Pyridine-containing 6-hydrazinonicotinamide derivatives as potential bifunctional chelators for 99mTc-labeling of small biomolecules
Pyridine-containing 6-hydrazinonicotinamide derivatives as potential bifunctional chelators for 99mTc-labeling of small biomolecules
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DOI：
10.1021/bc034141c
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发表时间：
2004-07-01
影响因子：
4.7
通讯作者：
Edwards, DS
中科院分区：
文献类型：
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作者：
Purohit, A;Liu, S;Edwards, DS
作为我们对新型 Tc-99m 螯合系统兴趣的延续，我们合成了几种含吡啶的 HYNIC（6-肼烟酰胺）衍生物 (L1-L5)，并通过 NMR（H-1 和 C-13）和 LC-MS 进行了表征。 L1-L5 的 Tc-99m 复合物是通过 HYNIC 衍生物与 (99)mTCO(4)(-) 在过量 Tricine 和氯化亚锡存在下反应制备的。这项研究的结果表明，接头的附着位点对于大环 Tc-99m 复合物的形成至关重要。例如，L3 中的吡啶-N 无法与 Tc 键合，因为赖氨酸连接基连接到 4 位。当连接基位于2位时，L1形成大环配合物[Tc-99m(L1)(tricine)]，但放射化学纯度较低。如果连接基连接到吡啶环的 3 位，HYNIC 衍生物会以高产率 (>95%) 形成大环配合物 [Tc-99m(L)(tricine)]（L2、L4 和 L5）。 HPLC 数据表明大环复合物 [Tc-99m(L2)(tricine)] 在溶液中以四种异构体存在：两种非对映异构体和两种构象异构体。非对映异构体是由赖氨酸接头和 Tc 螯合物的手性组合产生的。用五亚甲基二胺连接体取代赖氨酸会产生具有两种构象异构体的大环复合物 [Tc-99m(L4)(tricine)]，这两种异构体在室温下可快速相互转化。将连接体从五亚甲基二胺更改为六亚甲基二胺并没有消除次要异构体；但次要异构体的百分比从 [Tc-99m(L4)(tricine)] 的大约 10% 减少到 [Tc-99m(L5)(tricine)] 的仅 6%。连接体长度是最小化次要异构体的重要参数。配合物 [Tc-19m(L)(tricine)]（L2、L4 和 L5）的 LC-MS 数据与其提议的成分完全一致。根据这些数据，得出的结论是，如果连接体连接到吡啶环的 3 位，则含吡啶的 HYNIC 衍生物具有作为小生物分子 Tc-99m 标记的双功能螯合剂的潜力。
As a continuation of our interest in novel Tc-99m chelating systems, several pyridine-containing HYNIC (6-hydrazinonicotinamide) derivatives (L1-L5) have been synthesized and characterized by NMR (H-1 and C-13) and LC-MS. Tc-99m complexes of L1-L5 were prepared by the reaction of the HYNIC derivative with (99)mTCO(4)(-) in the presence of excess tricine and stannous chloride. Results from this study show that the attachment site of the linker is critical for the formation of macrocyclic Tc-99m complexes. For example, the pyridine-N in L3 is not able to bond to the Tc, because the lysine linker is attached to the 4-position. When the linker is at the 2-position, L1 forms the macrocyclic complex [Tc-99m(L1)(tricine)], but the radiochemical purity is relatively low. If the linker is attached to the 3-position of the pyridine ring, the HYNIC derivatives form macrocyclic complexes [Tc-99m(L)(tricine)] (L2, L4, and L5) in high yield (>95%). The HPLC data suggest that the macrocyclic complex [Tc-99m(L2)(tricine)] exists in solution as four isomers: two diastereomers and two conformational isomers. Diastereomers are due to a combination of the chirality of the lysine linker and of the Tc chelate. Replacing lysine with a pentamethylenediamine linker results in the macrocyclic complex [Tc-99m(L4)(tricine)] with two conformational isomers, which interconvert rapidly at room temperature. Changing the linker from pentamethylenediamine to hexamethylenediamine did not eliminate the minor isomer; but the percentage of the minor isomer was reduced from similar to10% for [Tc-99m(L4)(tricine)] to only 6% for [Tc-99m(L5)(tricine)]. The linker length is an important parameter to minimize the minor isomer. LC-MS data of complexes [Tc-19m(L)(tricine)] (L2, L4, and L5) are completely consistent with their proposed compositions. On the basis of these data, it is concluded that pyridine-containing HYNIC derivatives have the potential as bifunctional chelators for Tc-99m-labeling of small biomolecules if the linker is attached to the 3-position of the pyridine ring.