Hanaoka Hirofumi, Tominaga Hideyuki, Yamada Keiich, Paudyal Pramila, Iida Yasuhiko, Watanabe Shigeki, Paudyal Bishnuhari, Higuchi Tetsuya, Oriuchi Noboru, Endo Keigo
Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Showa-machi, Maebashi 371-8511, Japan.
Ann Nucl Med. 2009 Aug;23(6):559-67. doi: 10.1007/s12149-009-0274-0. Epub 2009 Jun 6.
In-111 ((111)In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ((64)Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a (64)Cu-labeled octreotide analog, (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D: -Phe(1)-Tyr(3)-octreotide ((64)Cu-DOTA-TOC).
(64)Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 degrees C. The stability of (64)Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of (64)Cu-DOTA-TOC and (111)In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of (64)Cu-DOTA-TOC or (64)Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC). The tumor was imaged using (64)Cu-DOTA-TOC, (64)Cu-TETA-OC, and FDG with an animal PET scanner.
(64)Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. (64)Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of (64)Cu was higher than that of (111)In in all organs except kidney. In tumor-bearing mice, (64)Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 +/- 1.17 at 6 h after administration. (64)Cu-DOTA-TOC showed significantly higher accumulation in the tumor than (64)Cu-TETA-OC. (64)Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of (18)F-FDG PET and very similar to that of (64)Cu-TETA-OC.
(64)Cu-DOTA-TOC clearly imaged a somatostatin receptor-positive tumor and seemed to be a potential PET tracer in the clinical phase.
铟 - 111（¹¹¹In）标记的奥曲肽已在临床上用于生长抑素受体阳性肿瘤的成像，并且已开发出用于正电子发射断层扫描（PET）的放射性标记奥曲肽类似物。铜 - 64（⁶⁴Cu；半衰期为12.7小时）是一种用于PET成像的有吸引力的放射性核素，可使用小型生物医学回旋加速器以高比活度生产。本研究的目的是制备并从根本上研究一种⁶⁴Cu标记的奥曲肽类似物，即⁶⁴Cu - 1,4,7,10 - 四氮杂环十二烷 - 1,4,7,10 - 四乙酸 - D - 苯丙氨酸（¹） - 酪氨酸（³） - 奥曲肽（⁶⁴Cu - DOTA - TOC）。
使用生物医学回旋加速器生产的⁶⁴Cu在45℃下与DOTA - TOC反应30分钟。通过高效液相色谱分析在体外（与血清一起孵育）和体内（给药后采集血液）评估⁶⁴Cu - DOTA - TOC的稳定性。通过给予⁶⁴Cu - DOTA - TOC和¹¹¹In - DOTA - TOC的混合溶液在正常小鼠中进行生物分布研究，并通过给予⁶⁴Cu - DOTA - TOC或⁶⁴Cu - 1,4,8,11 - 四氮杂环十四烷 - 1,4,8,11 - 四乙酸 - 奥曲肽（⁶⁴Cu - TETA - OC）在生长抑素受体阳性U87MG荷瘤小鼠中进行生物分布研究。使用动物PET扫描仪用⁶⁴Cu - DOTA - TOC、⁶⁴Cu - TETA - OC和氟代脱氧葡萄糖（FDG）对肿瘤进行成像。
可以以足够用于临床研究的量且具有高放射化学产率制备⁶⁴Cu - DOTA - TOC。⁶⁴Cu - DOTA - TOC在体外稳定，但注射到小鼠体内后观察到与蛋白质的时间依赖性转螯合。在生物分布研究中，除肾脏外，所有器官中⁶⁴Cu的放射性均高于¹¹¹In。在荷瘤小鼠中，⁶⁴Cu - DOTA - TOC在肿瘤中显示出高蓄积，给药后6小时肿瘤与血液的比率高达8.81±1.17。⁶⁴Cu - DOTA - TOC在肿瘤中的蓄积明显高于⁶⁴Cu - TETA - OC。⁶⁴Cu - DOTA - TOC PET显示出非常清晰的肿瘤图像，与¹⁸F - FDG PET相当，并且与⁶⁴Cu - TETA - OC非常相似。
⁶⁴Cu - DOTA - TOC清晰地对生长抑素受体阳性肿瘤进行了成像，似乎是临床阶段一种潜在的PET示踪剂。
