Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Nucl Med Biol. 2022 Nov-Dec;114-115:18-28. doi: 10.1016/j.nucmedbio.2022.08.003. Epub 2022 Aug 19.
Radiolabeled peptides and low-molecular-weight (LMW) polypeptides show high and persistent radioactivity levels in the kidney. To develop a DOTA-based bifunctional chelating agent that provides a radiometabolite with a rapid elimination rate from the kidney, a para-carboxyl Bn-DOTA (p-COOH-Bn-DOTA) was designed, synthesized, and evaluated.
A precursor compound, p-COOH-Bn-DOTA(Bu), was synthesized in 9 steps using N-Boc-p-iodo-L-phenylalanine as the starting material. A synthetic somatostatin analog (TOC) was used as a representative peptide metabolized in the renal lysosomes. p-COOH-Bn-DOTA-conjugated TOC (DOTA-Bn-TOC) was synthesized by the conventional solid-phase peptide synthesis using p-COOH-Bn-DOTA(Bu). DOTA-tris(Bu ester) was also conjugated with TOC to prepare DOTATOC. In-labeling of the peptides was conducted under similar conditions. The radiochemical conversions, stability against apo-transferrin (apoTf), and in vivo behaviors were compared.
[In]In-DOTA-Bn-TOC was obtained with higher radiochemical conversions than [In]In-DOTATOC. Both In-labeled TOC derivatives remained stable against apoTf. In biodistribution studies, [In]In-DOTA-Bn-TOC exhibited higher initial uptake in the kidney, followed by a faster elimination rate of radioactivity into the urine than [In]In-DOTATOC. The metabolic studies showed that the shorter residence time of the radiometabolite from [In]In-DOTA-Bn-TOC was responsible for the renal radioactivity decline.
p-COOH-Bn-DOTA provides stable In-labeled peptides in high yields at low peptide concentrations. p-COOH-Bn-DOTA also provides a radiometabolite with a short residence time in the kidney. Such characteristics would render p-COOH-Bn-DOTA useful to the future application to radiolabeled LMW polypeptides with low renal radioactivity levels.
放射性标记的肽和低分子量（LMW）多肽在肾脏中表现出高且持久的放射性水平。为了开发一种基于 DOTA 的双功能螯合剂，以提供一种从肾脏中快速消除放射性代谢物的物质，设计、合成并评价了一种对羧基苄基-DOTA（p-COOH-Bn-DOTA）。
以 N-Boc-p-碘-L-苯丙氨酸为起始原料，经 9 步反应合成前体化合物 p-COOH-Bn-DOTA（Bu）。采用合成的生长抑素类似物（TOC）作为在肾溶酶体中代谢的代表性肽。通过常规固相肽合成，以 p-COOH-Bn-DOTA（Bu）为原料合成了 p-COOH-Bn-DOTA 偶联的 TOC（DOTA-Bn-TOC）。还将 DOTA-三（Bu 酯）与 TOC 偶联，制备 DOTATOC。在相似条件下对肽进行放射性标记。比较了放射性化学转化率、对脱铁转铁蛋白（apoTf）的稳定性以及体内行为。
与 DOTATOC 相比，[In]In-DOTA-Bn-TOC 的放射性化学转化率更高。两种放射性标记的 TOC 衍生物均能稳定抵抗 apoTf。在生物分布研究中，与[In]In-DOTATOC 相比，[In]In-DOTA-Bn-TOC 初始肾脏摄取更高，放射性进入尿液的清除速度更快。代谢研究表明，[In]In-DOTA-Bn-TOC 放射性代谢物在体内停留时间较短，导致肾脏放射性下降。
p-COOH-Bn-DOTA 在低肽浓度下以高产率提供稳定的放射性标记肽。p-COOH-Bn-DOTA 还提供一种在肾脏中放射性代谢物半衰期较短的物质。这些特性将使 p-COOH-Bn-DOTA 能够用于放射性标记低肾放射性水平的 LMW 多肽的未来应用。
