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Evaluation of [^99mTc/EDDA/HYNIC⁰]Octreotide Derivatives Compared with [¹¹¹In-DOTA⁰,Tyr³, Thr⁸]Octreotide and [¹¹¹In-DTPA⁰]Octreotide: Does Tumor or Pancreas Uptake Correlate with the Rate of Internalization?

¹ Division of Radiological Chemistry, Department of Radiology, University Hospital of Basel, Basel, Switzerland
² Department of Nuclear Medicine, Philipps-University of Marburg, Marburg, Germany
³ Radioisotope Centre Polatom, Otwock-wierk, Poland

Radiolabeled somatostatin analogs are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin receptor–positive tumors. The aim of this study was to compare 3 somatostatin analogs designed for the labeling with ^99mTc (where HYNIC is 6-hydrazinopyridine-3-carboxylic acid): 6-hydrazinopyridine-3-carboxylic acid⁰-octreotide (HYNIC-OC/^99mTc-(1)), [HYNIC⁰,Tyr³]octreotide (HYNIC-TOC/^99mTc-(2)), and [HYNIC⁰,Tyr³,Thr⁸]octreotide (HYNIC-TATE/^99mTc-(3)), using ethylenediamine-N,N'-diacetic acid (EDDA) as a coligand. In addition, we compared the ^99mTc-labeled peptides [¹¹¹In-diethylenetriaminepentaacetic acid⁰]octreotide ([¹¹¹In-DTPA]-OC) and [¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid⁰,Tyr³,Thr⁸]octreotide ([¹¹¹In-DOTA]-TATE) with regard to the rate of internalization and the biodistribution in AR4-2J (expressing the somatostatin receptor subtype 2) tumor-bearing rats. The main attention was directed toward a potential correlation between the rate of internalization and the tumor or pancreas uptake. Methods: Synthesis was performed on solid phase using a standard Fmoc strategy. Internalization was studied in cell culture (AR4-2J) and biodistribution was studied using a Lewis rat tumor model (AR4-2J). Results: The 5 radiopeptides showed a specific internalization into AR4-2J cells in culture (as shown by blocking experiments). The rate of internalization of the 5 radiopeptides differed significantly according to the following order: ^99mTc-(1) [¹¹¹In-DTPA]-OC < ^99mTc-(2) < ^99mTc-(3) [¹¹¹In-DOTA]-TATE. All radiopeptides displayed a rapid blood clearance and a fast clearance from all somatostatin receptor–negative tissues predominantly via the kidneys. A receptor-specific uptake of radioactivity was observed for all compounds in somatostatin receptor–positive organs such as the pancreas, the adrenals, and the stomach. After 4 h, the uptake in the AR4-2J tumor was comparable for ^99mTc-(2) (3.85 ± 1.0 injected dose per gram tissue (%ID/g)), ^99mTc-(3) (3.99 ± 0.58 %ID/g), and [¹¹¹In-DOTA]-TATE (4.12 ± 0.74 %ID/g) but much lower for [¹¹¹In-DTPA]-OC (0.99 ± 0.08 %ID/g) and ^99mTc-(1) (0.70 ± 0.13 %ID/g). The specificity was determined by blocking experiments using a large excess of [Tyr³]octreotide. ^99mTc-(3) displayed the highest tumor-to-kidney ratio (2.5:1), followed by ^99mTc(2) (1.9:1) and [¹¹¹In-DOTA]-TATE (1.7:1). Conclusion: These data show that the 5 radiopeptides are specific radioligands for the somatostatin receptor subtype 2. The rate of internalization correlates with the uptake in the tumor (R² = 0.75; P = 0.026) and pancreas (R² = 0.98; P = 7.4·10^–5). [Tyr³,Thr⁸]octreotide derivatives show superiority over the corresponding octreotide and [Tyr³]octreotide derivatives, indicating that [¹¹¹In-DOTA]-TATE and [^99mTc/EDDA/HYNIC]-TATE are suitable candidates for clinical studies.

Key Words: DOTA • HYNIC • internalization • somatostatin receptor • octreotide

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