Degrado T R, Zalutsky M R, Vaidyanathan G
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
Nucl Med Biol. 1995 Jan;22(1):1-12. doi: 10.1016/0969-8051(94)00084-w.
In order to clarify the uptake and retention mechanisms of radioiodinated meta-iodobenzylguanidine (MIBG) in heart, the kinetics of no-carrier-added [123I]MIBG were studied in the isolated working rat heart in interaction with pharmacologic agents. The tracer was administered in the perfusate as a 10-min pulse, followed by a 90-min washout period. Kinetic analysis of the externally monitored time-activity curves of control hearts showed avid uptake (Ki = 4.4 +/- 0.7 mL/min/g), and monoexponential clearance (ko = 0.0056 +/- 0.0017 l/min), indicating a distribution volume (Vd = Ki/ko) of 834 +/- 214 mL/g. Blocking experiments (n = 41) were performed with neuronal uptake (uptake-1) inhibitor desipramine (DMI; 50-100 nM) and the extraneuronal uptake (uptake-2) inhibitor N-(9-fluorenyl)-N-methyl-beta-chloroethylamine (SKF550; 0.4-0.8 microM). Uptake rate was 27% reduced (P < 0.05) by 50 nM DMI but not significantly affected by 0.4 microM SKF550. Distribution volume was 88% reduced (P < 0.0005) by 50 nM DMI and 28% reduced (P < 0.05) by 0.4 microM SKF550. In DMI-blocked hearts, uptake rate was dramatically decreased (-80%, P < 0.0005) by SKF550 (0.4 microM), indicating uptake-2 transport contributed predominantly to the extraneuronal uptake of the tracer. The slow uptake rate seen with concomitant inhibition of uptake-1 and uptake-2 was further decreased by addition of unlabeled MIBG (1-10 microM) in a concentration-dependent manner, yet unaffected by addition of the vesicular uptake inhibitor Ro 4-1284 (1 microM). Thus, the uptake rate of [123I]MIBG is primarily dependent on uptake-1 and uptake-2 activity. Other possible mechanisms of uptake such as passive diffusion in association with intracellular binding are significant only in conditions where uptake-1 and uptake-2 mechanisms are largely inhibited.
为了阐明放射性碘标记的间碘苄胍（MIBG）在心脏中的摄取和滞留机制，在离体工作大鼠心脏中，研究了无载体添加的[123I]MIBG与药理试剂相互作用时的动力学。示踪剂以10分钟脉冲的形式注入灌注液中，随后是90分钟的洗脱期。对对照心脏外部监测的时间-活性曲线进行动力学分析，结果显示摄取活跃（Ki = 4.4 +/- 0.7 mL/min/g），且清除呈单指数形式（ko = 0.0056 +/- 0.0017 l/min），表明分布容积（Vd = Ki/ko）为834 +/- 214 mL/g。采用神经元摄取（摄取-1）抑制剂地昔帕明（DMI；50 - 100 nM）和非神经元摄取（摄取-2）抑制剂N-（9-芴基）-N-甲基-β-氯乙胺（SKF550；0.4 - 0.8 microM）进行阻断实验（n = 41）。50 nM DMI使摄取率降低27%（P < 0.05），但0.4 microM SKF550对其无显著影响。50 nM DMI使分布容积降低88%（P < 0.0005），0.4 microM SKF550使其降低28%（P < 0.05）。在DMI阻断的心脏中，0.4 microM SKF550使摄取率显著降低（-80%，P < 0.0005），表明摄取-2转运主要促成了示踪剂的非神经元摄取。同时抑制摄取-1和摄取-2时出现的缓慢摄取率，通过添加未标记的MIBG（1 - 10 microM）以浓度依赖的方式进一步降低，但不受囊泡摄取抑制剂Ro 4-1284（1 microM）添加的影响。因此，[123I]MIBG的摄取率主要取决于摄取-1和摄取-2活性。其他可能的摄取机制，如与细胞内结合相关的被动扩散，仅在摄取-1和摄取-2机制受到很大抑制的情况下才显著。
