There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [⁶⁴Cu]Cu-CB-TE1A1P-LLP2A (⁶⁴Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of ⁶⁴Cu-LLP2A for potential use in MM patients. Methods: A single-dose [^natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. ⁶⁴Cu-LLP2A was synthesized in accordance with good-manufacturing-practice–compliant procedures. Three MM patients and six healthy participants underwent ⁶⁴Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time–activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio–high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time–activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of ⁶⁴Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4–5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to ⁶⁴Cu-LLP2A were observed in the human participants. Conclusion: ⁶⁴Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.

对于多发性骨髓瘤（MM）的分子靶向显像剂的需求仍然未得到满足。整合素极晚期抗原 4 (VLA4) 在恶性 MM 细胞和致病性炎症微环境细胞中差异表达。[ ⁶⁴ Cu]Cu-CB-TE1A1P-LLP2A ( ⁶⁴ Cu-LLP2A) 是一种针对 VLA4 的高亲和力放射性药物，在治疗 MM 患者方面具有广阔的应用前景。^{在这里，我们评估了64} Cu-LLP2A 在 MM 患者中的潜在用途的安全性和人体辐射剂量测定。方法：对 CD-1 (Hsd:ICR) 雄性和雌性小鼠进行单剂量 [ ^{nat Cu]Cu-LLP2A (Cu-LLP2A) 耐受性和毒性研究。64}Cu-LLP2A 是根据符合良好生产规范的程序合成的。三名 MM 患者和六名健康参与者在最多 3 个时间点接受了^{64 Cu-LLP2A-PET/CT 或 PET/MRI，以帮助确定示踪剂生物分布、药代动力学和辐射剂量测定。}为每个参与者绘制了时间-活动曲线。使用OLINDA软件计算平均器官吸收剂量和有效剂量。通过细胞结合测定评估示踪剂生物活性，并使用分析放射性高效液相色谱分析人类血液样本中的代谢物。如果可行，使用 14 色流式细胞术评估活检组织中的 VLA4 表达。结果：雄性和雌性 CD-1 小鼠可以很好地耐受超出所需成像剂量 150 倍的质量（未观察到不良反应水平）。人体成像数据的时间-活性曲线显示示踪剂通过肾脏和膀胱从血液中快速清除。有效剂量⁶⁴人体中 Cu-LLP2A 为 0.036 ± 0.006 mSv/MBq，脾脏的摄取量最高，为 0.142 ± 0.034 mSv/MBq。在所有组织中，红骨髓的停留时间最长。图像质量分析支持早期成像时间（注射放射性示踪剂后 4-5 小时）为最佳。细胞研究显示，所有人类研究产生的示踪剂均具有统计显着性阻断 (82.42% ± 13.47%)。血液代谢研究证实注射放射性药物后 1 小时内有稳定的产物峰 (>90%)。在人类参与者中未观察到与⁶⁴ Cu-LLP2A相关的临床或实验室不良事件。结论： ⁶⁴ Cu-LLP2A 在人体中使用时表现出良好的剂量测定和安全性。