Instant kit preparation of 68Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [68Ga]Ga-DATA-TOC
Instant kit preparation of 68Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [68Ga]Ga-DATA-TOC
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DOI：
10.1186/s13550-019-0516-7
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发表时间：
2019-05-23
期刊：
影响因子：
3.2
通讯作者：
Roesch, Frank
中科院分区：
文献类型：
--
作者：
Sinnes, Jean-Philippe;Nagel, Johannes;Roesch, Frank
Ga-68在正电子发射断层扫描（PET）中的广泛应用依赖于放射性药物前体的开发，这些前体可以以简单、快速和方便的方式进行放射性标记和分配。DATA（6-氨基-1，4-二氮杂卓-三乙酸酯）支架代表了一种新的混合螯合剂结构，具有环状和非环状特征，可以在临床上方便地获得Ga-68标记的示踪剂。我们报告的第一个双功能数据螯合剂共轭[Tyr（3）]奥曲肽（TOC），生长抑素亚型2受体（SST 2）的成像和功能表征的SSTR 2表达tumors.MethodsThe放射性药物前体，DATA-TOC，靶向载体，如前所述合成和用于复杂的Ga-nat（III）和Ga-68（III）。在转染以稳定表达hSST（2，3，5）受体亚型之一的HEK 293细胞（HEK 293-hSST（2/3/5）细胞）膜中进行[Ga-nat]Ga-DATA-TOC或[Ga-nat]Ga-DOTA-TOC与[I-125-Tyr（25）] LTT-SS 28的竞争结合试验。首先在携带SST 2阳性小鼠嗜铬细胞瘤mCherry（MPC-mCherry）肿瘤的雌性NMRI裸鼠中进行体内研究，以比较[Ga-68]Ga-DATA-TOC与[Ga-68]Ga-DOTA-TOC参比的体内SST 2特异性肿瘤靶向及其总体药代动力学。另外，在一名46岁的分化良好的NET男性患者中进行了[Ga-68]Ga-DATA-TOC与成熟的PET放射性示踪剂[Ga-68]Ga-DOTA-TOC的直接比较。（神经内分泌肿瘤），结果[Ga-68] Ga-DATA-TOC经Ga-68标记后，标记效率>95%，标记率为95在环境温度下小于10分钟。摩尔活性达35 MBq/nmol。发现[Ga-nat]Ga-DATA-TOC和[Ga-nat]Ga-DOTA-TOC的hSST（2）-亲和力相似，各自的IC 50值仅存在亚纳摩尔差异。在小鼠中，[Ga-68]Ga-DATA-TOC能够可视化肿瘤病变，显示出与[Ga-68]Ga-DOTA-TOC相似的标准化摄取值（SUV）。NET患者中的两种PET示踪剂的直接比较揭示了两种Ga-68-放射性示踪剂的非常相似的肿瘤摄取，但是[Ga-68]Ga-DATA-TOC.Conclusion具有更高的肿瘤-肝脏对比度，制备了[Ga-68] Ga-DATA-TOC，其质量适合于体内使用，遵循高效的试剂盒类型过程。此外，这种新型放射性药物在所有临床前测试中与[Ga-68]Ga-DOTA-TOC相当或更好，在NET患者中实现了更高的肿瘤与肝脏对比度。结果说明了DATA螯合剂在常规临床放射性药物环境中促进Ga-68-放射性示踪剂的获得和制备的潜力。
PurposeThe widespread use of Ga-68 for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to Ga-68-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr(3)]octreotide (TOC), a somatostatin subtype 2 receptor (SST2)-targeting vector for imaging and functional characterisation of SSTR2 expressing tumours.MethodsThe radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex Ga-nat(III) and Ga-68(III). Competition binding assays of [Ga-nat]Ga-DATA-TOC or [Ga-nat]Ga-DOTA-TOC against [I-125-Tyr(25)]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST(2,3,5) receptor subtypes (HEK293-hSST(2/3/5) cells). First in vivo studies were performed in female NMRI-nude mice bearing SST2-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST2-specific tumour-targeting of [Ga-68]Ga-DATA-TOC and its overall pharmacokinetics versus the [Ga-68]Ga-DOTA-TOC reference. A direct comparison of [Ga-68]Ga-DATA-TOC with the well-established PET radiotracer [Ga-68]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [Ga-68]Ga-DATA-TOC.ResultsDATA-TOC was labelled with Ga-68 with a radiolabelling efficiency of >95% in less than 10min at ambient temperature. A molar activity up to 35MBq/nmol was achieved. The hSST(2)-affinities of [Ga-nat]Ga-DATA-TOC and [Ga-nat]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC50 values. In mice, [Ga-68]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [Ga-68]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two Ga-68-radiotracers, but with a higher tumour-to-liver contrast for [Ga-68]Ga-DATA-TOC.Conclusion[Ga-68]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [Ga-68]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of Ga-68-radiotracers in a routine clinical radiopharmacy setting.