Zheng Qi-Huang, Fei Xiangshu, DeGrado Timothy R, Wang Ji-Quan, Stone K Lee, Martinez Tanya D, Gay Dawn J, Baity Winston L, Mock Bruce H, Glick-Wilson Barbara E, Sullivan Michael L, Miller Kathy D, Sledge George W, Hutchins Gary D
Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Nucl Med Biol. 2003 Oct;30(7):753-60. doi: 10.1016/s0969-8051(03)00086-6.
(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [(11)C]methyl ester ([(11)C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [(11)C]FMAME was prepared by appropriate precursor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by [(11)C]methyl triflate through O-[(11)C]methylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on (11)CO(2), decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [(11)C]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1 alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [(11)C]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1 alpha implanted mice and 1.37% dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.05 +/- 0.29 (T/M, MCF-7's), 0.77 +/- 0.20 (T/B, MCF-7's) and 0.99 +/- 0.35 (T/M, MDA-MB-435), 1.44 +/- 0.69 (T/B, MDA-MB-435), respectively. Pretreatment of MCF-7 transfected with IL-1 alpha tumor-bearing mice with MMP inhibitor FMA had no effect on [(11)C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [(11)C]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1 alpha tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [(11)C]FMAME using a dedicated high resolution (<3 mm full-width at half-maximum) PET imaging system (Indy-PET II scanner). The initial dynamic micro-PET images of [(11)C]FMAME in a MCF-7 transfected with IL-1 alpha tumor-bearing mouse during different time periods of 0-15, 15-30, 30-45 and 45-60 min were performed by Indy-PET II. The PET images clearly showed both tumors were visible with [(11)C]FMAME. These results suggest that the localization of [(11)C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [(11)C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.
（2R）-2-[[4-（6-氟己-1-炔基）苯基]磺酰氨基]-3-甲基丁酸[（11）C]甲酯（[（11）C]FMAME）是一种新型的碳-11标记的基质金属蛋白酶（MMP）抑制剂，已被合成用于评估作为新的潜在正电子发射断层扫描（PET）癌症生物标志物。[（11）C]FMAME由适当的前体（2R）-2-[[4-（6-氟己-1-炔基）苯基]磺酰氨基]-3-甲基丁酸（FMA）制备，FMA由（D）-缬氨酸经六步合成，化学产率为71%。该酸前体在碱性条件下通过O-[(11)C]甲基化方法用[（11）C]甲基三氟甲磺酸酯进行标记，并通过固相萃取（SPE）纯化进行分离，以基于轰击结束时衰变校正后的（11）CO2和15 - 20分钟的合成时间，以40 - 55%的放射化学产率产生纯的目标化合物。在静脉注射后30分钟，在植入了转染IL-1α的MCF-7乳腺癌动物模型和植入了MDA-MB-435的无胸腺小鼠中测定了[（11）C]FMAME的生物分布。结果显示，在植入转染IL-1α的小鼠的MCF-7肿瘤中，[（11）C]FMAME的摄取量为1.13%剂量/克，在植入MDA-MB-435的小鼠中为1.37%剂量/克；肿瘤/肌肉（T/M）和肿瘤/血液（T/B）的比率分别为1.05±0.29（T/M，MCF-7）、0.77±0.20（T/B，MCF-7）和0.99±0.35（T/M，MDA-MB-435）、1.44±0.69（T/B，MDA-MB-435）。用MMP抑制剂FMA对植入转染IL-1α肿瘤的小鼠进行预处理对[（11）C]FMAME的生物分布没有影响。同样，用FMA对植入MDA-MB-435肿瘤的小鼠进行预处理也对[（11）C]FMAME的生物分布没有影响。在静脉注射1 mCi的[（1）C]FMAME后30分钟，使用专用的高分辨率（半高宽<3 mm）PET成像系统（Indy-PET II扫描仪），从植入转染IL-1α肿瘤的小鼠或植入MDA-MB-435肿瘤的小鼠中采集15分钟的微型PET图像。Indy-PET II对植入转染IL-1α肿瘤的小鼠在0 - 15、15 - 30、30 - 45和45 - 60分钟不同时间段内[（11）C]FMAME的初始动态微型PET图像进行了采集。PET图像清楚地显示两种肿瘤都能用[（11）C]FMAME看到。这些结果表明，[（11）C]FMAME在肿瘤中的定位是由非特异性过程介导的，并且使用Indy-PET II扫描仪在肿瘤上对[（11）C]FMAME的可视化与非特异性结合有关。
