合成及评价 18F 标记的苄胍类似物作为靶向人去甲肾上腺素转运体的探针。
Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter.
机构信息
Department of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, 10065, USA.
出版信息
Eur J Nucl Med Mol Imaging. 2014 Feb;41(2):322-32. doi: 10.1007/s00259-013-2558-9. Epub 2013 Oct 31.
PURPOSE
Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts.
METHODS
[(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG.
RESULTS
The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7%) than meta-isomer (21 ± 5%). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2% (n = 12) for [(18)F]MFBG and 41 ± 12% (n = 5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs.
CONCLUSION
[(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG.
目的
碘-131 和碘-123 标记的间碘苄胍（MIBG）已广泛用于靶向成像去甲肾上腺素转运体（NET）的临床。人 NET（hNET）基因已成功用 124I-MIBG 正电子发射断层扫描（PET）在注射后 24 小时以上的时间点进行成像。18F 标记的 MIBG 类似物可能是在 8 小时内成像 hNET 表达的理想选择。我们开发了改进的方法来合成已知的 MIBG 类似物，[18F]MFBG 和[18F]PFBG，并在 hNET 报告基因转导的 C6 大鼠神经胶质瘤细胞和异种移植瘤中进行了评估。
方法
手动使用三步合成方案合成[18F]MFBG 和[18F]PFBG。使用野生型和 hNET 报告基因转导的 C6 大鼠神经胶质瘤细胞和异种移植瘤来比较评估（123）I/（124）I-MIBG 与[18F]标记类似物的放射性配体。
结果
苯甲腈的氟代效率主要取决于三甲铵基团的位置。对位异构体的产率（75±7%）高于间位异构体（21±5%）。[18F]氟苄基胺与 1H-吡唑-1-甲脒的反应比与 2-甲基-2-硫代尿嘧啶的反应更有效。（18F）MFBG 的总体放射化学产率（衰变校正）分别为 11±2%（n=12）和 41±12%（n=5）。[18F]MFBG 和[18F]PFBG 在 C6-hNET 细胞中的特异性摄取相似，但比[123I]/[124I]MIBG 低 4 倍。然而，在 1 小时时，[18F]MFBG 在 C6-hNET 肿瘤中的积累是[18F]PFBG 的 1.6 倍，而在 4 小时时它们的摄取相似。尽管[18F]MFBG 对 hNET 的亲和力低 2.8 倍，体外细胞摄取率低 4 倍，但 PET 成像表明[18F]MFBG 比[124I]MIBG 更能可视化 C6-hNET 异种移植瘤。生物分布研究表明，[18F]MFBG 和 123I-MIBG 具有相似的肿瘤积累，低于无载体添加的[124I]MIBG，但[18F]MFBG 表现出更快的体内清除和更低的大多数非靶向器官摄取。
结论
在更温和的条件下，以合理的放射化学产率合成了[18F]MFBG 和[18F]PFBG。与[18F]PFBG 和[123I]/[124I]MIBG 相比，[18F]MFBG 是一种更好的 PET 配体，可在 1-4 小时内体内成像 hNET 表达。
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