Notni Johannes, Steiger Katja, Hoffmann Frauke, Reich Dominik, Schwaiger Markus, Kessler Horst, Wester Hans-Jürgen
Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany
Institute of Pathology, Technische Universität München, Munich, Germany.
J Nucl Med. 2016 Oct;57(10):1618-1624. doi: 10.2967/jnumed.116.173948. Epub 2016 May 5.
Ga-aquibeprin and Ga-avebetrin are tracers for selective in vivo mapping of integrins αβ and αβ, respectively, by PET. Because both tracers exhibit high affinity to their respective targets, the aim of this study was to investigate the influence of the specific activity of preparations of both tracers on in vivo imaging results.
Fully automated Ga labeling of 0.3 nmol of aquibeprin or avebetrin was done using buffered eluate fractions (600-800 MBq, pH 2) of an SnO-based generator, affording the radiopharmaceuticals with specific activities greater than 1,000 MBq/nmol. Lower values ranging from 150 to 0.4 MBq/nmol were adjusted by addition of inactive compound (∼0.15-50 nmol) to the injected activity (∼20 MBq for PET, 5-7 MBq for biodistribution). For in vivo experiments, 6- to 12-wk-old female severe combined immunodeficiency mice bearing M21 xenografts (human melanoma, expressing both integrins αβ and αβ) were used. The expression density of integrin β was determined by immunohistochemistry on paraffin slices.
For mass doses (specific activities) of less than 20 pmol (>1,000 MBq/nmol) and 1 nmol (20 MBq/nmol) per mouse, respectively, uptake of Ga-aquibeprin and Ga-avebetrin in M21 tumors dropped from 5.3 and 3.5 to 3.0 and 2.4 percentage injected dose per gram (%ID/g), respectively. When less than 20 pmol was applied, high uptake of Ga-aquibeprin in the eyes (4.5 %ID/g) or Ga-avebetrin in adrenals (25.9 %ID/g), respectively, were found, which was reduced by 90% and 65% (0.44 and 6.2 %ID/g, respectively), for doses of 1 nmol. The highest tumor-to-tissue ratios were observed both in ex vivo biodistribution and PET for comparably large doses, for example, 6 nmol (0.65 mg/kg) Ga-aquibeprin per mouse (3.5 MBq/nmol).
Presumably because of their high affinities, Ga-aquibeprin and Ga-avebetrin allow for selective addressing of target sites with different integrin expression levels by virtue of adjusting specific activity, which can be exploited for visualization of low-level target expression or optimization of tumor-to-background contrast.
镓-阿奎贝普林和镓-阿韦贝普林分别是用于通过正电子发射断层扫描（PET）在体内选择性绘制整合素αβ和αβ图谱的示踪剂。由于这两种示踪剂对各自的靶点都表现出高亲和力，本研究的目的是调查这两种示踪剂制剂的比活对体内成像结果的影响。
使用基于SnO的发生器的缓冲洗脱液馏分（600 - 800 MBq，pH 2）对0.3 nmol的阿奎贝普林或阿韦贝普林进行全自动镓标记，得到比活大于1000 MBq/nmol的放射性药物。通过向注射活性（PET约20 MBq，生物分布5 - 7 MBq）中添加非活性化合物（约0.15 - 50 nmol）来调整150至0.4 MBq/nmol的较低值。对于体内实验，使用携带M21异种移植物（人黑色素瘤，表达整合素αβ和αβ）的6至12周龄雌性严重联合免疫缺陷小鼠。通过对石蜡切片进行免疫组织化学测定整合素β的表达密度。
对于每只小鼠分别低于20 pmol（>1000 MBq/nmol）和1 nmol（20 MBq/nmol）的质量剂量（比活），M21肿瘤中镓-阿奎贝普林和镓-阿韦贝普林的摄取分别从5.3和3.5降至3.0和2.4每克注射剂量百分比（%ID/g）。当应用低于20 pmol时，分别发现镓-阿奎贝普林在眼中的高摄取（4.5 %ID/g）或镓-阿韦贝普林在肾上腺中的高摄取（25.9 %ID/g），对于1 nmol的剂量，分别降低了90%和65%（分别为0.44和6.2 %ID/g）。在离体生物分布和PET中，对于相当大的剂量，例如每只小鼠6 nmol（0.65 mg/kg）镓-阿奎贝普林（3.5 MBq/nmol），观察到最高的肿瘤与组织比值。
推测由于它们的高亲和力，镓-阿奎贝普林和镓-阿韦贝普林通过调整比活能够选择性地靶向具有不同整合素表达水平的靶点，这可用于可视化低水平靶点表达或优化肿瘤与背景对比度。
