开发一种对骨具有高亲和力的新型99mTc螯合物共轭双膦酸盐作为骨闪烁显像剂。

Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent.

作者信息

Ogawa Kazuma, Mukai Takahiro, Inoue Yasuyuki, Ono Masahiro, Saji Hideo

机构信息

Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

出版信息

J Nucl Med. 2006 Dec;47(12):2042-7.

PMID:17138748

Abstract

UNLABELLED

In bone scintigraphy using (99m)Tc with methylenediphosphonate ((99m)Tc-MDP) and hydroxymethylenediphosphonate ((99m)Tc-HMDP), it takes 2-6 h after an injection before imaging can start. This interval could be shortened with a new radiopharmaceutical with higher affinity for bone. Here, based on the concept of bifunctional radiopharmaceuticals, we designed a (99m)Tc-mercaptoacetylglycylglycylglycine (MAG3)-conjugated hydroxy-bisphosphonate (HBP) ((99m)Tc-MAG3-HBP) and a (99m)Tc-6-hydrazinopyridine-3-carboxylic acid (HYNIC)-conjugated hydroxy-bisphosphonate ((99m)Tc-HYNIC-HBP).

METHODS

(99m)Tc-MAG3-HBP was prepared by complexation of MAG3-HBP with (99m)Tc using SnCl(2) as a reductant. The precursor of (99m)Tc-HYNIC-HBP, HYNIC-HBP, was obtained by deprotection of the Boc group after the coupling of Boc-HYNIC to a bisphosphonate derivative. (99m)Tc-HYNIC-HBP was prepared by a 1-pot reaction of HYNIC-HBP with (99m)TcO(4)(-), tricine, and 3-acetylpyridine in the presence of SnCl(2). Affinity for bone was evaluated in vitro by hydroxyapatite-binding assays for (99m)Tc-HMDP, (99m)Tc-MAG3-HBP, and (99m)Tc-HYNIC-HBP. Biodistribution experiments for the 3 (99m)Tc-labeled compounds were performed on normal rats.

RESULTS

(99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP were each prepared with a radiochemical purity of >95%. In the in vitro binding assay, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had greater affinity for hydroxyapatite than (99m)Tc-HMDP. In the biodistribution experiments, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had higher levels of radioactivity in bone than (99m)Tc-HMDP. (99m)Tc-MAG3-HBP was cleared from the blood slower than (99m)Tc-HMDP, whereas there was no significant difference in clearance between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP.

CONCLUSION

We developed a novel (99m)Tc-chelate-conjugated bisphosphonate with high affinity for bone and rapid clearance from blood, based on the concept of bifunctional radiopharmaceuticals. The present findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy.

摘要

未标记

在使用（99m）锝与亚甲基二膦酸盐（（99m）Tc-MDP）和羟基亚甲基二膦酸盐（（99m）Tc-HMDP）进行骨闪烁显像时，注射后需要2至6小时才能开始成像。使用对骨具有更高亲和力的新型放射性药物，这一间隔时间可以缩短。在此，基于双功能放射性药物的概念，我们设计了一种（99m）锝-巯基乙酰甘氨酰甘氨酰甘氨酸（MAG3）-共轭羟基双膦酸盐（HBP）（（99m）Tc-MAG3-HBP）和一种（99m）锝-6-肼基吡啶-3-羧酸（HYNIC）-共轭羟基双膦酸盐（（99m）Tc-HYNIC-HBP）。

方法

以氯化亚锡作为还原剂，通过MAG3-HBP与（99m）锝络合制备（99m）Tc-MAG3-HBP。（99m）Tc-HYNIC-HBP的前体HYNIC-HBP是在Boc-HYNIC与双膦酸盐衍生物偶联后通过Boc基团的脱保护获得的。（99m）Tc-HYNIC-HBP是通过在氯化亚锡存在下，使HYNIC-HBP与（99m）高锝酸盐、三羟甲基氨基甲烷和3-乙酰吡啶进行一锅法反应制备的。通过对（99m）Tc-HMDP、（99m）Tc-MAG3-HBP和（99m）Tc-HYNIC-HBP进行羟基磷灰石结合试验，在体外评估对骨的亲和力。对这3种（99m）锝标记的化合物在正常大鼠身上进行生物分布实验。

结果

（99m）Tc-MAG3-HBP和（99m）Tc-HYNIC-HBP的放射化学纯度均>95%。在体外结合试验中，（99m）Tc-MAG3-HBP和（99m）Tc-HYNIC-HBP对羟基磷灰石的亲和力高于（99m）Tc-HMDP。在生物分布实验中，（99m）Tc-MAG3-HBP和（99m）Tc-HYNIC-HBP在骨中的放射性水平高于（99m）Tc-HMDP。（99m）Tc-MAG3-HBP从血液中的清除速度比（99m）Tc-HMDP慢，而（99m）Tc-HYNIC-HBP和（99m）Tc-HMDP之间的清除率没有显著差异。因此，（99m）Tc-HYNIC-HBP的骨血比高于（99m）Tc-HMDP。