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Crucial Role for Somatostatin Receptor Subtype 2 in Determining the Uptake of [¹¹¹In-DTPA-D-Phe¹]Octreotide in Somatostatin Receptor–Positive Organs

¹ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, Bern, Switzerland
³ Merck Laboratories, New York, New York
⁴ Mallinckrodt Discovery, St. Louis, Missouri
⁵ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Human somatostatin (SS) receptor (sst)–positive tumors can be visualized by gamma camera scintigraphy after the injection of [¹¹¹In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe¹] octreotide. Uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide is dependent on sst-mediated internalization of the radioligand by the tumor cells. Human sst-positive tumors frequently express multiple sst subtypes. In vitro studies have demonstrated that the 5 sst subtypes (sst_1–5) differentially internalize sst-bound ligand. The present study was performed to evaluate the role of sst₂ in vivo in determining the uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide, as well as of the more "universal" ligand [¹¹¹In-DTPA]SS-14, by sst-positive organs expressing multiple sst subtypes. Methods: Wild-type and sst₂ knockout mice (n = 4 per treatment group) were injected intravenously with 1 MBq (0.1 µg) [¹¹¹In-DTPA-D-Phe¹]octreotide or [¹¹¹In-DTPA]SS-14. After 24 h, the animals were sacrificed and radioactivity in the organs under investigation was determined. In addition, the sst subtype messenger RNA (mRNA) expression pattern in these organs was determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Results: RT-PCR analysis demonstrated the presence of all 5 sst subtype mRNAs in the adrenals and pituitary of wild-type mice but no sst₂ in the knockout mice. The thymus expressed mRNA for sst₂ and sst₄ mRNA in wild-type mice, whereas no sst₂ was detected in knockout mice. In wild-type mice, the in vivo uptake values (in percentage injected dose per gram of tissue) of [¹¹¹In-DTPA-D-Phe¹]octreotide for the pituitary, adrenals, pancreas, and thymus amounted to 1.2 ± 0.2, 0.26 ± 0.03, 0.18 ± 0.03, and 0.30 ± 0.05, respectively, in wild-type mice. Compared with wild-type mice, sst₂ knockout mice had dramatically lower uptake values in these organs—lower by 97%, 83%, 96%, and 94%, respectively (P < 0.01 vs. wild type). Comparable differences in the uptake of radioactivity between wild-type and knockout mice were found using [¹¹¹In-DTPA]SS-14 as the radiotracer. Interestingly, in some organs expressing sst₂ mRNA (liver, muscle, and peripheral blood mononuclear cells), no specific binding of [¹¹¹In-DTPA-D-Phe¹]octreotide or [¹¹¹In-DTPA]SS-14 to sst in vivo was found, suggesting that the sst₂ protein expression level was very low in these tissues. Conclusion: The uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide and [¹¹¹In-DTPA]SS-14 in sst-positive organs is determined predominantly by sst₂.

Key Words: [¹¹¹In-DTPA-D-Phe¹]octreotide • uptake • sst₂ • knockout • mouse

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