Pirmettis I C, Papadopoulos M S, Chiotellis E
Institute of Radioisotopes-Radiodiagnostic Products, NCSR, Demokritos, Aghia Paraskevi, Athens, Greece.
J Med Chem. 1997 Aug 1;40(16):2539-46. doi: 10.1021/jm960273y.
A series of neutral, lipophilic 99mTc mixed-ligand complexes of the general formula 99mTcOL1L2, where L1H2 is an N-substituted bis-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)2], [SNS], and L2H is a monodentate thiol (RSH), [S], has been synthesized and evaluated in rodents for potential use in brain blood flow imaging. The complexes were prepared by ligand exchange reaction using 99mTc(V)O-glucoheptonate as precursor and equimolar quantities of the two ligands. In all cases the syn isomer was formed in a high yield, whereas the anti isomer was not always present. The formation of two isomeric complexes-syn and anti-was expected, since the N-substituent (X-CH2CH2N) can assume syn or anti configuration with respect to the 99mTcO3+ core during complexation. One anti and all syn isomers were isolated by HPLC. Their identity was confirmed by comparative HPLC studies with the analogous 99Tc complexes of established structure. In vivo distribution, in particular brain uptake and retention, greatly depended on the type of either tridentate (L1H2) or monodentate (L2H) ligand. All 99mTc complexes showed significant brain uptake in mice (0.78-4.35% injected dose per organ at 5 min postinjection). This initial uptake remained nearly constant for at least 30 min for most of the complexes. Structure-activity relationships of novel 99mTc(V)O SNS/S complexes in mice are reported and discussed. Selected complexes were further studied in rats. High brain uptake, comparable to that of 99mTc-d,l-HMPAO, and sufficient retention 60 min postinjection were provided with complex 18 [X = (C2H5)2N and R = p-CH3OC6H4CH2].
合成了一系列通式为99mTcOL1L2的中性亲脂性99mTc混合配体配合物，其中L1H2为N-取代双（2-巯基乙基）胺[X-CH2CH2N(CH2CH2SH)2]，即[SNS]，L2H为单齿硫醇（RSH），即[S]，并在啮齿动物中进行了评估，以探讨其在脑血流成像中的潜在应用。这些配合物通过配体交换反应制备，以99mTc(V)O-葡庚糖酸盐为前体，加入等摩尔量的两种配体。在所有情况下，顺式异构体均以高产率形成，而反式异构体并非总是存在。由于在络合过程中N-取代基（X-CH2CH2N）相对于99mTcO3+核心可以呈现顺式或反式构型，因此预期会形成两种异构体配合物——顺式和反式。通过高效液相色谱法分离出一种反式异构体和所有顺式异构体。通过与结构已确定的类似99Tc配合物进行比较高效液相色谱研究，证实了它们的身份。体内分布，特别是脑摄取和滞留，在很大程度上取决于三齿（L1H2）或单齿（L2H）配体的类型。所有99mTc配合物在小鼠中均表现出显著的脑摄取（注射后5分钟时每个器官摄取0.78-4.35%注射剂量）。对于大多数配合物，这种初始摄取至少在30分钟内几乎保持恒定。报道并讨论了新型99mTc(V)O SNS/S配合物在小鼠中的构效关系。对选定的配合物在大鼠中进行了进一步研究。配合物18[X = (C2H5)2N且R = p-CH3OC6H4CH2]具有与99mTc-d,l-HMPAO相当的高脑摄取，并且在注射后60分钟有足够的滞留。
