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Background  The positron-emitting radionuclide  89 Zr ( t   1/2  = 3.17 days) was used to prepare  89 Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/ neu -positive breast tumors. In addition, pharmacodynamic studies on HER2/ neu  expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted.    Methodology/Principal Findings  Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [ 89 Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic  nu / nu  mice bearing sub-cutaneous BT-474 (HER2/ neu  positive) and/or MDA-MB-468 (HER2/ neu  negative) tumor xenografts were conducted. The change in  89 Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET.  89 Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3±2.1 MBq/mg (2.82±0.05 mCi/mg of mAb).  In vitro  assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87±0.07.  In vivo  biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68±13.06%ID/g; 71.71±10.35%ID/g and 85.18±11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of  89 Zr-DFO-trastuzumab. Expression levels of HER2/ neu  were modulated during the first 24 and 48 h post-administration (29.75±4.43%ID/g and 41.42±3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64±12.17%ID/g) and Western blot analysis demonstrated that HER2/ neu  expression recovered to baseline levels.    Conclusions/Significance  The results indicate that  89 Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/ neu  positive tumors, and has potential to be used to measure the efficacy of long-term treatment with Hsp90 inhibitors, like PU-H71, which display extended pharmacodynamic profiles.

Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab