Kinetics of Perrhenate Uptake and Comparative Biodistribution of Perrhenate, Pertechnetate, and Iodide by NaI Symporter-Expressing Tissues In Vivo

Kinetics of Perrhenate Uptake and Comparative Biodistribution of Perrhenate, Pertechnetate, and Iodide by NaI Symporter–Expressing Tissues In Vivo

Lionel S. Zuckier, MD¹, Orshi Dohan, MD², Yi Li, MD³, Chee Jen Chang, PhD⁴, Nancy Carrasco, MD² and Ekaterina Dadachova, PhD³

¹ Department of Radiology, New Jersey Medical School, Newark, New Jersey
² Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York
³ Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York
⁴ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

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FIGURE 1. Activity in blood and NIS-expressing tissues. Error bars represent 1 SD. Note the variable y-axis scales. Radiopharmaceutical uptake was similar for the 3 radiopharmaceutical substrates, with the exception of iodide in the thyroid. Blood activity gradually decreased with time and was noted to be slightly greater in mice administered perchlorate, as a result of absence of competing excretory pathways. Uptake in NIS-expressing stomach and salivary gland was relatively high, remained elevated or increased over the initial 2 h, and subsequently washed out. This pattern also characterized perrhenate and pertechnetate uptake in the thyroid. However, iodide continued to increase through the 19-h time point, presumably as a result of organification. Blocking of NIS by coinjection of perchlorate decreased uptake of all 3 radiopharmaceuticals by the stomach, salivary glands, and thyroid and resulted in their rapid clearance, paralleling clearance in blood.

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FIGURE 2. Activity in tissues that did not significantly express NIS (liver, muscle, spleen, kidney). Error bars represent 1 SD. The y-axis scale is similar to that of blood (Fig. 1). The 3 radiopharmaceuticals showed similar patterns of uptake. Activities were lower than those of blood and sequentially decreased over time. Addition of perchlorate did not diminish activity and, in fact, resulted in a modest increase in renal activity at 20 min, probably the result of a reduction in uptake by competing NIS-dependent pathways.

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FIGURE 3. Images in representative mice demonstrated the marked amount of gastric uptake noted for all 3 radiopharmaceuticals on the 24- and 60-min images. By 24 h, the activity was less well defined and, at least in the case of ^99mTcO₄^-, more diffusely distributed within the bowel. For ^99mTcO₄^- and ¹⁸⁸ReO₄^-, a modest amount of concentration of activity was seen in the region of the thyroid gland at 24 and 60 min, but this faded by the 24-h time point. In contrast, ¹²³I^- gradually increased between the 24-min, 60-min, and 24-h images. Rhenium-based curves exhibited increased noise as a result of the lower abundance of ${gamma}$ -photons for this radionuclide. Time–activity curves based on ROIs over the stomach, mediastinum, and thyroid demonstrated similar appearances for the 3 radiopharmaceuticals. Because of limitations in external photon scanning, apparent magnitude of uptake may be less than that based on actual organ counting. Uptake in the stomach was most intense and increased over the 1 h of initial imaging, concentrating 20%–25% of injected activity. Thyroid uptake was more modest and also increased over time (5%–7% of injected activity). Mediastinal activity, representing blood pool, gradually decreased over the initial 1 h of measurements, representing approximately 2% of injected activity at the 60-min time point.

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FIGURE 4. Uptake of iodide and perrhenate in hNIS-transfected MDCK cells. Error bars denote 1 SD. (A) Time course of uptake. Cells were incubated with 20 µmol/L iodide or perrhenate supplemented with carrier-free ¹²⁵I^- and ¹⁸⁸ReO₄^-, respectively, for the indicated periods of time. Solid symbols represent uptake in NIS-transfected cells, and open symbols represent uptake in nontransfected cells. Uptake of iodide exceeds that of perrhenate at all time points in the transfected cells. Transfected cells in the presence of the potent NIS inhibitor perchlorate and non-NIS-transfected MDCK cells did not concentrate either anion. (B) Kinetic analysis of iodide and perrhenate uptake into hNIS-transfected MDCK cells based on 2-min uptake values at variable substrate concentrations. V_max and K_m values were estimated using the Marquard–Levenberg algorithm as 106 ± 3.2 and 24.6 ± 1.81 pmol/µg for iodide and 25.6 ± 1.4 and 4.06 ± 0.87 µmol/L for perrhenate (plotted symbols represent experimental data and solid lines the fitted curves).