Abstract
BackgroundImaging diagnosis of inflammation has been challenging for many years. Inflammation imaging agents commonly used in nuclear medicine, such as [67Ga]Ga-citrate and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) showed some limitations. The identification of a radiotracer with high specificity and low radiation dose is clinically important. With the commercialization of 68Ge/68Ga generators and the high 68Ga cyclotron production capacity, the study of 68Ga-based tracer for inflammation has increased and shown good potential. In the present work, we report the synthesis of 4HMSA, a new acyclic chelator, and its first investigation for 68Ga complexation and as a new positron emission tomography (PET) imaging agent of inflammation in comparison to [68Ga]Ga-citrate.ResultsThe present experimental studies have shown that the novel [68Ga]Ga-4HMSA is stable allowing imaging of inflammation in a preclinical model of adjuvant- and pathogen-based inflammation involving intraplantar injection of complete Freund’s adjuvant (CFA). We also found that [68Ga]Ga-4HMSA displayed similar uptakes in the inflamed paw than [68Ga]Ga-citrate, which are superior compared to those of contralateral (non-injected) paws at days 1–3 from PET imaging. [68Ga]Ga-citrate accumulated in the upper body of the animal such as the liver, lungs and the heart, whereas the [68Ga]Ga-4HMSA revealed low uptakes in the majority of the organs and was cleared relatively rapidly from blood circulation through the kidneys and bladder.ConclusionThe results highlight the potential of [68Ga]Ga-4HMSA as an interesting alternative to [68Ga]Ga-citrate for inflammation imaging by PET. The new PET tracer also offers additional advantages than [68Ga]Ga-citrate in term of dosimetry and lower overall background activity.
Highlights
Imaging diagnosis of inflammation has been challenging for many years
The present experimental studies have shown that the novel [68Ga]Ga-N-HydroxyN-methyl succinamide-based chelator (4HMSA) is stable allowing imaging of inflammation in a preclinical model of adjuvant- and pathogen-based inflammation involving intraplantar injection of complete Freund’s adjuvant (CFA)
We found that [68Ga]Ga-4HMSA displayed similar uptakes in the inflamed paw than [68Ga]Ga-citrate, which are superior compared to those of contralateral paws at days 1–3 from positron emission tomography (PET) imaging. [68Ga]Ga-citrate accumulated in the upper body of the animal such as the liver, lungs and the heart, whereas the [68Ga]Ga-4HMSA revealed low uptakes in the majority of the organs and was cleared relatively rapidly from blood circulation through the kidneys and bladder
Summary
Imaging diagnosis of inflammation has been challenging for many years. Inflammation imaging agents commonly used in nuclear medicine, such as [67Ga]Ga-citrate and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)showed some limitations. We report the synthesis of 4HMSA, a new acyclic chelator, and its first investigation for 68Ga complexation and as a new positron emission tomography (PET) imaging agent of inflammation in comparison to [68Ga]Ga-citrate. Ga-citrate was a prime radiotracer for imaging inflammation of musculoskeletal origin [3] for over 40 years but several shortcomings limit its clinical application including poor image quality and resolution as well as its high energy gamma rays delaying imaging of up to 72 h. We aimed to develop a bifunctional variant of the 4HMS for further evaluation and application in inflammation-based PET imaging This new bifunctional chelator called 4HMSA is functionalized with a carboxylic acid group at one of the terminal amine in order to improve its solubility at physiologic pH (Fig. 1). Our hypothesis is that 4HMSA will act as a transporter of 68Ga, which will modulate favorably its biodistribution profile making the resultant [68Ga] Ga-4HMSA an appropriate PET tracer for inflammation imaging
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