Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [11C]SA4503

Molecular Imaging and Biology, Dec 2015

Purpose Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET). Procedures Time-dependent uptake of [11C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function. Results In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (V T) and binding potential (BP ND) of the tracer. BP ND was reduced particularly in the (hypo)thalamus, pons, and medulla. Conclusions Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected.

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Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [11C]SA4503

Mol Imaging Biol Sigma-1 Agonist Binding in the Aging Rat Brain: 11 a MicroPET Study with [ C]SA4503 Nisha K. Ramakrishnan 1 2 Anniek K. D. Visser 2 Anna A. Rybczynska 2 Csaba J. Nyakas 0 4 Paul G. M. Luiten 0 4 Chantal Kwizera 2 Jurgen W. A. Sijbesma 2 Philip H. Elsinga 2 Kiichi Ishiwata 3 Rudi A. J. O. Dierckx 2 Aren van Waarde 2 0 Research Group of Molecular Neurobiology, University of Groningen , Nijenborgh 7, 9747 AG, Groningen , The Netherlands 1 Division of Imaging Sciences and Biomedical Engineering, King's College London , Strand, London, WC2R 2LS , UK 2 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen , Hanzeplein 1, 9713 GZ, Groningen , The Netherlands 3 Southern Tohoku Research Institute for Neuroscience , 7-115 Yatsuyamada, Koriyama, 963-8052 , Japan 4 Department of Morphology and Physiology, Semmelweis University , 17 Vas, H-1088, Budapest , Hungary Purpose: Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET). Procedures: Time-dependent uptake of [11C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function. Results: In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (VT) and binding potential (BPND) of the tracer. BPND was reduced particularly in the (hypo)thalamus, pons, and medulla. Conclusions: Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected. Senescence; Sigma-1 receptor; Agonist binding; Positron emission tomography; Kinetic modeling; Brainstem; Hypothalamus - Sigma-1 receptors are widely distributed throughout the brain and are expressed mainly on neurons, with the highest expression levels in various cranial nerve nuclei in the midbrain, pons, and medulla [1–4]. These receptors are ligand-regulated molecular chaperones in the endoplasmatic reticulum and play a modulatory role in intracellular calcium signaling [5]. Activated sigma-1 receptors translocate from the endoplasmatic reticulum to the plasma membrane and modulate the activity of ion channels and neurotransmitter release [5]. Sigma-1 receptor stimulation can increase the extracellular concentrations of dopamine [6–8], acetylcholine [9, 10], and glutamate [11–13]. Sigma-1 receptors have been implied in cellular differentiation [14], neuritogenesis [15], neuroprotection, and cognition [16]. Aging has a strong impact on neurotransmission in the mammalian brain. Particularly, the dopaminergic system has been widely examined, not only with in vitro techniques but also with in vivo imaging. Substantial losses of dopamine D1 and D2 receptors binding with increasing age have been observed in micro-positron emission tomography (microPET) studies of young (2 to 6 months) and old (18 to 24 months) rats [17, 18]. Cholinergic deficits have also been detected in this animal species, using microPET and the presynaptic cholinergic marker [18F]fluoroethoxybenzovesamicol. [19] In contrast to the extensive data on dopaminergic and cholinergic neurotransmission, sigma-1 receptors in the aging rodent brain have been little examined. Imaging studies in rats have not yet been reported, and published data from in vitro assays concerned either the whole brain [20–23] or only a single brain region, i.e., the striatum [24]. Moreover, most of these data were acquired with sigma ligands which lacked subtype-selectivity [20, 21, 24]. For this reason, we performed quantitative microPET studies with a subtype-selective radioligand in living rats of different ages and determined sigma-1 receptor binding potentials throughout the brain. We were interested in answering the question whether sigma-1 receptor populations in various brain regions are differently affected by healthy aging and whether observed changes (if any) could be related to changes of rodent physiology at advancing age. Materials and Methods Radioligand T h e l i g a n d 1 - [ 2 - ( 3 , 4 - d i m e t h o x y p h e n e t h y l ) ] - 4 - ( 3 phenylpropyl)piperazine ([11C]SA4503) was prepared by reaction of [11C]methyl iodide with 4-O-demethyl SA4503, according to a published method [25]. The decay-corrected radiochemical yield was ~24 %, the specific radioactivity was 9100 TBq/mmol at the moment of injection, and radiochemical purity was 998 %. The [11C]SA4503 solution had a pH of 6.0 to 7.0. Male Wistar Hannover rats were obtained from Harlan (The Netherlands) and Semmelweis University Budapest. Animals from the following age groups were included: 1.5 (n= 9) (...truncated)


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Nisha K. Ramakrishnan, Anniek K. D. Visser, Anna A. Rybczynska, Csaba J. Nyakas, Paul G. M. Luiten, Chantal Kwizera, Jurgen W. A. Sijbesma, Philip H. Elsinga, Kiichi Ishiwata, Rudi A. J. O. Dierckx, Aren van Waarde. Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [11C]SA4503, Molecular Imaging and Biology, 2016, pp. 588-597, Volume 18, Issue 4, DOI: 10.1007/s11307-015-0917-6