Uehara Tomoya, Jin Zhe Long, Ogawa Kazuma, Akizawa Hiromichi, Hashimoto Kazuyuki, Nakayama Morio, Arano Yasushi
Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
Nucl Med Biol. 2007 Jan;34(1):79-87. doi: 10.1016/j.nucmedbio.2006.10.001. Epub 2006 Nov 16.
The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design.
Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined.
The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP.
Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.
铼-186（186Re）-单氨基单酰胺二硫醇共轭物或186Re-巯基乙酰三甘氨酸共轭双膦酸盐（BPs）具有良好的药代动力学特性，这表明该分子设计适用于其他放射性核素，如68Ga、99mTc、153Sm和177Lu。在本研究中，研究了影响螯合物共轭BP药代动力学的关键因素，以评估分子设计的有效性和适用性。
将化学惰性且特性明确的三羰基[186Re][（环戊二烯基羰基氨基）-乙酸]铼（[186Re]CpTR-Gly）与3-氨基-1-羟基亚丙基-1,1-双膦酸共轭，并通过高效液相色谱（HPLC）纯化，以制备186Re铼（[186Re]CpTR-Gly-APD）。将[186Re]CpTR-Gly-APD的血浆稳定性、血浆蛋白结合、羟基磷灰石（HA）结合及药代动力学与186Re 1-羟基亚乙基-1,1-二膦酸盐（HEDP）进行比较。还测定了HEDP共同给药和预先给药对[186Re]CpTR-Gly-APD药代动力学的影响。
HPLC纯化的[186Re]CpTR-Gly-APD比186Re-HEDP具有更高的血浆稳定性、更高的HA结合、更高的骨摄取和更低的血浆蛋白结合。然而，在相似的HEDP浓度下，[186Re]CpTR-Gly-APD的HA结合降至略高于186Re-HEDP的水平。当[186Re]CpTR-Gly-APD与相当于186Re-HEDP中的HEDP共同注射时，[186Re]CpTR-Gly-APD的骨摄取也降至与186Re-HEDP相似的水平。相反，HEDP预处理并未损害两种186Re标记化合物的骨摄取。然而，特别是186Re-HEDP出现了血液清除延迟和肾脏放射性水平增加的情况。
尽管186Re-HEDP具有与[186Re]CpTR-Gly-APD相似的HA结合和骨摄取，但发现186Re标记的BPs的比活在骨摄取和血液清除中起关键作用。因此，螯合物共轭BP的分子设计通过选择能提供高比活的螯合分子，对于开发具有多种放射性核素的亲骨放射性药物将是有用的。
