The Korean Journal of Nuclear Medicine (대한핵의학회지)

The Korean Society of Nuclear Medicine (대한핵의학회)
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Synthesis and Evaluation of $2-[^{18}F]Fluoro-A85380$, a Radioligand for ${\alpha}_4{\beta}_2$ Nicotinic Acetylcholine Receptor Imaging

${\alpha}_4{\beta}_2$ 니코틴성 아세틸콜린 수용체 영상 방사성리간드 $2-[^{18}F]fluoro-A85380$의 합성 및 평가

  • Ryu, Eun-Kyoung (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Choe, Yearn-Seong (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Sang-Eun (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Hwang, Sae-Hwan (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Paik, Jin-Young (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Choi, Yong (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Kyung-Han (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Byung-Tae (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • 류은경 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 최연성 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 김상은 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 황세환 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 백진영 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 최용 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 이경환 (성균관대학교 의과대학 핵의학과, 생명의공학과) ;
  • 김병태 (성균관대학교 의과대학 핵의학과, 생명의공학과)
  • Published : 2002.08.30
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Abstract

Purpose: Nicotinic acetylcholine receptors (nAChRs), which mediate excitatory neurotransmission, are known to participate in various neurophysiological functions. Severe losses of nAChRs have been noted in Alzheimer's and Parkinson's diseases. Therefore, noninvasive and quantitative imaging of nAChRs would offer a better understanding on the function of these receptors. In this study, $2-[^{18}F]fluoro-A85380\;([^{18}F]1)$, an ${\alpha}_4{\beta}_2$ nAChRs radioligand, was prepared using one HPLC purification and evaluated in mouse brain, and the results were compared with those in the literature. Materials and Methods: $[^{18}F]1$ was prepared by $[^{18}F]$fluorination of the iodo precursor followed by acidic deprotection and then purified by HPLC. Tissue distribution studies were performed in mouse brain at the indicated time points and the result was expressed as %ID/g. Inhibition studies were also carried out with pretreatment of various ligands. Results: One HPLC purification method gave the desired product in 15-20% radiochemical yield and with high specific activity ($38-55GBq/{\mu}mol$). Tissue distribution studies showed that $[^{18}F]1$ specifically labeled nAChRs in mouse brain with a high thalamus to cerebellum uptake ratio (13.8 at 90 min). Inhibition studios demonstrated selective binding of $[^{18}F]1$ to nAChRs, blocking the uptake of the $[^{18}F]1$ in nAChR-rich legions by selective ligands such as cytisine and nicotine which are well-known nAChRs agonists. Conclusion: This study demonstrated that the $[^{18}F]1$ produced by the method using one HPLC purification gave the results similar to those reported in the literature. Therefore, this synthetic method can be readily applied to the routine preparation of $[^{18}F]1$, a PET radioligand for ${\alpha}_4{\beta}_2$ nAChRs imaging.

목적: nAChRs의 ${\alpha}_4{\beta}_2$ 아형에 높은 친화력과 선택성을 갖는 리간드인 $2-[^{18}F]fluoro-A85380([^{18}F]1)$의 효율적인 합성과정을 연구하여 방사화학적 수율, 비방사능, 합성시간, 마우스에서 생물학적 평가의 측면에서 문헌에 보고된 결과들과 비교 평가하였다. 대상 밀 방법: 전구물질의 I을 $^{18}F$으로 치환한 다음 중간물질을 분리하지 않고 trifluoroacetic acid를 가하여 보호기를 제거하였다. 반응혼합액을 HPLC로 정제하여 얻은 방사성리간드($[^{18}F]1$)를 마우스의 꼬리 정맥에 주사한 후에 정해진 시간별로 6개의 뇌조직 (소뇌, 해마, 선조체, 피질, 시상, 상구)을 분리하여 무게를 측정하고 감마계수기를 이용하여 방사능을 측정하였다. 또한 스코폴라민, 메카밀아민, 사이티신, (-)니코틴, 비방사성 표준물질(1)을 마우스에 피하주사로 투여하고 방사성리간드 주사 후 90분에 6개의 뇌조직을 분리하여 무게 및 방사능을 측정하여 %ID/g으로 나타내었다. 이 결과를 대조군과 비교하였다. 결과: $^{18}F$ 표지 후 중간물질을 분리하지 않고 한 번의 HPLC 정제를 통하여 $[^{18}F]1$을 15-20%의 방사화학적 수율로 합성하였으며 비방사능은 $38-55GBq/{\mu}mol$이었다. 이 방사성리간드의 마우스 뇌에서의 분포결과, 주사 후 30분에 nAChRs가 풍부하게 분포되어 있는 시상과 상구에서 가장 많은 섭취를 보였고 이 수용체가 부족한 소뇌에는 거의 섭취되지 않았다. 여러 리간드를 사용하여 $[^{18}F]1$ 섭취의 억제효과를 본 실험에서는 nAChRs 작용제인 사이티신 및 (-)니코틴의 전처리가 시상 및 상구에서 $[^{18}F]1$의 섭취를 70-90% 감소시켰으며, 소뇌에서는 억제효과가 관측되지 않았다. 결론: 이 연구에서 사용된 방법으로 얻어진 $[^{18}F]1$의 방사화학적 수율, 비방사능, 뇌에서의 분포 그리고 여러 리간드에 의한 억제효과는 문헌에 보고된 결과와 유사하였다. 따라서 중간물질을 분리하지 않고 한번의 HPLC를 사용하는 방법이 $[^{18}F]1$의 상용생산에 유용하게 사용될 수 있을 것으로 기대한다.

Keywords

References

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