Purpose

This first-in-human study aimed to evaluate the radiation dosimetry and whole-body biodistribution of [¹⁸F]AlF-NYM005, a novel small-molecule carbonic anhydrase IX (CAIX) targeting agent, and to investigate its ability to detect CAIX-positive tumors using PET scans in a cohort of clear cell renal cell carcinoma (ccRCC) patients.

Methods

[¹⁸F]AlF-NYM005 was synthesized using a fully automatic cassette module Mortenon M1 (Nuoyu, China). Thirty-five patients with a suspicious lesion considered primary renal malignancy or a history of ccRCC were prospectively recruited and studied. All patients underwent [¹⁸F]AlF-NYM005 PET/CT examinations and the maximum standardized uptake value (SUVmax) was measured on conventional [¹⁸F]AlF-NYM005 PET/CT images. Among these patients, five patients underwent dynamic [¹⁸F]AlF-NYM005 PET/CT scanning (120 min) of the lower abdomen. Another subset of five ccRCC patients underwent sequential whole-body PET scans at 30, 60, 90, and 120 min (one of the five patients underwent additional 150 min and 180 min scans) after [¹⁸F]AlF-NYM005 injection to assess biodistribution and dosimetry. The influx constant (Ki) was calculated from the dynamic [¹⁸F]AlF-NYM005 PET/CT data using the Patlak model. Whole-body biodistribution was calculated as time-activity curves (TACs) describing dynamic uptake patterns in the patients’ major organs, followed by calculation of tracer kinetics and cumulative organ activity. Effective doses of [¹⁸F]AlF-NYM005 and individual organ doses were also calculated.

Results

[¹⁸F]AlF-NYM005 was successfully synthesized with a radiochemical purity of > 95% and an average labeling yield of 36.5 ± 8.3%. All patients tolerated the PET examinations well, and no adverse side effects were observed. The total body effective dose was 7.6E-03 mSv/MBq. The highest agent uptake was observed in the kidneys, stomach, and liver, contributing to an effective dose of 0.0126 ± 0.0029 mSv/MBq. The TACs showed optimal normal organ uptake with high tumor uptake and long retention of up to 2 h post-injection. Notably, a rapid increase of the tracer followed by a rapid decrease in the blood pool, kidney, liver, and tumor lesions was observed, indicating that [¹⁸F]AlF-NYM005 was rapidly eliminated from blood and urine. For the kinetic data analysis, the Ki for the primary kidney lesions had a mean of 0.082 ± 0.057 ml/g/min. The CAIX-positive tumors displayed rapid uptake, and all lesions were detectable within 30 min, with no additional lesions observed in the subsequent multi-time point scans. The patient-level sensitivity, specificity, and accuracy of [¹⁸F]AlF-NYM005 PET/CT were 93.8%, 75.0%, and 90% for group 1 and 92.3%, 100%, and 93.3% for group 2, respectively. For per-lymph node analysis, [¹⁸F]AlF-NYM005 PET/CT demonstrated 92.9% sensitivity, 90.5% specificity, and 91.8% accuracy in diagnosing metastatic lymph nodes. For per-distant metastasis analysis, it showed 90.5% sensitivity, 91.3% specificity, and 90.6% accuracy. The SUVmax of [¹⁸F]AlF-NYM005 PET/CT for primary ccRCC lesions was 15.5 ± 7.35. Tumor uptake was positive correlated with immunohistochemical staining findings.

Conclusion

This pilot study in ccRCC patients has demonstrated the safety, acceptable radiation dosimetry, favorable biodistribution, and exceptional tumor uptake of [¹⁸F]AlF-NYM005. The preliminary diagnostic study indicated the potential utility of [¹⁸F]AlF-NYM005 PET/CT, showing promising results in the diagnosis of primary or metastatic ccRCC.

Trial registration

This study was registered at ClinicalTrial.gov (ChiCTR2200058108) as NYPILOT on 29 March, 2022.

中文翻译：

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[18F]AlF-NYM005 的安全性、生物分布、剂量测定和透明细胞肾细胞癌的初步经验评价：前瞻性试验的中期分析

 目的

这项首次人体研究旨在评估 [¹⁸F]AlF-NYM005 的辐射剂量测定和全身生物分布，这是一种新型小分子碳酸酐酶 IX （CAIX） 靶向剂，并研究其在透明细胞肾细胞癌 （ccRCC） 患者队列中使用 PET 扫描检测 CAIX 阳性肿瘤的能力。

 方法

[¹⁸个地址]AlF-NYM005 是使用全自动盒式模块 Mortenon M1 （Nuoyu， China） 合成的。前瞻性招募和研究了 35 例疑似病变被认为是原发性肾恶性肿瘤或有 ccRCC 病史的患者。所有患者均接受 [¹⁸F]AlF-NYM005 PET/CT 检查，在常规 [¹⁸F]AlF-NYM005 PET/CT 图像上测量最大标准化摄取值 （SUVmax）。在这些患者中，5 例患者接受了下腹部动态 [¹⁸F]AlF-NYM005 PET/CT 扫描 （120 min）。另一组 5 名 ccRCC 患者在注射 [¹⁸F]AlF-NYM005 后 30 、 60 、 90 和 120 分钟接受了连续全身 PET 扫描 （5 名患者中的一名接受了额外的 150 分钟和 180 分钟扫描），以评估生物分布和剂量测定。内流常数 （Ki） 是使用 Patlak 模型根据动态 [¹⁸F]AlF-NYM005 PET/CT 数据计算的。将全身生物分布计算为描述患者主要器官动态摄取模式的时间-活动曲线 （TAC），然后计算示踪剂动力学和累积器官活动。还计算了 [¹⁸F]AlF-NYM005 的有效剂量和单个器官剂量。

 结果

[¹⁸个地址]成功合成了 AlF-NYM005，放射化学纯度为 > 95%，平均标记产率为 36.5 ± 8.3%。所有患者对 PET 检查的耐受性良好，未观察到不良副作用。全身有效剂量为 7.6E-03 mSv/MBq。在肾脏、胃和肝脏中观察到最高的药物摄取，有效剂量为 0.0126 ± 0.0029 mSv/MBq。TACs 显示最佳的正常器官摄取，肿瘤摄取高，注射后长达 2 小时的保留时间长。值得注意的是，观察到示踪剂的快速增加，随后血池、肾脏、肝脏和肿瘤病变的快速减少，表明 [¹⁸F]AlF-NYM005 从血液和尿液中迅速消除。对于动力学数据分析，原发性肾脏病变的 Ki 平均值为 0.082 ± 0.057 ml/g/min。CAIX 阳性肿瘤表现出快速摄取，所有病灶在 30 分钟内可检测到，在随后的多时间点扫描中未观察到额外的病灶。[¹⁸F]AlF-NYM005 PET/CT 的患者水平敏感性、特异性和准确性对第 1 组分别为 93.8%、75.0% 和 90%，对第 2 组分别为 92.3%、100% 和 93.3%。对于每个淋巴结分析，[¹⁸F]AlF-NYM005 PET/CT 在诊断转移性淋巴结方面表现出 92.9% 的敏感性、90.5% 的特异性和 91.8% 的准确性。对于每个远处转移分析，它显示出 90.5% 的敏感性、91.3% 的特异性和 90.6% 的准确性。[¹⁸F]AlF-NYM005 PET/CT 对原发性 ccRCC 病灶的 SUVmax 为 15.5 ± 7.35。肿瘤摄取与免疫组化染色结果呈正相关。

 结论

这项在 ccRCC 患者中进行的初步研究表明 [¹⁸F]AlF-NYM005 的安全性、可接受的放射剂量测定、良好的生物分布和出色的肿瘤摄取。初步诊断研究表明 [¹⁸F]AlF-NYM005 PET/CT 的潜在用途，在诊断原发性或转移性 ccRCC 方面显示出有希望的结果。

 试用注册

这项研究于 2022 年 3 月 29 日在 ClinicalTrial.gov （ChiCTR2200058108） 注册为 NYPILOT。