Automated synthesis of [⁶⁸Ga]oxine, improved preparation of⁶⁸Ga-labeled erythrocytes for blood-pool imaging, and preclinical evaluation in rodents

Abstract

Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities. With the coming of age of modern Ge/Ga generator systems, gallium-68 is now widely accessible. In this paper we describe an updated method for the preparation of Ga-labeled erythrocytes and their preliminary use in rodent blood pool imaging. A novel automated synthesis of [Ga]oxine using a Ga/Ge generator and automated synthesis module is reported. [Ga]Oxine was synthesized in 50 ± 5% ( = 3) non-decay corrected radiochemical yield and >99% radiochemical purity. Rat and human erythrocytes were successfully labeled with the complex in 42% RCY, and the Ga-labeled erythrocytes have been shown to clearly image the blood pool in a healthy rat. Human erythrocytes labelled with [Ga]oxine were shown to be viable up to 2 hours post-labelling, and washout of the radiolabel was minimal up to 1 hour post-labelling. Further optimization of the labeling method to translate for use in human cardiac and oncologic blood pool PET imaging studies, is underway.

Direct Cell Radiolabeling for in Vivo Cell Tracking with PET and SPECT Imaging

“…Surface-labeling of RBCs with 18 F has been used to detect small areas of intracranial hemorrhage . Other candidates for PET imaging of RBCs include oxine complexes of 64 Cu and 89 Zr. , …”

“…153 Other candidates for PET imaging of RBCs include oxine complexes of 64 Cu and 89 Zr. 84,361 Radiolabeled platelets have previously been used clinically for thrombus imaging, for example to detect deep vein thrombosis or pulmonary embolism, again mostly with [ 111 In]In-oxine, [ 111 In]In-tropolone, and [ 99m Tc]Tc-HMPAO. [326][327][328][329]362 However, the relatively slow accumulation of platelets at the target site and interference by anticoagulant agents 363 limit the utility of the procedure.…”

PET/CT with [68Ga]gallium-oxine-labeled heat-denatured red blood cells for detection of dystopic splenic tissue

“…We report the first-in-human use of [ 68 Ga]gallium-oxine-labeled hd-RBC for detection of dystopic splenic tissue. The PET tracer was validated according to Good Manufacturing Practice (GMP) guidelines [ 5 ]. Erythrocytes separated from 10 ml blood were labeled with 500 MBq [ 68 Ga]Ga-oxine synthesized from [ 68 Ga]Ga-chloride and 8-hydroxyquinoline (oxine) at 48 °C for 10 min, simultaneously achieving heat denaturation of the blood cells.…”

Evaluation of different 89Zr-labeled synthons for direct labeling and tracking of white blood cells and stem cells in healthy athymic mice

“…PET, however, has many advantages over SPECT including two to threefold higher sensitivity, superior spatial resolution in the clinical setting, and with its quantitative nature it is a preferred imaging modality for tracking a single cell or small number of administered radiolabeled cells with more precise quantification and hence, requires lower radiation exposure 34 . Examples of commercial PET probes used to label cells include [ 18 F]FDG (t 1/2 = 109.7 min, β + = 97%) 35 , [ 64 Cu]Cu-PTSM (t 1/2 = 12.7 h, β + = 17.9% ) 36 and [ 68 Ga]Ga-oxine (t 1/2 = 68 min, β + = 88.8%) 37 , 38 .…”