Effect of co-ligands on chemical and biological properties of 99mTc(III) complexes [99mTc(L)(CDO)(CDOH)2BMe] (L=Cl, F, SCN and N3; CDOH2=cyclohexanedione dioxime)

Abstract

Introduction 99mTc-Teboroxime ([99mTcCl(CDO)(CDOH)2BMe]) is a member of the BATO (boronic acid adducts of technetium dioximes) class of 99mTc(III) complexes. This study sought to explore the impact of co-ligands on solution stability, heart uptake and myocardial retention of [99mTc(L)(CDO)(CDOH)2BMe] (99mTc-Teboroxime: L = Cl; 99mTc-Teboroxime(F): L = F; 99mTc-Teboroxime(SCN): L = SCN; and 99mTc-Teboroxime(N3): L = N3). Methods Radiotracers 99mTc-Teboroxime(L) (L = F, SCN and N3) were prepared by reacting 99mTc-Teboroxime with NaF, NaSCN and NaN3, respectively. Biodistribution and imaging studies were carried out in Sprague-Dawley rats. Image quantification was performed to compare their heart retention and liver clearance kinetics. Results Complexes 99mTc-Teboroxime(L) (L = F, SCN and N3) were prepared in high yield with high radiochemical purity. All new radiotracers were stable for >6 h in the kit matrix. In its HPLC chromatogram, 99mTc-Teboroxime showed one peak at ~15.5 min, which was shorter than that of 99mTc-Teboroxime(F) (~16.4 min). There were two peaks for 99mTc-Teboroxime(SCN) at 16.5 and 18.3 min. 99mTc-Teboroxime(N3) appeared as a single peak at 18.4 min. Their heart retention and liver clearance curves were best fitted to the bi-exponential decay function. The half-times of fast/slow components were 1.6 ± 0.4/60.7±8.9 min for 99mTc-Teboroxime, 0.8±0.2/101.7±20.7 min for 99mTc-Teboroxime(F), 1.2±0.3/84.8±16.6 min for 99mTc-Teboroxime(SCN), and 2.9±0.9/51.6±5.0 min for 99mTc-Teboroxime(N3). The 2-min heart uptake followed the order of 99mTc-Teboroxime (3.00±0.37%ID/g) > 99mTc-Teboroxime(N3) (2.66±0.01 %ID/g) ≈ 99mTc-Sestamibi (2.55±0.46 %ID/g) > 99mTcN-MPO (2.38±0.15 %ID/g). 99mTc-Teboroxime remains the best in first-pass extraction. The best image acquisition window is 0 – 5 min for 99mTc-Teboroximine and 0 – 15 min for 99mTc-Teboroximine(N3). Conclusion Co-ligands had significant impact on the heart uptake and myocardial retention of complexes [99mTc(L)(CDO)(CDOH)2BMe] (L = Cl, F, SCN and N3). Future studies should be directed towards minimizing the liver uptake and radioactivity accumulation in the blood vessels while maintaining their high heart uptake.

Novel 99m Tc(III)-azide complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R] (CDOH 2 = cyclohexanedione dioxime) as potential radiotracers for heart imaging

“…5). The initial heart uptake of 99m Tc-ISboroxime-N 3 (5.5 ± 0.4%ID) and 99m Tc-PYboroxime-N 3 (4.7 ± 0.7%ID) was comparable to that reported for 99m Tc-Teboroxime (5.6 ± 0.7%ID), 99m Tc-ISboroxime (5.0 ± 1.1%ID) and 99m Tc-PYboroxime (4.1 ± 0.8%ID), respectively, within the experimental errors [44,45]. The initial heart uptake of 99m Tc-Uboroxime-N 3 (4.6 ± 0.9%ID) was higher ( p < 0.05) than that for 99m Tc-Uboroxime (3.2 ± 0.7%ID) [45].…”

“…First, complexes [ 99m TcCl(CDO)(CDOH) 2 B-R] (R = IS, MP, PA, PY and 5U) were prepared using the literature method [11,44,45], and then were allowed to react with NaN 3 . Heating at 100 °C was needed to complete the Cl-N 3 ligand exchange because their RCP was <5% when the reaction was performed at room temperature.…”

“…The results from biodistribution and imaging studies showed that 99m Tc-PAboroxime had the heart uptake comparable to that of 99m Tc-Teboroxime, but it had much longer myocardial retention time [45]. We also found that 99m Tc-Teboroxime-N 3 had longer heart retention time than 99m Tc-Teboroxime [44]. These promising results lead us to prepare complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R] (Fig.…”

“…All 99m Tc(III) radiotracers were prepared using the kit formulation[44,45]. Each lyophilized vial contains 2 mg of CDOH 2 , 4–5 mg of boronic acid, 50–60 μg of SnCl 2° 2H 2 O, 9 mg of citric acid, 2 mg of DTPA and 20 mg of NaCl and 10 mg of γ-cyclodextrin.…”

“…We kept the CDOH 2 -core in order to maintain the high initial heart uptake for 99m Tc(III) complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R]. The azide coligand is of our particular interest because 99m Tc-Teboroxime-N 3 has a longer myocardial retention than 99m Tc-Teboroxime [44]. The main objective of this study is to explore the impact of azide coligand and boronate caps on biodistribution properties (initial heart uptake and myocardial retention times) of 99m Tc(III)-azide complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R].…”