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Efficient 18F-Labeling of Large 37-Amino Acid pHLIP Peptide Analogues and their Biological Evaluation

机译：高效的38F标记大37氨基酸phlip肽类似物及其生物学评估

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摘要

Solid tumors often develop an acidic microenvironment, which plays a critical role in tumor progression and is associated with increased level of invasion and metastasis. The 37-residue pH (low) insertion peptide (pHLIP®) is under study as an imaging platform because of its unique ability to insert into cell membranes at a low extracellular pH (pHe<7). Labeling of peptides with [18F]-fluorine is usually performed via prosthetic groups using chemoselective coupling reactions. One of the most successful procedures involves the alkyne-azide copper(I) catalyzed cycloaddition (CuAAC). However, none of the known “click” methods have been applied to peptides as large as pHLIP. We designed a novel prosthetic group and extended the use of the CuAAC “click chemistry” for the simple and efficient 18F-labeling of large peptides. For the evaluation of this labeling approach, a D-amino acid analogue of WT-pHLIP and a L-amino acid control peptide K-pHLIP, both functionalized at the N-terminus with 6-azidohexanoic acid, were used. The novel 6-[18F]fluoro-2-ethynylpyridine prosthetic group, was obtained via nucleophilic substitution on the corresponding bromo-precursor after 10 min at 130 °C with a radiochemical yield of 27.5 ± 6.6% (decay corrected) with high radiochemical purity ≥ 98%. The subsequent Cu>I catalyzed “click” reaction with the azido functionalized pHLIP peptides was quantitative within 5 min at 70 °C in a mixture of water and ethanol using Cu-acetate and sodium L-ascorbate. [18F]-D-WT-pHLIP and [18F]-L-K-pHLIP were obtained with total radiochemical yields of 5–20% after HPLC purification. The total reaction time was only 85 min including formulation. In vitro stability tests revealed high stability of the [18F]-D-WT-pHLIP in human and mouse plasma after 120 min, with the parent tracer remaining intact at 65 and 85%, respectively. PET imaging and biodistribution studies in LNCaP and PC-3 xenografted mice with the [18F]-D-WT-pHLIP and the negative control [18F]-L-K-pHLIP revealed pH-dependent tumor retention. This reliable and efficient protocol promises to be useful for the 18F-labeling of large peptides such as pHLIP and will accelerate the evaluation of numerous [18F]-pHLIP analogues as potential PET tracers.
机译：实体瘤通常会形成酸性微环境，该环境在肿瘤的进展中起关键作用，并与侵袭和转移的水平升高有关。目前正在研究将具有37个残基的pH（低）插入肽（pHLIP ®）作为成像平台，因为它具有在低细胞外pH（pHe <7）时插入细胞膜的独特能力。 [[sup> 18 F]-氟标记的肽通常通过使用化学选择性偶联反应的辅基进行。最成功的方法之一涉及炔-叠氮化物铜（I）催化的环加成反应（CuAAC）。但是，没有一种已知的“点击”方法适用于pHLIP大小的肽。我们设计了一个新的假肢组，并扩展了CuAAC“点击化学”的使用，以简单而有效地对大肽段进行 18 F标记。为了评估该标记方法，使用了WT-pHLIP的D-氨基酸类似物和L-氨基酸对照肽K-pHLIP，它们都在N-末端用6-叠氮己酸官能化。新型的6-[ 18 F]氟-2-乙炔基吡啶假体基团，在130°C下放置10分钟后，通过相应溴前体的亲核取代获得，放射化学产率为27.5±6.6％ （校正衰变），放射化学纯度≥98％。随后在70°C下于5分钟内使用乙酸铜和乙酸铜在水和乙醇混合物中定量分析与叠氮基官能化pHLIP肽催化的随后的Cu > I 反应。 L-抗坏血酸钠。 HPLC纯化后获得[ 18 F] -D-WT-pHLIP和[ 18 F] -L-K-pHLIP，总放射化学产率为5–20％。包括配方在内，总反应时间仅为85分钟。体外稳定性测试显示[ 18 F] -D-WT-pHLIP在120分钟后在人和小鼠血浆中具有很高的稳定性，亲本示踪剂分别保持完整，分别为65％和85％。 [ 18 F] -D-WT-pHLIP和阴性对照[ 18 F] -LK-在LNCaP和PC-3异种移植小鼠中的PET成像和生物分布研究pHLIP显示pH依赖性肿瘤保留。这种可靠而有效的方案有望用于大肽如pHLIP的 18 F标记，并将加速许多[ 18 F] -pHLIP类似物的评估。潜在的PET示踪剂。

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