Design, synthesis, and initial evaluation of high-affinity technetium bombesin analogues
Design, synthesis, and initial evaluation of high-affinity technetium bombesin analogues
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DOI：
10.1021/bc9701959
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发表时间：
1998-03-01
影响因子：
4.7
通讯作者：
Wagner, HN
中科院分区：
文献类型：
--
作者：
Baidoo, KE;Lin, KS;Wagner, HN
蛙皮素样肽的有效拮抗剂在癌症治疗中显示出巨大的应用潜力。一个Tc-99 m标记的药物能够识别患者谁可以从这些新兴的疗法中受益将有很大的影响，病人的管理。本研究涉及有效的蛙皮素类似物Pyr-Gln-Lys-Leu-Gln-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH_2（Lys（3）-bombesin）衍生的二胺二硫代锝类似物的合成和初步评价。我们将两种二胺二硫醇（DADT）双功能螯合剂（BCAs 1和2）偶联到N-末端区域的Lys（3）残基上，这不是与受体结合所必需的。通过在室温下向加合物溶液中加入[Tc-99 m（3）]葡庚糖酸盐进行配体交换进行Tc-99 m标记。通过HPLC分析，从每种加合物获得两种产物。Tc-99 m标记的类似物的主要与次要产物比对于来自BCA 1的产物为3：1，对于来自BCA 2的产物为9：1。使用[Tc-99]葡庚糖酸盐类似地制备宏观量的Tc-99类似物。在这种情况下，对于来自两种BCA的产物，主要与次要比率为2：1。为了初步评价Tc标记肽与蛙皮素受体的结合，在大鼠脑皮质膜中对[I-125-Tyr（4）]蛙皮素进行体外竞争性结合试验时使用Tc-99类似物。体外试验结果显示，BCA 1产物的主要和次要产物的抑制常数（Ki）分别为3.5 +/- 0.7和3.9 +/- 1.5 nM; BCA 2产物的抑制常数（Ki）分别为7.4 +/- 2.0和5.2 +/- 1.5 nM。这些锝类似物所表现出的高亲和力表明它们具有用于具有蛙皮素受体的癌症的非侵入性体内生物化学表征的潜力。
Potent antagonists of bombesin-like peptides have shown great potential for applications in cancer therapy. A Tc-99m-labeled agent capable of identifying patients who could benefit from these emerging therapies would have a great impact on patient management. This study involves the synthesis and initial evaluation of technetium diaminedithiolate analogues derived from the potent bombesin analogue Pyr-Gln-Lys-Leu-Gln-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (Lys(3)-bombesin). We coupled two diaminedithiol (DADT) bifunctional chelating agents (BCAs 1 and 2) to the Lys(3) residue at the N-terminal region that is not required for binding to the receptor. Tc-99m labeling was performed by ligand exchange on addition of [Tc-99m(3)]glucoheptonate to a solution of the adduct at room temperature. Two products were obtained from each adduct on analysis by HPLC. The major to minor product ratios of the Tc-99m-labeled analogues were 3:1 for products from BCA 1 and 9:1 for the products from BCA 2. Macroscopic amounts of the Tc-99 analogues were similarly prepared using [Tc-99]glucoheptonate. In this case, the major to minor ratios were 2:1 for the products from both BCAs. For initial evaluation of the binding of the Tc-labeled peptides to bombesin receptors, the Tc-99 analogues were used in vitro in competitive binding assays in rat brain cortex membranes against [I-125-Tyr(4)]bombesin. Results of the in vitro assays showed that the inhibition constants (K-i) of the major and minor products were 3.5 +/- 0.7 and 3.9 +/- 1.5 nM, respectively, for the products from BCA 1; and 7.4 +/- 2.0 and 5.2 +/- 1.5 nM for the products derived from BCA 2, respectively. The high affinity exhibited by these technetium analogues is an indication of their potential for use in non-invasive in vivo biochemical characterization of cancers that possess receptors for bombesin.