放射性核素标记的硼携带剂

Radionuclide-labeled boron delivery agents

硼中子俘获治疗(boron neutron capture therapy,BNCT)面临的严峻挑战之一就是缺少精确的剂量测算体系.核素成像是一种非侵入且能提供体内硼携带剂分布的技术.本文介绍了核素成像中硼携带剂的放射性核素标记方法的研究进展.^(18)F标记的4-硼-L-苯丙氨酸(^(18)F-BPA)最早是由亲电取代法制备的,也是研究最多的一种放射性标记的硼携带剂.研究表明,BPA和^(18)F-BPA在正常组织/器官中具有相似的药代动力学.[^(18)F]-FBPA也可以从高价碘叶立德前体进行亲核氟化反应得到,该方法标记时间较短,比活度高.作为靶向肿瘤的正电子发射断层扫描显像剂,^(18)F标记的含硼酪氨酸衍生物([^(18)F]-FBY)可以通过同位素交换法非常高效地制备.利用亲电碘化反应可以对巢式和闭式的碳硼烷进行放射性碘(^(131)I和^(125)I)的标记.利用同位素交换反应也可以实现放射性碘标记碳硼烷衍生物,但是标记产物比活度较低.在水溶液中可以制备[^(99m)Tc(CO)_(3)]^(+)标记的碳硼烷,以及^(99m)Tc标记的BPA.总的来说,放射性核素标记的硼携带剂还处于起步阶段,在后期发展中需要考虑多方面因素,主要包括放射性核素选择、放射性核素标记位置的选择、标记方法的选择、标记化合物稳定性及其影响因素、给药方式和给药时间等.

Boron neutron capture therapy (BNCT),as a duality radiotherapy method that combines neutron irradiation and boroncontaining targeted drugs,has attracted much attention.The successful BNCT mainly depends on three aspects:(1) Ideal boron delivery agents,(2) reasonable neutron source,and (3) accurate dose measurement system.Therefore,it is very important to realize the rapid and accurate measurement of the boron concentration in the patient.There are a variety of methods that have been used to measure the boron concentration.The indirect measurement method often requires the blood/tissue sample,so it can only give an estimate of the boron concentration at a single time point and sampling point,but cannot accurately describe the biodistribution of ^(10)B concentration and the boron concentration ratio between target and non-target tissues.The sensitivity of magnetic resonance imaging (MRI) is poor,while radionuclide imaging is a noninvasive method and can provide the distribution of boron delivery agents in vivo.This article briefly describes the existing methods of measuring the boron concentration in BNCT,and the progress of radionuclide (^(18)F,^(125)I/^(131)I,and^(99m)Tc) labeling methods of boron delivery agents (such as 4-borono-L-phenylalanine (BPA) and disodium mercaptoundecahydrododecaborate (BSH)) for radionuclide imaging.The common methods for labeling boron delivery agents with^(18)F are[^(18)F]F_(2) electrophilic substitution with a carrier,[^(18)F]F^(-) nucleophilic substitution without a carrier,and isotope exchange.^(18)F-labeled BPA ([^(18)F]-FBPA) was first prepared by the electrophilic substitution method.Research has shown that BPA and[^(18)F]-FBPA had similar pharmacokinetics and biodistribution results.Although electrophilic fluorination can yield[^(18)F]-FBPAwith high radiochemical purity,the overall yield of the reaction is low,and the[^(18)F]F_(2) used in this process is relatively active and highly corrosive.The effect of stable F;gas carrier on the reaction cannot be ignored,which makes the specific activity of the product lower and the imaging quality worse.[^(18)F]-FBPA can also be obtained from the high-value iodine-ylide precursors by nucleophilic fluoridation reaction.This method has a short labeling time and high specific activity.Fluoroboronotyrosine (FBY),a metabolically stable boron-tyrosine derivative,can also be used as a boron delivery agent,and[^(18)F]-FBY has been prepared easily and quickly with a high radiochemical yield and radiochemical purity by isotope exchange as a tumor-targeting PET imaging agent.[^(18)F]-FBY was stable in vitro,and it had the highest uptake in tumor and low uptake in normal tissue in mice with cutaneous melanoma grafts.The boron delivery agents of nested and closed carboranes can be radioiodine-labeled using N-chlorosuccinimide (NCS)as oxidant by electrophile iodization reaction at room temperature for 10-30 min,the radiochemical yield was basically above 70%.Radioiodine-labeled carborane derivatives can also be achieved using isotope exchange reactions under catalytic conditions,but they had a lower specific activity.Unfortunately,as for the radioiodine-labeled carborane compounds,most studies only described the labeling method without further in vivo experimental data.[^(99m)Tc(CO)_(3)]^(+)-labeled carboranes have been prepared in aqueous solution in the presence of potassium fluoride under mild conditions,but no further biological experiments were conducted.^(99m)Tc-labeled BPA (^(99m)Tc-DMG-BPA) was also obtained.Biodistribution result showed that the complex was selectively enriched in the tumor and cleared faster in nontarget tissues,but unfortunately,its uptake in liver and kidney was relatively high,which may affect tumor imaging.In conclusion,radionuclide-labeled boron delivery agents are still in their infancy,and there are many aspects that need to be considered,such as radionuclide (half-life and decay type),radionuclide labeling position (influence on the biological activity of the boron delivery agent),labeling method (nucleophilic substitution,electrophilic substitution,isotope exchange,and coordination chemistry),the stability of the labeled compound and its influencing factors,and the administration method and time,etc.