当前位置: X-MOL 学术Bioorg. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Synthesis and evaluation of new mixed “2 + 1” Re, 99mTc and 186Re tricarbonyl dithiocarbamate complexes with different monodentate ligands
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2021-08-19 , DOI: 10.1016/j.bmc.2021.116373
Antonio Shegani 1 , Myrto Ischyropoulou 2 , Ioanna Roupa 2 , Christos Kiritsis 2 , Konstantina Makrypidi 2 , Afroditi Papasavva 2 , Catherine Raptopoulou 3 , Vassilis Psycharis 3 , Heather M Hennkens 4 , Maria Pelecanou 5 , Minas S Papadopoulos 2 , Ioannis Pirmettis 2
Affiliation  

A series of “2 + 1” mixed ligand tricarbonyl complexes of the general formula fac-[Re/99mTc/186Re(CO)3(DDTC)(L)] containing diethyldithiocarbamate (DDTC) as a monoanionic bidentate ligand and a series of monodentate ligands L was synthesized, characterized and evaluated. The impact of ligand L on the radiochemical yield (RCY) and biodistribution of the final compounds was also investigated. DDTC and the appropriate L ligand [cyclohexyl isocyanide (cisc), tert-butyl isocyanide (tbi), triphenylphosphine (PPh3), methyldiphenylphosphine (PPh2Me), triphenylarsine (AsPh3), imidazole (im), and 4-aminopyridine (4AP)] readily reacted in equimolar amounts with the [Et4N]2[Re(CO)3Br3] precursor to afford fac-[Re(CO)3(DDTC)(cisc)], Re1, fac-[Re(CO)3(DDTC)(tbi)], Re2, fac-[Re(CO)3(DDTC)(PPh3)], Re3, fac-[Re(CO)3(DDTC)(PPh2Me)], Re4, fac-[Re(CO)3(DDTC)(AsPh3)], Re5, fac-[Re(CO)3(DDTC)(im)], Re6 and fac-[Re(CO)3(DDTC)(4AP)], Re7, complexes in high yields (>80%). All Re complexes were fully characterized by IR, NMR, and in addition Re4, Re5, and Re7 with X-ray crystallography. Analogous reactions as performed with Re were subsequently explored on the 99mTc and 186Re-tracer levels using the corresponding fac-[99mTc/186Re(CO)3(H2O)3]+ precursor. Complexes 99mTc199mTc5, 186Re1 and 186Re3 were obtained in high radiochemical yield (>91%), while the complexes 99mTc6, 99mTc7 and 186Re7 formed with radiochemical yields of 55%, 28%, and 75%, respectively. The 99mTc and 186Re-complexes were characterized by comparative HPLC analysis using the analogous Re complexes. During histidine and cysteine challenge experiments at 37 °C through 6 h, complexes 99mTc199mTc5 remained > 92% stable, while complexes 99mTc6 and 99mTc7 remained only 8% stable through 3 h. Similar studies for 186Re-complexes showed that 186Re1 and 186Re3 remained > 95% stable for up to 48 h, while 186Re7 had decreased to 7% after 3 h. LogD7.4 data of 99mTc199mTc5, 186Re1, and 186Re3 complexes, which ranged from 2.59 to 3.39, suggested high lipophilicity. Biodistribution studies in healthy Swiss albino mice showed hepatobiliary excretion for 99mTc1, 99mTc2, and 99mTc4, fast blood clearance for 99mTc4, while high liver uptake and retention for 99mTc3 and 99mTc5 were measured. Moreover, 99mTc2 showed high accumulation in the lungs with sustained retention (52.80% ID/g at 4 h p.i.) and significant brain uptake at 2 min p.i. (1.89% ID/g). The study showed the great influence of monodentate ligand in the synthesis and biodistribution of the mixed ligand complexes.



中文翻译:

具有不同单齿配体的新型混合“2+1”Re、99mTc和186Re三羰基二硫代氨基甲酸酯配合物的合成与评价

一系列“2 + 1”混合配体三羰基配合物,通式为fac -[Re/ 99m Tc/ 186 Re(CO) 3 (DDTC)(L)],含有二乙基二硫代氨基甲酸酯(DDTC)作为单阴离子双齿配体和一系列合成、表征和评估了单齿配体 L。还研究了配体 L 对最终化合物的放射化学产率 (RCY) 和生物分布的影响。DDTC 和合适的 L 配体 [环己基异氰化物 (cisc)、丁基异氰化物 (tbi)、三苯膦 (PPh 3 )、甲基二苯膦 (PPh 2 Me)、三苯胂 (AsPh 3)、咪唑 (im) 和 4-氨基吡啶 (4AP)] 容易以等摩尔量与 [Et 4 N] 2 [Re(CO) 3 Br 3 ] 前体反应得到fac -[Re(CO) 3 (DDTC )(cisc)], Re1 , fac -[Re(CO) 3 (DDTC)(tbi)], Re2 , fac -[Re(CO) 3 (DDTC)(PPh 3 )], Re3 , fac -[Re( CO) 3 (DDTC)(PPh 2 Me)], Re4 , fac -[Re(CO) 3 (DDTC)(AsPh 3 )],Re5fac -[Re(CO) 3 (DDTC)(im)]、Re6fac -[Re(CO) 3 (DDTC)(4AP)]、Re7以高产率 (>80%) 配合。所有 Re 配合物均通过 IR、NMR 以及Re4Re5Re7与 X 射线晶体学进行了充分表征。随后使用相应的fac -[ 99m Tc/ 186 Re(CO) 3 (H 2 O) 3 ] +在99m Tc 和186 Re-tracer 水平上探索了与 Re 进行的类似反应前体。复合物99m Tc199m Tc5 , 186 Re1186 Re3的放射化学收率高(>91%),而复合物99m Tc6 , 99m Tc7186 Re7的放射化学收率分别为 55%, 28% 和 75%,分别。99m Tc 和186 Re-配合物通过使用类似 Re 配合物的比较 HPLC 分析来表征。在 37 °C 至 6 小时的组氨酸和半胱氨酸挑战实验期间,复合99m Tc199m Tc5保持 > 92% 稳定,而复合物99m Tc699m Tc7在 3 小时内仅保持 8% 稳定。对186 Re-complexes的类似研究表明,186 Re1186 Re3在长达 48 小时内保持 > 95% 的稳定性,而186 Re7在 3 小时后下降到 7%。99m Tc199m Tc5、186 Re1186 Re3LogD 7.4数据_复合物的范围从 2.59 到 3.39,表明具有高亲脂性。在健康的瑞士白化病小鼠中进行的生物分布研究表明,99m Tc1、99m Tc299m Tc4可在肝胆中排泄, 99m Tc4的血液清除速度快,而99m Tc399m Tc5的肝脏摄取量和滞留量也较高。此外,99m Tc2显示在肺中的高积累并持续滞留(4 小时后 52.80% ID/g)和 2 分钟后显着的脑摄取(1.89% ID/g)。研究表明单齿配体对混合配体配合物的合成和生物分布有很大影响。

更新日期:2021-08-29
down
wechat
bug