Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [⁶⁸Ga]Ga-DOTA-TATE (NETSPOT) and [¹⁷⁷Lu]Lu-DOTA-TATE (LUTATHERA) received U.S. Food and Drug Administration approval for positron emission tomography (PET) imaging and PRRT of NETs, respectively. However, to the best of our knowledge a well-described synthesis of DOTA-TATE has not been reported in the literature. Herein, we report a fully reoptimized DOTA-TATE synthesis, including the application of a simple ultrasonic bath to greatly improve yields, reduce coupling times, and decrease the amount of reagents required for each coupling step by a half. The most prevalently used cyclizing agents such as iodine, thallium(III) trifluoroacetate, hydrogen peroxide, and dimethyl sulfoxide were compared. On-resin cyclizations using mechanical agitation showed higher yields (23% and 25% using I₂ and Tl(III), respectively) than off-resin (1.3% and 11% using DMSO and H₂O₂, respectively), and the total synthesis time of DOTA-TATE was ∼540 min excluding the cyclization step, with a total synthesis yield of ∼23%. The same manual SPPS methods/reagents were reoptimized with ultrasonic (US) agitation, resulting in an immense reduction in the total synthesis time by ∼8-fold to ∼70 min for DOTA-TATE with a higher yield (∼29% yield), and ∼13-fold to 105 min for DOTA-PEG₄-TATE (∼29% yield). Also, the use of US agitation reduces the need for excess molar equivalents of the reagents to a half, which is particularly important when coupling expensive or custom-synthesized groups such as bifunctional chelators and linkers. Finally, the synthesized DOTA-TATE was successfully radiolabeled with [⁶⁸Ga]Ga³⁺ (t_1/2 = 68 min) with high radiochemical yields (30 min, 95 °C). We believe this work opens the door to the facile and low-cost synthesis of many new chelator-linker-peptide conjugates that were previously cumbersome or cost-prohibitive to produce with manual SPPS.

中文翻译：

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DOTA-TATE 和 DOTA-linker-TATE 衍生物的超声辅助固相肽合成作为一种简便合成螯合剂-肽缀合物的简单低成本方法

肽已被广泛用作生物靶向载体，用于分子成像和肽受体放射性核素治疗 (PRRT)。生长抑素 (SST) 类似物如奥曲酸 (TATE) 是生长抑素受体 (SSTR) 的外源配体，其在神经内分泌肿瘤 (NET) 上高度表达。最近，[ ⁶⁸ Ga]Ga-DOTA-TATE (NETSPOT) 和 [ ¹⁷⁷Lu]Lu-DOTA-TATE (LUTATHERA) 分别获得了美国食品和药物管理局的批准，用于 NET 的正电子发射断层扫描 (PET) 成像和 PRRT。然而，据我们所知，文献中尚未报道过详细描述的 DOTA-TATE 合成。在此，我们报告了一种完全重新优化的 DOTA-TATE 合成，包括应用简单的超声波浴来大大提高产量、减少偶联时间并将每个偶联步骤所需的试剂量减少一半。比较了最常用的环化剂，如碘、三氟乙酸铊 (III)、过氧化氢和二甲基亚砜。使用机械搅拌的树脂上环化显示出更高的产率（23% 和 25% 使用 I ₂和 Tl(III)）比离树脂（分别使用 DMSO 和 H ₂ O ₂分别为1.3% 和 11% ），并且 DOTA-TATE 的总合成时间为 540 分钟，不包括环化步骤，总共合成收率约为 23%。相同的手动 SPPS 方法/试剂通过超声 (US) 搅拌重新优化，导致 DOTA-TATE 的总合成时间大幅减少约 8 倍至约 70 分钟，并具有更高的产率（约 29% 产率）， DOTA-PEG _{4 约 13}倍至 105 分钟-TATE（~29% 产率）。此外，使用 US 搅拌可将多余摩尔当量的试剂需求减少到一半，这在偶联昂贵或定制合成的基团（如双功能螯合剂和接头）时尤为重要。最后，合成的 DOTA-TATE 成功地用 [ ⁶⁸ Ga]Ga ³⁺ ( t _1/2 = 68 分钟) 进行放射性标记，放射化学产率高 (30 分钟，95 °C)。我们相信，这项工作为许多新的螯合剂-接头-肽缀合物的轻松和低成本合成打开了大门，这些缀合物以前用手动 SPPS 生产很麻烦或成本过高。