EVALUATION OF THE MONOAMINE UPTAKE SITE LIGAND [I-123] METHYL 3-BETA-(4-IODOPHENYL)-TROPANE-2-BETA-CARBOXYLATE ([I-123)BETA-CIT) IN NONHUMAN-PRIMATES - PHARMACOKINETICS, BIODISTRIBUTION AND SPECT BRAIN IMAGING COREGISTERED WITH MRI
EVALUATION OF THE MONOAMINE UPTAKE SITE LIGAND [I-123] METHYL 3-BETA-(4-IODOPHENYL)-TROPANE-2-BETA-CARBOXYLATE ([I-123)BETA-CIT) IN NONHUMAN-PRIMATES - PHARMACOKINETICS, BIODISTRIBUTION AND SPECT BRAIN IMAGING COREGISTERED WITH MRI
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DOI：
10.1016/0969-8051(93)90028-s
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发表时间：
1993-07-01
影响因子：
3.1
通讯作者：
INNIS, RB
中科院分区：
文献类型：
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作者：
BALDWIN, RM;ZEAPONCE, Y;INNIS, RB
在狒狒和黑长尾猴中评价了多巴胺和5-羟色胺转运蛋白的新型放射性碘标记探针[I-123]甲基3 β-（4-碘苯基）托烷-2 β-羧酸酯（[I-123]beta-CIT）的体内特性。以65.2 +/- 2.8%的产率制备标记产物（平均值+/- SEM; n = 18），在过氧乙酸存在下，使三丁基锡烷基前体与[I-123]NaI反应，然后进行高压液相色谱（HPLC）纯化，得到放射化学纯度为97.5 ± 0.5%，比活度为500-1200 Ci/mmol的产物。静脉内给药后，全脑活动在注射后（p.i.）并以双相方式洗脱，快速组分和慢速组分的清除半衰期分别为1-2小时和7-35小时。排泄主要通过肝胆途径进行，5 h后约30%的注射剂量出现在胃肠道中。脑、胆囊壁、大肠下壁和膀胱壁的辐射吸收剂量分别为0.01、0.1、0.2和0.03 mGy/MBq，狒狒的高分辨SPECT显像显示纹状体区域有较高的示踪剂摄取（纹状体：小脑比率4.0），在下丘脑中脑区包括中缝、黑质和上级丘（比率2.0），在210 min p.i. [I-123]beta-CIT。SPECT图像上的区域的解剖位置通过与MRI的共配准来确认。通过乙酸乙酯提取和HPLC分析狒狒和长尾猴的血浆代谢物和药代动力学。主要代谢物是极性、不可提取的部分，在p.i.给药后30-45 min增加至血浆活性的> 50%。还观察到少量亲脂性（可浸提）代谢产物，在注射后2 - 3 h增加至约4%。通过超滤法测定血浆蛋白结合分数。为74.8 ± 1.4%（n = 6）。动脉输入函数的特征在于游离母体化合物浓度的半衰期分别为0.3-1.7、9.7-24.9和77-166 min的三个指数项之和。[I-123]beta-CIT有望成为SPECT研究灵长类动物脑内单胺摄取系统的有用标记物。
The in vivo properties of a new radioiodinated probe of the dopamine and serotonin transporter, [I-123]Methyl 3beta-(4-iodophenyl)tropane-2beta-carboxylate ([I-123]beta-CIT) were evaluated in baboons and vervet monkeys. The labeled product was prepared in 65.2 +/- 2.8% yield (mean +/- SEM; n = 18) by reaction of the tributylstannyl precursor with [I-123]NaI in the presence of peracetic acid followed by high pressure liquid chromatography (HPLC) purification to give a product with radiochemical purity of 97.5 +/- 0.5% and specific activity of 500-1200 Ci/mmol. After intravenous administration, whole brain activity peaked at 6-10% injected dose within 1 h post injection (p.i.) and washed out in a biphasic manner with clearance half-lives of 1-2 and 7-35 h for the rapid and slow components, respectively. Excretion occurred primarily through the hepatobiliary route, with about 30% of the injected dose appearing in the GI tract after 5 h. Estimates of radiation absorbed dose gave 0.01, 0.1, 0.2 and 0.03 mGy/MBq to the brain, gall bladder wall, lower large intestine wall and urinary bladder wall, respectively.High resolution SPECT imaging in a baboon demonstrated high uptake of tracer in the region of the striatum (striatum:cerebellum ratio 4.0), in the hypothalamus (ratio 2.6) and in a midbrain region comprising raphe, substantia nigra and superior colliculus (ratio 2.0), with regional brain uptakes measured at 210 min p.i. of [I-123]beta-CIT. The anatomical locations of the regions on the SPECT image were confirmed by coregistration with MRI.Plasma metabolites and pharmacokinetics were analyzed in baboons and vervets by ethyl acetate extraction and HPLC. The major metabolite was a polar, non-extractable fraction, which increased to > 50% of the plasma activity by 30-45 min p.i. A minor lipophilic (extractable) metabolite was also observed, increasing to about 4% at 2 3 h p.i. The plasma protein bound fraction, determined by ultrafiltration. was 74.8 +/- 1.4% (n = 6). The arterial input function was characterized by the sum of three exponential terms with half-lives of 0.3-1.7, 9.7-24.9 and 77-166 min, respectively, for the concentration of free parent compound. [I-123]beta-CIT promises to be a useful marker for SPECT study of the monoamine uptake system in primate brain.