Heimbold I, Drews A, Kretzschmar M, Varnäs K, Hall H, Halldin C, Syhre R, Kraus W, Pietzsch H-J, Seifert S, Brust P, Johannsen B
Forschungszentrum Rossendorf, Institut für Bioanorganische und Radiopharmazeutische Chemie, PF 510119, D-01314 Dresden, Germany.
Nucl Med Biol. 2002 May;29(4):375-87. doi: 10.1016/s0969-8051(01)00313-4.
This paper reports the synthesis, biological evaluation, in vitro and ex vivo autoradiography of the first Tc-99m ligand with subnanomolar affinity for the 5-HT(1A) receptor and a remarkably high affinity for the alpha1-adrenergic receptor. The neutral "3+1" mixed-ligand complex combines 4-(6-mercaptohexyl)-1-(2-methoxyphenyl)piperazine as monodentate and 3-(N-methyl)azapentane-1,5-dithiol as tridentate unit with oxotechnetium(V). The analogous rhenium complex was synthesized for complete structural characterization and used in receptor binding assays. In competition experiments both complexes display subnanomolar affinity for the 5-HT(1A) receptor (IC(50)0.24 nM for Re, 0.13 nM for Tc) but also very high affinities for the alpha1-adrenergic receptor (IC(50) 0.05 nM for Re, 0.03 nM for Tc). Biodistribution studies show a brain uptake in rat of 0.22% ID five minutes post injection. In vitro autoradiographic studies in rat brain and postmortem human brain indicate accumulation of the Tc-99m complex in brain areas which are rich in 5-HT(1A) receptors or in alpha1-adrenergic receptors. This in vitro enrichment can be blocked respectively by the 5-HT(1A) receptor agonist 8-OH-DPAT or by prazosin hydrochloride, an alpha1-adrenergic receptor antagonist. Ex vivo autoradiographic studies in rats show a slight accumulation of the Tc-99m complex in 5-HT(1A) receptor-rich areas of the brain, which could not be blocked, as well as in regions rich in alpha1-adrenergic receptors, which could be blocked by prazosin hydrochloride.
本文报道了首个对5-HT(1A)受体具有亚纳摩尔亲和力且对α1-肾上腺素能受体具有极高亲和力的Tc-99m配体的合成、生物学评价、体外和离体放射自显影研究。中性的“3 + 1”混合配体络合物将4-(6-巯基己基)-1-(2-甲氧基苯基)哌嗪作为单齿配体，3-(N-甲基)氮杂戊烷-1,5-二硫醇作为三齿配体单元与锝(V)氧基结合。合成了类似的铼络合物用于完整的结构表征，并用于受体结合测定。在竞争实验中，两种络合物对5-HT(1A)受体均表现出亚纳摩尔亲和力（铼的IC(50)为0.24 nM，锝的IC(50)为0.13 nM），但对α1-肾上腺素能受体也具有非常高的亲和力（铼的IC(50)为0.05 nM，锝的IC(50)为0.03 nM）。生物分布研究表明，注射后5分钟大鼠脑摄取率为0.22% ID。大鼠脑和人死后脑组织的体外放射自显影研究表明，Tc-99m络合物在富含5-HT(1A)受体或α1-肾上腺素能受体的脑区中积累。这种体外富集可分别被5-HT(1A)受体激动剂8-OH-DPAT或α1-肾上腺素能受体拮抗剂盐酸哌唑嗪阻断。大鼠的离体放射自显影研究表明，Tc-99m络合物在富含5-HT(1A)受体的脑区有轻微积累，这种积累无法被阻断，而在富含α1-肾上腺素能受体的区域有积累，可被盐酸哌唑嗪阻断。
