Radionuclide-labeled boron delivery agents

Abstract

<p indent="0mm">Boron neutron capture therapy (BNCT), as a duality radiotherapy method that combines neutron irradiation and boron-containing 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 ¹⁰B 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 non-invasive method and can provide the distribution of boron delivery agents <italic>in vivo</italic>. This article briefly describes the existing methods of measuring the boron concentration in BNCT, and the progress of radionuclide (¹⁸F, ¹²⁵I/¹³¹I, and ^99mTc) labeling methods of boron delivery agents (such as 4-borono-<italic>L</italic>-phenylalanine (BPA) and disodium mercaptoundecahydrododecaborate (BSH)) for radionuclide imaging. The common methods for labeling boron delivery agents with ¹⁸F are [¹⁸F]F₂ electrophilic substitution with a carrier, [¹⁸F]F⁻ nucleophilic substitution without a carrier, and isotope exchange. ¹⁸F-labeled BPA ([¹⁸F]-FBPA) was first prepared by the electrophilic substitution method. Research has shown that BPA and [¹⁸F]-FBPA had similar pharmacokinetics and biodistribution results. Although electrophilic fluorination can yield [¹⁸F]-FBPA with high radiochemical purity, the overall yield of the reaction is low, and the [¹⁸F]F₂ used in this process is relatively active and highly corrosive. The effect of stable F₂ gas carrier on the reaction cannot be ignored, which makes the specific activity of the product lower and the imaging quality worse. [¹⁸F]-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 [¹⁸F]-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. [¹⁸F]-FBY was stable <italic>in vitro</italic>, 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 <sc>10−30 min,</sc> 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 <italic>in vivo</italic> experimental data. [^99mTc(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. ^99mTc-labeled BPA (^99mTc-DMG-BPA) was also obtained. Biodistribution result showed that the complex was selectively enriched in the tumor and cleared faster in non-target 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.