ABSTRACT
The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.
Subject(s)
Microglia/metabolism , Molecular Imaging , Positron-Emission Tomography , Purinergic P2X Receptor Antagonists/chemistry , Radiopharmaceuticals/chemistry , Receptors, Purinergic P2X7/chemistry , Animals , Brain/diagnostic imaging , Brain/metabolism , Humans , Microglia/drug effects , Molecular Structure , Positron-Emission Tomography/methods , Protein Binding , Purinergic P2X Receptor Antagonists/pharmacokinetics , Radiochemistry , Radiopharmaceuticals/pharmacokinetics , Rats , Staining and Labeling , Tissue DistributionABSTRACT
Molecular imaging of matrix metalloproteinases (MMPs) may allow detection of atherosclerotic lesions vulnerable to rupture. In this study, we develop a novel radiolabelled compound that can target gelatinase MMP subtypes (MMP2/9) with high selectivity and inhibitory potency. Inhibitory potencies of several halogenated analogues of MMP subtype-selective inhibitors (N-benzenesulfonyliminodiacetyl monohydroxamates and N-halophenoxy-benzenesulfonyl iminodiacetyl monohydroxamates) were in the nanomolar range for MMP2/9. The analogue with highest inhibitory potency and selectivity was radiolabelled with [123I], resulting in moderate radiochemical yield, and high radiochemical purity. Biodistribution studies in mice, revealed stabilization in blood 1 hour after intravenous bolus injection. Intravenous infusion of the radioligand and subsequent autoradiography of excised aortas showed tracer uptake in atheroprone mice. Distribution of the radioligand showed co-localization with MMP2/9 immunohistochemical staining. In conclusion, we have developed a novel selective radiolabeled MMP2/9 inhibitor, suitable for single photon emission computed tomography (SPECT) imaging that effectively targets atherosclerotic lesions in mice.
Subject(s)
Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Plaque, Atherosclerotic/diagnostic imaging , Animals , Female , Ligands , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Radioligand Assay , Tissue Distribution , Tomography, Emission-Computed, Single-PhotonABSTRACT
Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised. In addition, new molecular targets for imaging of neuroinflammation, such as monoamine oxidases, adenosine receptors and cannabinoid receptor type 2, are discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
