Herth Matthias M, Kramer Vasko, Piel Markus, Palner Mikael, Riss Patrick J, Knudsen Gitte M, Rösch Frank
Institute of Nuclear Chemistry Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.
Bioorg Med Chem. 2009 Apr 15;17(8):2989-3002. doi: 10.1016/j.bmc.2009.03.021. Epub 2009 Mar 14.
Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to improve molecular imaging properties of [(11)C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K(i)-values in the nanomolar range towards the 5-HT(2A) receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic (18)F-tracers for visualization of the 5-HT(2A) receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K(i) values between 30 and 120 nM. All promising compounds show logP values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of (18)F-labelled analogues for 5-HT(2A) imaging with PET.
放射性标记的哌啶衍生物，如[(11)C]MDL 100907和[(18)F]阿坦色林，在诊断血清素能神经传递功能障碍方面发挥了重要作用。合成了多种可用(18)F-氟标记的新型哌啶MDL 100907衍生物，以改善[(11)C]MDL 100907的分子成像特性。测定了它们对多种神经受体的体外亲和力及其亲脂性，并与临床使用的参考化合物MDL 100907和阿坦色林进行了比较。新型化合物MA-1(53)和(R)-MH.MZ(56)对5-HT(2A)受体的K(i)值在纳摩尔范围内，与其他5-HT受体亚型或受体的结合不显著。有趣的是，化合物MA-1(53)、MH.MZ(55)和(R)-MH.MZ(56)提供了与MDL 100907相似的受体选择性谱。这些化合物可能是用于可视化5-HT(2A)受体状态的更优拮抗(18)F示踪剂。合成了中等亲和力的化合物(VK-1(32)、(51)、(52)、(54))，其K(i)值在30至120 nM之间。所有有前景的化合物的logP值在2至3之间，即在已确立的放射性示踪剂阿坦色林和MDL 100907的范围内。因此，新型化合物MA-1(53)和(R)-MH.MZ(56)似乎是用于PET 5-HT(2A)成像的有前景的高亲和力和选择性(18)F标记类似物示踪剂。
