clinical translation, in order to clarify the current and potential future role of this class of molecules in nuclear medicine. In particular, this review underlines the value of FAPI radiopharmaceuticals in the diagnosis or therapy of tumors or benign conditions. However, limitations in present studies have hampered a precise evaluation of FAPI radiopharmaceuticals. Despite this, it will likely be worthwhile to further explore the clinical value of FAPI in diagnosis and therapy through better-designed and larger-population clinical trials in the future.[3]

C40H56N10O10

836.93

836.418

2370952-98-8

138454802

White to off-white solid powder

1.43±0.1 g/cm3(Predicted)

1143.9±65.0 °C(Predicted)

-7.2

244

4

17

16

60

1490

1

C1C[C@H](N(C1)C(=O)CNC(=O)C2=C3C=C(C=CC3=NC=C2)OCCCN4CCN(CC4)C(=O)CN5CCN(CCN(CCN(CC5)CC(=O)O)CC(=O)O)CC(=O)O)C#N

CRWOFMLXEOYIEP-PMERELPUSA-N

InChI=1S/C40H56N10O10/c41-24-30-3-1-9-50(30)35(51)25-43-40(59)32-6-7-42-34-5-4-31(23-33(32)34)60-22-2-8-44-18-20-49(21-19-44)36(52)26-45-10-12-46(27-37(53)54)14-16-48(29-39(57)58)17-15-47(13-11-45)28-38(55)56/h4-7,23,30H,1-3,8-22,25-29H2,(H,43,59)(H,53,54)(H,55,56)(H,57,58)/t30-/m0/s1

2-[4,7-bis(carboxymethyl)-10-[2-[4-[3-[4-[[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]carbamoyl]quinolin-6-yl]oxypropyl]piperazin-1-yl]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid

FAPI-2; 2370952-98-8; UNII-54MD7EU3MC; 54MD7EU3MC; FAPI-02; SCHEMBL21257060;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (119.48 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (2.99 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (2.99 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (2.99 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。