Synthesis and Preclinical Evaluation of Kit-Type 99mTc-Labeled N-(2-Aminoethyl)-3-(4-(2-hydroxy-3-(isopropylaminopropoxy)phenyl)propanamide for SPECT Imaging of Cardiac β1-Adrenoceptor

Abstract

Technetium-99m is the most widely used radionuclide for SPECT (single-photon emission computed tomography) imaging nowadays because of its ideal nuclear properties (t1/2 = 6 h, 141 keV), simple production, low cost and extensive functional group tolerance. β1-Adrenoreceptor is inextricably bound up with cardiac nervous system and usually have selective reduction in failing human heart. In this work, a novel 99mTc-labeled radiotracer for specific β1-adrenoreceptor binding was prepared and its preclinical evaluation was carried out by serial SPECT images in normal rats. In order to develop radiotracers for β1-adrenoreceptor, 99mTc-labeled N-(2-aminoethyl)-3-(4-(2-hydroxy-3-(isopropylaminopro- poxy)phenyl)propanamide ([99mTc]1) was synthesized by kit-type formulation. To optimize the labeling condition, a variety of attempts were investigated with different stabilizers including mannitol, NaCl and cyclodextrin. Using mannitol as stabilizer, the precursor was reacted with 99mTcO4－ in presence of SnF2 (reducing agent) and ascorbic acid (anti-oxidant) at room temperature for 30 sec, to give [99mTc]1 in excellent radiochemical yield (>95%) and with high radiochemical purity (>98%). Mass Spectrometric and NMR data of the cold authentic compound, rhenium coordinated N-(2-aminoethyl)-3-(4-(2-hydroxy-3-(isopropylaminopropoxy)phenyl)propanamide ([185/187Re]1), were used for the speculation of the structure of [99mTc]1 based on the similar chemical properties between 99mTc and 185/187Re complexes. In serial SPECT images, [99mTc]1 showed high accumulation in the heart and kidneys, while radio-uptake was relatively low in the liver and lung. In vivo inhibition study with excess esmolol (18 mg/kg) or atenolol (2 mg/kg) resulted in remarkable reduced radio-uptake in the heart by 92% and 76%, respectively. This study describes synthesis of precursor (4) and the cold authentic compound ([185/187Re]1), radio-synthesis and in vivo imaging study of [99mTc]1 to evaluate the expression of β1-adrenoceptor in the heart. Our results demonstrated that [99mTc]1 exhibits specific β1-adrenoreceptor binding and potential in vivo bio-kinetic characteristics which make it a promising SPECT radiotracer for assessment of β1-adrenoreceptor in heart diseases.