Baidoo K E, Lin K S, Zhan Y, Finley P, Scheffel U, Wagner H N
Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Bioconjug Chem. 1998 Mar-Apr;9(2):218-25. doi: 10.1021/bc9701959.
Potent antagonists of bombesin-like peptides have shown great potential for applications in cancer therapy. A 99mTc-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-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (Lys3-bombesin). We coupled two diaminedithiol (DADT) bifunctional chelating agents (BCAs 1 and 2) to the Lys3 residue at the N-terminal region that is not required for binding to the receptor. 99mTc labeling was performed by ligand exchange on addition of [99mTc]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 99mTc-labeled analogues were 3:1 for products from BCA 1 and 9:1 for the products from BCA 2. Macroscopic amounts of the 99Tc analogues were similarly prepared using [99Tc]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 99Tc analogues were used in vitro in competitive binding assays in rat brain cortex membranes against [125I-Tyr4]bombesin. Results of the in vitro assays showed that the inhibition constants (Ki) 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.
蛙皮素样肽的强效拮抗剂在癌症治疗应用中已显示出巨大潜力。一种能够识别可从这些新兴疗法中获益患者的99mTc标记剂，将对患者管理产生重大影响。本研究涉及从强效蛙皮素类似物Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2（Lys3-蛙皮素）衍生的二胺二硫醇锝类似物的合成及初步评估。我们将两种二胺二硫醇（DADT）双功能螯合剂（BCA 1和2）偶联至N端区域中与受体结合不需要的Lys3残基上。通过在室温下将[99mTc]葡庚糖酸盐加入加合物溶液中进行配体交换来进行99mTc标记。通过HPLC分析，每种加合物均得到两种产物。对于BCA 1的产物，99mTc标记类似物的主要产物与次要产物之比为3:1；对于BCA 2的产物，该比例为9:1。使用[99Tc]葡庚糖酸盐类似地制备了大量的99Tc类似物。在这种情况下，两种BCA产物的主要产物与次要产物之比均为2:1。为了初步评估Tc标记肽与蛙皮素受体的结合，99Tc类似物在体外用于大鼠脑皮质膜中针对[125I-Tyr4]蛙皮素的竞争性结合试验。体外试验结果表明，对于BCA 1的产物，主要产物和次要产物的抑制常数（Ki）分别为3.5±0.7和3.9±1.5 nM；对于BCA 2衍生的产物，分别为7.4±2.0和5.2±1.5 nM。这些锝类似物表现出的高亲和力表明它们有潜力用于对具有蛙皮素受体的癌症进行非侵入性体内生化特征分析。
