通过替换螯合基团，开发了第一个具有高靶向亲和力和肿瘤积累的18F标记放射性杂交小胃素衍生物。
Development of the First 18F-Labeled Radiohybrid-Based Minigastrin Derivative with High Target Affinity and Tumor Accumulation by Substitution of the Chelating Moiety.
发表日期：2023 Mar 03
作者：
Thomas Günther, Nadine Holzleitner, Daniel Di Carlo, Nicole Urtz-Urban, Constantin Lapa, Hans-Jürgen Wester
来源：
PHYSICAL THERAPY & REHABILITATION JOURNAL
摘要：
为了优化以前报道的小胃泌素衍生物在升高的肾脏中的潜留，我们在（R）-DOTAGA-rhCCK-16/-18中用DOTA替换了（R）-DOTAGA。使用AR42J细胞确定了新化合物的CCK-2R介导的内化和亲和力。在AR42J肿瘤携带的CB17-SCID小鼠中进行了1和24小时p.i.的生物分布和μSPECT/CT成像研究。DOTA含量的小胃泌素类似物的IC50值比它们的（R）-DOTAGA类似物高3到5倍。natLu标记的肽比其natGa标记的类似物具有更高的CCK-2R亲和力。在体内，最亲和的化合物[19F]F-[177Lu]Lu-DOTA-rhCCK-18在24小时p.i.的肿瘤摄取量比其（R）-DOTAGA类似物和参考化合物[177Lu]Lu-DOTA-PP-F11N分别高1.5倍和13倍。但肾脏中的活性水平也升高了。在1小时p.i.时，[19F]F-[177Lu]Lu-DOTA-rhCCK-18和[18F]F-[natLu]Lu-DOTA-rhCCK-18的肿瘤和肾脏累积量很高。我们可以证明螯合剂和放射性金属的选择对小胃泌素类似物的CCK-2R亲和力和肿瘤摄取有重要影响。虽然[19F]F-[177Lu]Lu-DOTA-rhCCK-18的肾脏潜留还需要进一步研究与放射性配体治疗有关，但其放射性杂交类似物[18F]F-[natLu]Lu-DOTA-rhCCK-18可能由于其1小时p.i的高肿瘤积累和氟-18的有利物理性质而非常适合正电子发射断层扫描（PET）成像。
In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted (R)-DOTAGA by DOTA in (R)-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µSPECT/CT imaging studies at 1 and 24 h p.i. were carried out in AR42J tumor-bearing CB17-SCID mice. Both DOTA-containing minigastrin analogs exhibited 3- to 5-fold better IC50 values than their (R)-DOTAGA-counterparts. natLu-labeled peptides revealed higher CCK-2R affinity than their natGa-labeled analogs. In vivo, tumor uptake at 24 h p.i. of the most affine compound, [19F]F-[177Lu]Lu-DOTA-rhCCK-18, was 1.5- and 13-fold higher compared to its (R)-DOTAGA derivative and the reference compound, [177Lu]Lu-DOTA-PP-F11N, respectively. However, activity levels in the kidneys were elevated as well. At 1 h p.i., tumor and kidney accumulation of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 and [18F]F-[natLu]Lu-DOTA-rhCCK-18 was high. We could demonstrate that the choice of chelators and radiometals has a significant impact on CCK-2R affinity and thus tumor uptake of minigastrin analogs. While elevated kidney retention of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 has to be further addressed with regard to radioligand therapy, its radiohybrid analog, [18F]F-[natLu]Lu-DOTA-rhCCK-18, might be ideal for positron emission tomography (PET) imaging due to its high tumor accumulation at 1 h p.i. and the attractive physical properties of fluorine-18.