Kar Somnath, Chakraborty Avik, N Lakshminarayanan, C Rajesh, Chaudhuri Pradip, Ray Mukti Kanta, Bose Kakoli, Banerjee Sharmila, Basu Sandip, Mallia Madhava B
Radiation Medicine Centre, BARC Parel Mumbai-400012 India.
Homi Bhabha National Institute Anushaktinagar Mumbai-400094 India.
RSC Adv. 2025 Jul 10;15(29):23943-23953. doi: 10.1039/d5ra02999f. eCollection 2025 Jul 4.
The overexpression of the sigma-1 receptor (σ1R) in a variety of cancers makes it a potential target for developing anticancer drugs or diagnostic/therapeutic radiopharmaceuticals. Molecules with piperidine or piperazine substructures have shown high binding affinity towards σ1R. Docking and MD simulation studies on commercially available piperidine/piperazine-containing compounds identified 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone (PPZ) as a potential ligand for targeting σ1R. Docking studies on its fluorinated analogue, 1-(4-(4-(2-fluoroethoxy)phenyl)piperazin-1-yl)ethanone (FEt-PPZ), showed good affinity towards σ1R, comparable to that of a clinically evaluated radiopharmaceuticals such as [F]fluspidine. The root mean square deviation (RMSD) value of 2 A° in the MD simulations over a period of 50 ns indicated the excellent stability of the FEt-PPZ-σ1R receptor-ligand complex. Based on these results, the radiosynthesis of [F]FEt-PPZ was carried out to evaluate its potential to target σ1R. The radiotracer was prepared through a one-pot, two-step method using a GE PETtrace cyclotron and PETtracer synthetic module with an activity yield of 32% ± 5.8% ( = 6). The radiochemical purity (RCP) of [F]FEt-PPZ was >95%, as assessed through radioTLC and radio-HPLC. cell binding studies on [F]FEt-PPZ in U-87 MG and B16F10 cells showed maximum uptakes of 13.28% ± 1.04% and 10.74% ± 0.82%, respectively, at 60 min post-incubation. Inhibition studies carried out in the presence of an excess non-radioactive compound (FEt-PPZ) showed a reduction of ∼55% in radiotracer uptake in glioma cells and ∼48% in melanoma cells, indicating its specificity towards σ1R. Bio-distribution and small animal PET/CT imaging studies on melanoma-tumor-bearing C57BL6 mice showed a significant tumor uptake (10.55% ± 1.3% ID per g organ) at 60 min post-injection and an hepatic and renal mode of excretion. Preclinical studies on [F]FEt-PPZ developed using an approach demonstrated its potential to target σ1R, thus warranting further investigation.
σ1受体（σ1R）在多种癌症中过表达，使其成为开发抗癌药物或诊断/治疗放射性药物的潜在靶点。具有哌啶或哌嗪亚结构的分子对σ1R表现出高结合亲和力。对市售含哌啶/哌嗪化合物的对接和分子动力学（MD）模拟研究确定1-(4-(4-羟基苯基)哌嗪-1-基)乙酮（PPZ）是靶向σ1R的潜在配体。对其氟化类似物1-(4-(4-(2-氟乙氧基)苯基)哌嗪-1-基)乙酮（FEt-PPZ）的对接研究表明，它对σ1R具有良好的亲和力，与临床评估的放射性药物如[F]氟司必林相当。在50 ns期间的MD模拟中2 Å的均方根偏差（RMSD）值表明FEt-PPZ-σ1R受体-配体复合物具有出色的稳定性。基于这些结果，进行了[F]FEt-PPZ的放射性合成以评估其靶向σ1R的潜力。使用GE PETtrace回旋加速器和PETtracer合成模块通过一锅两步法制备放射性示踪剂，活度产率为32%±5.8%（n = 6）。通过放射性薄层色谱法（radioTLC）和放射性高效液相色谱法（radio-HPLC）评估，[F]FEt-PPZ的放射化学纯度（RCP）>95%。在U-87 MG和B16F10细胞中对[F]FEt-PPZ的细胞结合研究表明，孵育60分钟后最大摄取量分别为13.28%±1.04%和10.74%±0.82%。在过量非放射性化合物（FEt-PPZ）存在下进行的抑制研究表明，胶质瘤细胞中放射性示踪剂摄取减少约55%，黑色素瘤细胞中减少约48%，表明其对σ1R的特异性。对荷黑色素瘤肿瘤的C57BL6小鼠的生物分布和小动物PET/CT成像研究表明，注射后60分钟肿瘤有显著摄取（每克器官10.55%±1.3%注射剂量），且通过肝脏和肾脏排泄。使用一种方法开发的关于[F]FEt-PPZ的临床前研究证明了其靶向σ1R的潜力，因此值得进一步研究。
