Lever J R, Ilgìn N, Musachio J L, Scheffel U, Finley P A, Flesher J E, Natarajan T K, Wagner H N, Frost J J
Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Synapse. 1998 Jun;29(2):172-82. doi: 10.1002/(SICI)1098-2396(199806)29:2<172::AID-SYN8>3.0.CO;2-4.
The feasibility of imaging cerebral opioid receptors by single photon emission computed tomography (SPECT) has been established in baboon using a novel analog of diprenorphine (DPN) radiolabeled with iodine-123. The radioligand, [123I]-O-IA-DPN (C6-O-[123I]iodoallyl-DPN), was prepared in good yield (80%) with high radiochemical purity (>97%) and high specific radioactivity (>2,400 mCi/micromol). In ex vivo autoradiographic studies, with and without naltrexone blockade, [123I]-O-IA-DPN specifically labeled opioid receptors throughout the mouse brain. Nonmetabolized radioligand accounted for >90% of the signal observed in extracts of whole mouse brain. SPECT imaging trials showed that [123I]-O-IA-DPN selectively localized in regions of baboon brain known to have high densities of opioid receptors, such as striatum, thalamus, and temporal cortex. A much lower level of radioligand uptake and retention was noted for cerebellum, a region with few opioid binding sites. Pretreatment with naltrexone (6.5 pmol/kg) blocked [123I]-O-IA-DPN binding in all brain regions. Using naltrexone blockade to define the nonspecific component for a given region of interest, total to nonspecific binding ratios increased linearly (r > or = 0.98) over the SPECT study with maximal values for striatum (9.8), thalamus (7.1), and temporal cortex (6.9) reached at the last time point investigated (3.5 h). Specific binding for these regions, assessed as the difference between regional SPECT activity for the control and blocked states, proved irreversible over the observation period. By the end of the time course, specific [123I]-O-IA-DPN binding was >85% of total radioactivity in regions rich in opioid receptors and 62% of total radioactivity in cerebellum. The aggregate data are consistent with visualization of multiple opioid receptor types. Thus, [123I]-O-IA-DPN should prove useful for SPECT studies within the constraints imposed by a lack of innate selectivity for a single type of brain opioid receptor.
利用一种用碘 - 123标记的新型二丙诺啡（DPN）类似物，已在狒狒身上证实了通过单光子发射计算机断层扫描（SPECT）对脑阿片受体进行成像的可行性。放射性配体[123I] - O - IA - DPN（C6 - O - [123I]碘烯丙基 - DPN）的制备产率良好（80%），放射化学纯度高（>97%），比活度高（>2400 mCi/μmol）。在离体放射自显影研究中，无论有无纳曲酮阻断，[123I] - O - IA - DPN都能特异性标记整个小鼠脑内的阿片受体。未代谢的放射性配体占全小鼠脑提取物中观察到信号的>90%。SPECT成像试验表明，[123I] - O - IA - DPN选择性地定位于狒狒脑内已知阿片受体密度高的区域，如纹状体、丘脑和颞叶皮质。而小脑（阿片结合位点较少的区域）对放射性配体的摄取和保留水平要低得多。用纳曲酮（6.5 pmol/kg）预处理可阻断所有脑区的[123I] - O - IA - DPN结合。利用纳曲酮阻断来确定给定感兴趣区域的非特异性成分，在SPECT研究中，总结合与非特异性结合比率呈线性增加（r≥0.98），在研究的最后时间点（3.5小时），纹状体（9.8）、丘脑（7.1）和颞叶皮质（6.9）达到最大值。这些区域的特异性结合，通过对照和阻断状态下区域SPECT活性的差异来评估，在观察期内被证明是不可逆的。在时间进程结束时，富含阿片受体区域的特异性[123I] - O - IA - DPN结合占总放射性的>85%，小脑占总放射性的62%。总体数据与多种阿片受体类型的可视化一致。因此，在对单一类型脑阿片受体缺乏固有选择性的限制条件下，[123I] - O - IA - DPN应被证明对SPECT研究有用。
