肽类树状大分子磁共振成像探针的合成与功能化

FUNCTIONAL PEPTIDE DENDRIMERS AS MAGNETIC RESONANCE IMAGING PROBES

通过优化设计,合成了高产率的DTPA和DOTA配体.通过液相发散法制得第三代肽类树状大分子,其外围氨基分别用两种不同保护基团保护,且两种保护基团的个数比精确控制为18∶6,通过选择性脱去保护基团,其中一种氨基与DTPA、DOTA偶联,或与丁二酸酐反应,并与金属离子钆螯合,制得G3-18Gd-DTPA-6COOH,G3-18Gd-DOTA-6COOH两种肽类树枝状磁共振成像(MRI)分子探针.所合成化合物的结构通过1 H-NMR,13 C-NMR,ESI-TOF-MS表征.水相弛豫研究表明,2种肽类树状大分子MRI分子探针在水相中表现出了优良的弛豫效能,最高达12.53 L.mmol-1.s-1,是临床试剂Gd-DTPA的3倍.

Novel synthetic strategies and methods have been developed for the synthesis of magnetic resonance imaging（MRI） contrasts.DTPA ligand,DOTA ligand and peptide dendrimer-based MRI probes with controllable structure were prepared.The third generation L-lysine dendrimers were synthesized by solution-phase synthesis method and convergent approach,and the primary amine groups on the surface of the dendrimers were protected by different groups.The ratio between Boc group and Cbz groups was 18 ∶ 6.The peptide dendrimers were selectively deprotected and reacted with DTPA or DOTA derivates in the presence of succinic anhydride to yield controllable ‘peripheral’functional dendrimer-based MRI contrast agents.The new compounds were confirmed by NMR,ESI-TOF MS and so on.The peptide dendrimer-based MRI probes possessing highly controlled structures and single molecular weight were tested at 1.5 T magnetic field in a clinical MRI scanner,and a 3-fold increase in T1 relaxivity to 12.53 Gd mmol.L-1.s-1 was noticed comparing to that of the clinical agent Gd-DTPA.The successful approach to synthesize the controllable dendrimer-based agent and the high T1 relaxivity of the agent opened an opportunity for the design of multifunctional dendritic contrasts for MRI.