Abstract
背景：菸鹼型乙醯膽鹼受體濃度的改變已被證實與許多神經退化性疾病有關；α7菸鹼型乙醯膽鹼受體密度在阿爾茲海默氏病患者腦中顯著減少。文獻報導GTS-21與α7菸鹼型乙醯膽鹼受體有中度的結合能力，但此化合物也與α4β2菸鹼型乙醯膽鹼受體有良好的結合。許多研究全圖政變GTS-21的官能基以改善對菸鹼型乙醯膽鹼受體的結合能力與特異性。本研究評估一種GTS-21衍生物，碘化GTS-21，與兩種菸鹼型乙醯膽鹼受體的結合能力與特異性，進而探討碘化GTS-21是否可作?中樞神經α7菸鹼型乙醯膽鹼受體造影劑的發展模型。方法：本研究合成GTS-21與碘化GTS-21，利用大鼠腦均質進行競爭性結合試驗，分別評估其對兩種菸鹼型乙醯膽鹼受體的特異性結合能力。幾種已知會與菸鹼型乙醯膽鹼受體結合的化合物同步進行試驗以?比較，並確認試驗方法的正確性。結果：碘化GTS-21結合α7與α4β4兩種菸鹼型乙醯膽鹼受體結合的抑制常數(K(下標 i))分別?＞1,000nM以及13nM。與GTS-21比較，碘化GTS-21對兩種菸鹼型乙醯膽鹼受體的結合能力未見提昇，但是碘化GTS-21對兩種菸鹼型乙醯膽鹼受體結合的選擇性顯然優於GTS-21。結論：碘化GTS-21不足以成?發展α7菸鹼型乙醯膽鹼受體新造影劑的模型。然而碘化GTS-21對兩種菸鹼型乙醯膽鹼受體結合的較佳選擇性值得進一步探討。
Background: Change of the nicotinic acetylcholine receptors (nAChR) concentration has been proven to be correlated with several neurodegenerative disorders. Subtype α7 nAChR density declines significantly in Alzheimer's disease patients. GTS-21 was reported to show moderate binding affinity to α7 nAChR. Although GTS-21 has capability to bind to α7 nAChR, however, it binds to α4β2 subtype as well. Several studies have attempted to improve the binding affinity and subtype selectivity of GTS-21 by modifying its functional groups. In the present study, we evaluated a novel derivative of GTS-21, iodo-GTS-21, for its binding affinity and selectivity to two subtypes of nAChR, and determine if iodo-GTS-21 can be a chemical model for developing radioiodinated tracer to image central α7 nAChR. Methods: GTS-21 and iodo-GTS-21 were synthesized for the study. In vitro competition binding assay was performed to estimate the binding affinity of iodo-GTS-21 using rat brain homogenates. Several known cold ligands were used as parallel comparison and methodology confirmation. Results: Iodo-GTS-21 did not increase the binding affinities, as compared to the parent compound GTS- 21, for either α7 nAChR or α4β2 subtype. However, iodo-GTS-21 possessed significant subtype selectivity than that of GTS-21, with K(subscript i) values>1,000 nM and 13 nM for α7 nAChR and α4β2 subtype, respectively. Conclusion: Iodo-GTS-21 may not be a model to develop new tracer for imaging α7 nAChR. The interesting profile that iodo-GTS-21 showed more selectivity than GTS-21 between bindings to two subtypes of nAChR may be worthwhile for further investigation.
Background: Change of the nicotinic acetylcholine receptors (nAChR) concentration has been proven to be correlated with several neurodegenerative disorders. Subtype α7 nAChR density declines significantly in Alzheimer's disease patients. GTS-21 was reported to show moderate binding affinity to α7 nAChR. Although GTS-21 has capability to bind to α7 nAChR, however, it binds to α4β2 subtype as well. Several studies have attempted to improve the binding affinity and subtype selectivity of GTS-21 by modifying its functional groups. In the present study, we evaluated a novel derivative of GTS-21, iodo-GTS-21, for its binding affinity and selectivity to two subtypes of nAChR, and determine if iodo-GTS-21 can be a chemical model for developing radioiodinated tracer to image central α7 nAChR. Methods: GTS-21 and iodo-GTS-21 were synthesized for the study. In vitro competition binding assay was performed to estimate the binding affinity of iodo-GTS-21 using rat brain homogenates. Several known cold ligands were used as parallel comparison and methodology confirmation. Results: Iodo-GTS-21 did not increase the binding affinities, as compared to the parent compound GTS- 21, for either α7 nAChR or α4β2 subtype. However, iodo-GTS-21 possessed significant subtype selectivity than that of GTS-21, with K(subscript i) values>1,000 nM and 13 nM for α7 nAChR and α4β2 subtype, respectively. Conclusion: Iodo-GTS-21 may not be a model to develop new tracer for imaging α7 nAChR. The interesting profile that iodo-GTS-21 showed more selectivity than GTS-21 between bindings to two subtypes of nAChR may be worthwhile for further investigation.
| Original language | American English |
|---|---|
| Pages (from-to) | 19-28 |
| Journal | 核子醫學雜誌 |
| Volume | 23 |
| Issue number | 1 |
| State | Published - 2010 |