A novel gallium bisaminothiolate complex as a myocardial perfusion imaging agent

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Abstract

The development of new myocardial perfusion imaging agents for positron emission tomography (PET) may improve the resolution and quantitation of changes in regional myocardial perfusion measurement. It is known that a 68Ge/68Ga generator can provide a convenient source of PET tracers because of the long physical half-life of 68Ge (271 days). A new ligand, 7,8-dithia-16,24-diaza-trispiro[5.2.5.2.5.3]pentacosa-15,24-diene, which consists of a N2S2-chelating core incorporated into three cyclohexyl rings, was prepared. To test feasibility and potential utility, the N2S2 ligand was successfully labeled and tested with 67Ga (half-life=3.26 day; γ=93.3, 184.6 and 300.2 keV), which showed >92% radiochemical purity. The corresponding “cold” Ga complex was synthesized, and its structure containing a pyramidal N2S2 chloride core was elucidated with X-ray crystallography. In vivo biodistribution of this novel 67Ga complex, evaluated in normal rats, exhibited excellent heart uptake and retention, with 2.1% and 0.9% initial dose/organ at 2 and 60 min, respectively, after an intravenous injection. Autoradiography was performed in normal rats and in rats that had the left anterior descending coronary artery permanently ligated surgically. Autoradiography showed an even uptake of activity in the normal heart, and there was a distinctively lower uptake in the damaged side of the surgically modified heart. In conclusion, the new N2S2 ligand was readily prepared and labeled with radioactive 67Ga. Biodistribution in rats revealed high initial heart uptake and relatively high retention reflecting regional myocardial perfusion.

Introduction

Myocardial perfusion has been traditionally evaluated with planar imaging or single photon emission computed tomography (SPECT), in conjunction with radiopharmaceuticals such as 201Tl, [99mTc]sestamibi or [99mTc]tetrofosmin [1], [2]. Currently, these types of myocardial perfusion imaging studies are part of normal patient workup and are performed on a routine basis. Recent advances in positron emission tomography (PET)/computed tomography (CT), as well as in multichannel CT for cardiac applications, advocated the need to develop new PET radiopharmaceuticals to improve the resolution and quantification of regional myocardial perfusion studies [3]. The purpose of this article is to report a new gallium N2S2 complex, which may take advantage of a 68Ge/68Ga generator to provide a convenient myocardial perfusion imaging in PET.

In the past few decades, many types of 68Ge/68Ga generator systems used for producing positron-emitting isotopes without an on-site cyclotron have been reported [4], [5], [6], [7]. The unique features of a radionuclide generator system are a relatively long parent half-life (68Ge; t1/2=270 days) and a suitable daughter half-life (68Ga; t1/2=68 min). Usually, separation of the desired daughter 68Ga from the parent 68Ge is achieved by using solid oxides (such as TiO2, ZrO2 or SiO2) supported with column chromatography. The column is eluted with a strong acid leading to Ga(III) complexes and avoids the formation of gallium hydroxide as a solid precipitate. A tin dioxide/1-N HCl generator also provides a sterile solution of Ga-68 in ionic form, which is ready for use in the preparation of many radiopharmaceuticals [6]. A similar column chromatography separation system using an organic polymer (phenolic ion exchanger), coupled in series with a small anion exchange column (AG-1), has been successfully employed for producing 68Ga for labeling [8]. Alternatively, a new organic polymer (macroporous styrene–divinylbenzene copolymer) containing N-methylglucamine groups has been reported for a new 68Ge/68Ga generator system [9]. The criteria for an ideal 68Ge/68Ga generator system include the following: (a) a high efficient separation of 68Ga from the column; (b) a minimum amount of “parent breakthrough” (a low level of 68Ge in the eluent); and (c) stability of the column over time. All of the reported 68Ge/68Ga generator systems can meet the basic criteria listed above; however, one major unmet need in the field of nuclear medicine is the lack of Food and Drug Administration-approved commercial 68Ge/68Ga generator system(s) for human use, which limits the potential for developing 68Ga-labeled radiopharmaceuticals for PET imaging [10].

Recently, there has been renewed interest in the use of 68Ga for PET imaging [10], [11], [12], [13]. Of particular interest is the recent development of 68Ga-labeled peptides targeting endocrine tumor receptors [14], [15], [16], [17], [18], [19]. Through the use of 1,4,7,10-tetraazacyclodododecane=1,4,7,10-tetraacetic (DOTA) or diethylenetriaminepentaacetic acid (DTPA) as the chelating group, various peptides, including analogs of somatostatin [11], [14], [20], epidermal growth factor receptor [15], substance P [21], bombesin [16], gastrin and cholecystokinin-B [22], have been successfully labeled with 68Ga for PET imaging. These complexes, when labeled with other radionuclides, can also be useful as radiotherapeutic agents, thus providing a “see-and-treat” approach in tumor diagnosis and treatment [16], [20], [23], [24], [25].

Gallium complexes of N2S2 (bisaminoethanethiolate (1)) [26], [27], [28], as well as NS3 [29], have been previously reported (Fig. 1). One unique feature of [Ga]1 complexes is that they have cationic character—+1-charged cation in aqueous solution. When Compound 1 is dissolved in water, the chloride ion would most likely be dissociated to form a Ga bisaminothiolate complex containing a positive charge. It was believed that the highly lipophilic cationic complex was trapped in myocardial tissues similar to those in 99mTc-labeled myocardial imaging agents [99mTc methoxyisobutylisonitrile (MIBI) and tetrafosamine]. To improve myocardial uptake and retention, we have prepared a new gallium complex consisting of Compound 1 with three “cyclohexyl” rings as a potential imaging agent for myocardial perfusion studies by PET. The extra “cyclohexyl” rings were added to improve stability and to enhance the lipophilicity of the gallium complex. The improved lipophilicity may enhance the first-pass extraction and the retention of the +1-charged cation in the myocardium. Reported herein are the preparation and in vivo testing of this novel Ga complex.

Section snippets

General procedures

1H and 13C nuclear magnetic resonance (NMR) spectra were determined with a Bruker DPX 200 spectrometer using tetramethylsilane or residual solvent peak as an internal standard. High-resolution mass spectra (HRMS) were recorded at the McMaster Regional Center for Mass Spectrometry using a Micromass/Waters GCT instrument (GC-EI/CI Time of Flight Mass Spectrometer), or at the University of Pennsylvania, Department of Radiology, Radiopharmaceutical Chemistry Section, using Agilent Technologies

Synthesis

The desired N2S2 ligand 9 containing three tricyclohexyl groups was prepared from two simple fragments, Compounds 5 and 6. The strategy involves the formation of diimine linkage between diamine 5 and dialdehyde 6. Subsequent one-pot reduction of imine and disulfide bonds affords the target ligand 9. The preparation of synthon 5 is depicted in Scheme 1. The amino-cyanation (Strecker) reaction of commercially available cyclohexanone 3 afforded the aminonitrile 4 in good yield (78%). The

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