RT Journal Article
SR Electronic
T1 Evaluation of [<sup>99m</sup>Tc/EDDA/HYNIC<sup>0</sup>]Octreotide Derivatives Compared with [<sup>111</sup>In-DOTA<sup>0</sup>,Tyr<sup>3</sup>, Thr<sup>8</sup>]Octreotide and [<sup>111</sup>In-DTPA<sup>0</sup>]Octreotide: Does Tumor or Pancreas Uptake Correlate with the Rate of Internalization?
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1561
OP 1569
VO 46
IS 9
A1 Daniel Storch
A1 Martin Béhé
A1 Martin A. Walter
A1 Jianhua Chen
A1 Pia Powell
A1 Renata Mikolajczak
A1 Helmut R. Mäcke
YR 2005
UL http://jnm.snmjournals.org/content/46/9/1561.abstract
AB 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 &lt; 99mTc-(2) &lt; 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.