More Kunal N, Lee Jun Young, Kim Dong-Yeon, Cho Nam-Chul, Pyo Ayoung, Yun Misun, Kim Hyeon Sik, Kim Hangun, Ko Kwangseok, Park Jeong-Hoon, Chang Dong-Jo
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
Radiation Instrumentation Research Division, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea.
Bioorg Med Chem Lett. 2018 Mar 1;28(5):915-921. doi: 10.1016/j.bmcl.2018.01.060. Epub 2018 Feb 1.
Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [F]-PET tracer (1) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 in vivo models other than SKRC-52. [F]-acetazolamide (1) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand in vivo behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors.
碳酸酐酶IX在包括缺氧肿瘤在内的许多实体瘤中过表达，是癌症治疗和诊断的潜在靶点。报道的靶向CA-IX的成像剂大多在透明细胞肾癌细胞（如SKRC-52）中取得成功，目前尚无用于CA-IX成像的候选药物在临床试验中获批。为了验证CA-IX作为缺氧肿瘤成像的有效靶点，我们基于作为著名的CA-IX抑制剂之一的乙酰唑胺设计并合成了新型[F] -PET示踪剂（1），并在除SKRC-52外的CA-IX表达缺氧肿瘤模型（如4T1和HT-29体内模型）中进行了成像研究。发现[F] -乙酰唑胺（1）在表达CA-IX的肿瘤中特异性积聚不足。这项研究可能有助于了解乙酰唑胺PET示踪剂的体内行为，并有助于未来开发成功的靶向CA-IX的PET成像剂。需要进一步研究以了解CA-IX靶向性差的机制，即CA-IX作为表达CA-IX的缺氧实体瘤成像的唯一靶点是否不可靠。
