Johannsen B, Berger R, Brust P, Pietzsch H J, Scheunemann M, Seifert S, Spies H, Syhre R
Institut für Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf e.V., Dresden, Germany.
Eur J Nucl Med. 1997 Mar;24(3):316-9. doi: 10.1007/BF01728770.
Low brain uptake is a generally accepted problem in developing technetium-99m brain receptor imaging agents. For a class of potential 5-HT2A receptor-binding agents we tried to improve the original low brain uptake of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pKa value leads to ionization of the molecule at blood pH, the pKa value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pKa value from 10.0 to 8.3 and dramatically increases the brain uptake to 1.3% ID at 5 min. The direct relationship between brain uptake and apparent pKa cannot be simply explained by the increase in the pKa-governed proportion of the neutral species.
在开发锝-99m脑受体显像剂的过程中，脑摄取率低是一个公认的问题。对于一类潜在的5-HT2A受体结合剂，我们试图通过改变分子的亲脂性来改善大鼠静脉注射后5分钟时原始脑摄取率低至0.4%注射剂量（ID）的情况。由于存在可质子化的氮，根据pKa值，该氮会导致分子在血液pH值下发生电离，因此pKa值被认为是最适合调节亲脂性的参数。在五个候选分子中插入醚氧可使表观pKa值从10.0降至8.3，并在5分钟时将脑摄取率显著提高至1.3%ID。脑摄取率与表观pKa之间的直接关系不能简单地用中性物种中由pKa控制的比例增加来解释。
