Monooxorhenium(V) complexes with 222-N₂S₂ MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation

详细信息    查看全文

• 作者：Dustin Wayne Demoin^a ; ^d ; Ashley N. Dame^a ; ^d ; William D. Minard^a ; Fabio Gallazzi^b ; Gary L. Seickman^d ; Tammy L. Rold^c ; ^d ; Nicole Bernskoetter^d ; Michael E. Fassbender^e ; Timothy J. Hoffman^a ; ^c ; ^d ; Carol A. Deakyne^a ; Silvia S. Jurisson^a ; ^{jurissons@missouri.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Rhenium-186 ; Rhenium(V) ; MAMA ligands ; Quantum chemical studies ; Bombesin ; Radiotherapy
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：43
• 期：12
• 页码：802-811
• 全文大小：1012 K

文摘

Targeted radiotherapy using the bifunctional chelate approach with ^186/188Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine–monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications.

Methods

A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7–14)NH₂) were synthesized, complexed with rhenium, radiolabeled with ^99mTc and ¹⁸⁶Re (carrier added and no carrier added), and evaluated in initial biological distribution studies.

Results

An IC₅₀ value of 2.0 ± 0.7 nM for ^natReO-222-MAMA(N-6-Ahx-BBN(7–14)NH₂) compared to [¹²⁵I]-Tyr⁴-BBN(NH₂) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added ^99mTc-222-N₂S₂(N-6-Ahx-BBN(7–14)NH₂) complex showed little gastric uptake and blockable pancreatic uptake in normal mice.

Conclusions

The ¹⁸⁶ReO-222-N₂S₂(N-6-Ahx-BBN(7–14)NH₂) complex showed stability in biological media, which indicates that the 222-N₂S₂ chelator is appropriate for chelating ^186/188Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N₂S₂(N-6-Ahx-BBN(7–14)NH₂) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The ^99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.