Initial evaluation of new ^99mTc(CO)₃ renal imaging agents having carboxyl-rich thioether ligands and chemical characterization of Re(CO)₃ analogues

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• 作者：Haiyang He ; Malgorzata Lipowska ; Anna Maria Christoforou ; Luigi G. Marzilli ; Andrew T. Taylor
• 关键词：Technetium ; Rhenium ; Kidney ; Renal radiopharmaceuticals
• 刊名：Nuclear Medicine and Biology
• 出版年：2007
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：August 2007
• 卷：34
• 期：6
• 页码：709-716
• 文件大小：392 K

摘要

The first human studies of a characterized radiopharmaceutical containing a {^99mTc(CO)₃}⁺ core, Na[^99mTc(CO)₃(LAN)], demonstrated that Na[^99mTc(CO)₃(LAN)] was an excellent renal imaging agent; however, its clearance was less than that of ¹³¹I-orthoiodohippurate (¹³¹I-OIH), and it did not provide a direct measure of effective renal plasma flow. In order to develop a ^99mTc renal agent with pharmacokinetic properties equivalent to those of ¹³¹I-OIH, we investigated the ^99mTc(CO)₃/Re(CO)₃ complexes formed from carboxymethylmercaptosuccinic acid (CMSAH₃) and thiodisuccinic acid (TDSAH₄). Once the ligand is bound to ^99mTc(CO)₃ through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter.

class="h4">Methods

X-ray crystal structural analysis of [NMe₄][Re(CO)₃(CMSAH)] was performed to interpret the nature of ^99mTc tracers. CMSAH₃ and TDSAH₄ were radiolabeled by incubating each ligand and the precursor [^99mTc(CO)₃(H₂O)₃]⁺ at 70°C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague–Dawley rats, with ¹³¹I-OIH as an internal control at 10 and 60 min.

class="h4">Results

Radiolabeling CMSAH₃ and TDSAH₄ with the [^99mTc(CO)₃(H₂O)₃]⁺ precursor gave products quantitatively. Analysis of the Re(CO)₃ complexes with the CMSAH₃ and TDSAH₄ ligands demonstrates that ligands are bound in ^99mTc/Re(CO)₃ complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of ¹³¹I-OIH) was 68±1%for Na₃[^99mTc(CO)₃(TDSA)] but was 98±1%for Na₂[^99mTc(CO)₃(CMSA)].

class="h4">Conclusion

In rats, Na₂[^99mTc(CO)₃(CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as ¹³¹I-OIH; consequently, Na₂[^99mTc(CO)₃(CMSA)] may provide a direct measure of effective renal plasma flow, and further evaluation in humans is warranted.