[68Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity,Bioconjugate Chemistry

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[68Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-08-06 , DOI: 10.1021/acs.bioconjchem.0c00401
George P Keeling ₁ , Billie Sherin ₁ , Jana Kim ₁ , Belinda San Juan ₁ , Tilmann Grus ₂ , Thomas R Eykyn ₁ , Frank Rösch ₂ , Gareth E Smith ₃ , Philip J Blower ₁ , Samantha Y A Terry ₁ , Rafael T M de Rosales ₁

Affiliation

Calcium minerals such as hydroxyapatite (HAp) can be detected noninvasively in vivo using nuclear imaging agents such as [¹⁸F]NaF (available from cyclotrons), for positron emission tomography (PET) and ^99mTc-radiolabeled bisphosphonates (BP; available from ^99mTc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabeling, we developed [⁶⁸Ga]Ga-THP-Pam. Radiolabeling with ⁶⁸Ga is achieved using a mild single-step kit (5 min, room temperature, pH 7) to high radiochemical yield and purity (>95%). NMR studies demonstrate that Ga binds via the THP chelator, leaving the BP free to bind to its biological target. [⁶⁸Ga]Ga-THP-Pam shows high stability in human serum. The calcium mineral binding of [⁶⁸Ga]Ga-THP-Pam was compared in vitro to two other ⁶⁸Ga-BPs which have been successfully evaluated in humans, [⁶⁸Ga]Ga-NO2AP^BP and [⁶⁸Ga]Ga-BPAMD, as well as [¹⁸F]NaF. Interestingly, we found that all ⁶⁸Ga-BPs have a high affinity for a broad range of calcium minerals implicated in vascular calcification disease, while [¹⁸F]NaF is selective for HAp. Using healthy young mice as a model of metabolically active growing calcium mineral in vivo, we compared the pharmacokinetics and biodistribution of [⁶⁸Ga]Ga-THP-Pam with [¹⁸F]NaF as well as [⁶⁸Ga]NO2AP^BP. These studies revealed that [⁶⁸Ga]Ga-THP-Pam has high in vivo affinity for bone tissue (high bone/muscle and bone/blood ratios) and fast blood clearance (t_1/2 < 10 min) comparable to both [⁶⁸Ga]NO2AP^BP and [¹⁸F]NaF. Overall, [⁶⁸Ga]Ga-THP-Pam shows high potential for clinical translation as a cyclotron-independent calcium mineral PET radiotracer, with simple and efficient radiochemistry that can be easily implemented in any radiopharmacy.

中文翻译：

[68Ga]Ga-THP-Pam：一种双膦酸盐 PET 示踪剂，具有简便的放射性标记和广泛的钙矿物亲和力

可以使用核显像剂（例如 [ ¹⁸ F]NaF（可从回旋加速器获得）、用于正电子发射断层扫描 (PET) 和^99m Tc 放射性标记双膦酸盐 (BP；可从^99m获得)）体内无创地检测羟基磷灰石 (HAp) 等钙矿物质。用于单光子发射计算机断层扫描 (SPECT) 或闪烁扫描的 Tc 发生器。这两种类型的显像剂可以检测骨转移（基于 HAp 的存在）和血管钙化病变（包含 HAp 和其他钙矿物质）。为了针对这些病变开发一种不依赖回旋加速器的 PET 放射性示踪剂，具有广泛的钙矿物质亲和力和简单的一步放射性标记，我们开发了 [ ⁶⁸ Ga]Ga-THP-Pam。使用温和的单步试剂盒（5 分钟，室温，pH 7）可实现⁶⁸ Ga 放射性标记，达到高放射化学产率和纯度 (>95%)。 NMR 研究表明 Ga 通过 THP 螯合剂结合，使 BP 自由结合其生物靶标。 [ ⁶⁸ Ga]Ga-THP-Pam 在人血清中表现出高稳定性。 [ ⁶⁸ Ga]Ga-THP-Pam 的钙矿物质结合在体外与已在人体中成功评估的两种⁶⁸ Ga-BP（[ ⁶⁸ Ga]Ga-NO2AP ^BP和 [ ⁶⁸ Ga]Ga-BPAMD）进行了比较，以及[ ¹⁸ F]NaF。有趣的是，我们发现所有^{68 种}Ga-BP 对与血管钙化疾病有关的多种钙矿物质都具有高亲和力，而 [ ¹⁸ F]NaF 对 HAp 具有选择性。使用健康的年轻小鼠作为体内代谢活跃的钙矿物质生长模型，我们比较了[ ⁶⁸ Ga]Ga-THP-Pam 与[ ¹⁸ F]NaF 以及[ ⁶⁸ Ga]NO2AP ^BP的药代动力学和生物分布。这些研究表明，[ ⁶⁸ Ga]Ga-THP-Pam 对骨组织具有高体内亲和力（高骨/肌肉和骨/血液比率）和快速血液清除率（ t _1/2 < 10 分钟），与 [ 68 Ga]Ga-THP-Pam 相当。 ⁶⁸ Ga]NO2AP ^BP和[ ¹⁸ F]NaF。总体而言，[ ⁶⁸ Ga]Ga-THP-Pam 作为一种独立于回旋加速器的钙矿物 PET 放射性示踪剂显示出临床转化的巨大潜力，具有简单有效的放射化学，可以在任何放射性制药中轻松实施。

更新日期：2020-08-06

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