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Background: The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention. Results: The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications. Conclusion: This study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability. [ABSTRACT FROM AUTHOR]

Background: Platelet-derived growth factor receptor beta (PDGFRβ) is a receptor overexpressed on activated hepatic stellate cells (aHSCs). Positron emission tomography (PET) imaging of PDGFRβ could potentially allow the quantification of fibrogenesis in fibrotic livers. This study aims to evaluate a fluorine-18 radiolabeled Affibody molecule ([18F]TZ-Z09591) as a PET tracer for imaging liver fibrogenesis. Results: In vitro specificity studies demonstrated that the trans-Cyclooctenes (TCO) conjugated Z09591 Affibody molecule had a picomolar affinity for human PDGFRβ. Biodistribution performed on healthy rats showed rapid clearance of [18F]TZ-Z09591 through the kidneys and low liver background uptake. Autoradiography (ARG) studies on fibrotic livers from mice or humans correlated with histopathology results. Ex vivo biodistribution and ARG revealed that [18F]TZ-Z09591 binding in the liver was increased in fibrotic livers (p = 0.02) and corresponded to binding in fibrotic scars. Conclusions: Our study highlights [18F]TZ-Z09591 as a specific tracer for fibrogenic cells in the fibrotic liver, thus offering the potential to assess fibrogenesis clearly. [ABSTRACT FROM AUTHOR]

Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [11C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [11C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague–Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [11C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [11C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [11C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [11C]UCB-J does not appear to have sufficient sensitivity for this application. [ABSTRACT FROM AUTHOR]

The Suzuki‐type cross coupling reaction is a palladium‐mediated multistep reaction that has been used to synthesize several 11C‐labeled tracers for PET. However, the impact of the selected organoborane reagent and reaction medium on the radiochemical yield (RCY) has not been thoroughly investigated. To bridge this gap, we studied the synthesis of 1‐[11C]methylnaphthalene using four different organoborane precursors in reactions performed in DMF/water and THF/water. In the synthesis of 1‐[11C]methylnaphthalene, the best radiochemical yields (RCYs), approximately 50%, were obtained with boronic acid and pinacol ester precursors, whereas less than 4% RCY was obtained when performing the reaction with the N‐methylimidodiacetic acid boronic ester (MIDA ester) precursor. 1‐[11C]methylnaphthalene was obtained in higher yields in almost all syntheses performed in THF/water as compared to DMF/water. This observation was in line with previously reported results for [11C]UCB‐J, a tracer for the synaptic vesicle glycoprotein 2A (SV2A) receptor, that also was obtained in higher RCY when synthesized in THF/water. The same trend was observed with [11C]cetrozole, where the RCY was more than doubled in THF/water compared to the previously published synthesis performed in DMF. These results suggest that THF/water could be the preferred reaction medium when producing PET tracers via the Suzuki‐type coupling reaction. [ABSTRACT FROM AUTHOR]

Here, we report the development of novel PET radiotracer ([11C]CW22) of BET proteins. In vivo imaging results in rodents and nonhuman primates (NHP) demonstrate that [11C]CW22 has excellent brain uptake, good specificity, good selectivity, suitable metabolism, appropriate kinetics and distribution in the brain. Our studies demonstrated that [11C]CW22 exhibits ideal properties as a PET imaging probe of BET proteins for further validation. [ABSTRACT FROM AUTHOR]

Background: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo.Objective: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy.Methods: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging.Results: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau.Conclusions: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the anti-amyloid effect of functionalized nanoliposomes (mApoE-PA-LIP) in a mouse model of Alzheimer's disease with use of positron emission tomography and β-amyloid (Aβ)–targeted tracer [ 11 C]Pittsburgh compound B ([ 11 C]PIB). APP23 mice were injected with mApoE-PA-LIP or saline (3 times per week for 3 weeks) and [ 11 C]PIB imaging was performed at baseline, after the treatment and after 3 months follow-up period, accompanied by Aβ immunohistochemistry and ELISA. After the treatment, [ 11 C]PIB binding ratios between mApoE-PA-LIP and saline groups were equivalent in all analyzed brain regions; however, in the saline group, binding ratios increased from the baseline, whereas no increase was detected in the mApoE-PA-LIP group. During the additional follow-up, [ 11 C]PIB binding increased significantly from baseline in both groups, and binding ratios correlated with the immunohistochemically defined Aβ load. This study further supports the use of [ 11 C]PIB positron emission tomography imaging as a biomarker of Aβ deposition in APP23 mice and highlights the benefits of noninvasive follow-up, that is, using baseline data for animal stratification and normalization of treatment effects to baseline values, for future anti-amyloid treatment studies. [ABSTRACT FROM AUTHOR]

The most used positron emission tomography (PET) tracer, 2-[ 18 F]fluoro-2-deoxy- d -glucose ([ 18 F]FDG), is a glucose analogue that is used to measure tissue glucose consumption. Traditionally, the Sokoloff model is the basis for [ 18 F]FDG modeling. According to this model, [ 18 F]FDG is expected to be trapped in a cell in the form of [ 18 F]FDG-6-phosphate ([ 18 F]FDG-6-P). However, several studies have shown that in tissues, [ 18 F]FDG metabolism goes beyond [ 18 F]FDG-6-P. Our aim was to develop radioHPLC and radioTLC methods for analysis of [ 18 F]FDG metabolites from tissue samples. The radioHPLC method uses a sensitive on-line scintillation detector to detect radioactivity, and the radioTLC method employs digital autoradiography to detect the radioactivity distribution on a TLC plate. The HPLC and TLC methods were developed using enzymatically in vitro– produced metabolites of [ 18 F]FDG as reference standards. For this purpose, three [ 18 F]FDG metabolites were synthesized: [ 18 F]FDG-6-P, [ 18 F]FD-PGL, and [ 18 F]FDG-1,6-P2. The two methods were evaluated by analyzing the [ 18 F]FDG metabolic profile from rodent ex vivo tissue homogenates. The HPLC method with an on-line scintillation detector had a wide linearity in a range of 5 Bq–5 kBq (LOD 46 Bq, LOQ 139 Bq) and a good resolution (Rs ≥1.9), and separated [ 18 F]FDG and its metabolites clearly. The TLC method combined with digital autoradiography had a high sensitivity in a wide range of radioactivity (0.1 Bq–2 kBq, LOD 0.24 Bq, LOQ 0.31 Bq), and multiple samples could be analyzed simultaneously. As our test and the method validation with ex vivo samples showed, both methods are useful, and at best they complement each other in analysis of [ 18 F]FDG and its radioactive metabolites from biological samples. [ABSTRACT FROM AUTHOR]

The aim of the present study was to synthesize functionalized 18 F-labeled NLs ( 18 F-NLs) and evaluate their biological behavior in mouse models of Alzheimer's disease (AD) using positron emission tomography (PET) and ex vivo brain autoradiography. 18 F-fluorine was introduced to 18 F-NLs either by using a core forming 18 F-lipid or by encapsulating a 18 F-tracer, 18 F-treg-curcumin inside the NLs. Phosphatidic acid (PA) and curcumin derivative (Curc) functionalized 18 F-NLs with or without additional mApoE functionalization were produced using thin film hydration. The biodistribution and β-amyloid plaque-binding ability of 18 F-NLs were studied in wild type mice and AD mouse models using in vivo PET imaging and ex vivo brain autoradiography at 60 min after 18 F-NL injection. Functionalized 18 F-NLs were successfully synthesized. The preclinical evaluation in mice showed that the functional group affected the biodistribution of 18 F-NLs. Further functionalization with mApoE increased the brain-to-blood ratio of 18 F-NLs but the overall brain uptake remained low with all functionalized 18 F-NLs. The liposomal encapsulation of 18 F-treg-curcumin was not successful and preclinical results of encapsulated 18 F-treg-curcumin and plain 18 F-treg-curcumin were identical. Although the studied functionalized 18 F-NLs were not suitable for PET imaging as such, the synthesis techniques introduced in this study can be utilized to modify the biological behavior of 18 F-labeled NLs. [ABSTRACT FROM AUTHOR]

The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase. [ABSTRACT FROM AUTHOR]

Background/Objective: Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. Methods: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). Results: The effects of age (p < 0.001), APOE ε4 carrier status (p = 0.003), and gender (p = 0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex. Conclusions: Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the potential of [F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [C]Pittsburgh compound B ([C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease. Methods: [F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [C]PIB and [F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry. Results: The pharmacokinetics of [F]flutemetamol resembled that of [C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [F]flutemetamol into radioactive metabolites was faster than that of [C]PIB. [F]Flutemetamol cleared more slowly from the brain than [C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [C]PIB and [F]flutemetamol were 2.28 and 6.65 μSv/MBq, respectively. Autoradiographs showed [F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice. Conclusion: Based on its pharmacokinetic profile, [F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging. [ABSTRACT FROM AUTHOR]

The mouse model of beta-amyloid (Aβ) deposition, APP/PS1-21, exhibits high brain uptake of the tau-tracer (S)-[18F]THK5117, although no neurofibrillary tangles are present in this mouse model. For this reason we investigated (S)-[18F]THK5117 off-target binding to Aβ plaques and MAO-B enzyme in APP/PS1-21 transgenic (TG) mouse model of Aβ deposition. APP/PS1-21 TG and wild-type (WT) control mice in four different age groups (2–26 months) were imaged antemortem by positron emission tomography with (S)-[18F]THK5117, and then brain autoradiography. Additional animals were used for immunohistochemical staining and MAO-B enzyme blocking study with deprenyl pre-treatment. Regional standardized uptake value ratios for the cerebellum revealed a significant temporal increase in (S)-[18F]THK5117 uptake in aged TG, but not WT, brain. Immunohistochemical staining revealed a similar increase in Aβ plaques but not endogenous hyper-phosphorylated tau or MAO-B enzyme, and ex vivo autography showed that uptake of (S)-[18F]THK5117 co-localized with the amyloid pathology. Deprenyl hydrochloride pre-treatment reduced the binding of (S)-[18F]THK5117 in the neocortex, hippocampus, and thalamus. This study's findings suggest that increased (S)-[18F]THK5117 binding in aging APP/PS1-21 TG mice is mainly due to increasing Aβ deposition, and to a lesser extent binding to MAO-B enzyme, but not hyper-phosphorylated tau. • This study investigated (S)-[18F]THK5117 in vivo binding selectivity and pharmacokinetic properties in APP/PS1-21 mouse model. • No NFTs are present in APP/PS1-21 mouse brain, only some endogenous p-tau within the vicinity of Aβ plaques. • A clear temporal increase in (S)-[18F]THK5117 uptake was present in the brain of APP/PS1-21 mouse as they aged. • (S)-[18F]THK5117 binding in APP/PS1-21 mice is mainly due to increasing Aβ plaques, and to a lesser extent due to binding to MAO-B enzyme, but not p-tau. [ABSTRACT FROM AUTHOR]

Introduction: [11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases. The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J. Results: After semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium. Conclusions: A robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications. [ABSTRACT FROM AUTHOR]

■ Synaptic density is decreased in a mouse model of alpha-synucleinopathy. ■ Ageing appears to be associated with decreased synaptic density in wild type mouse brain. ■ Model-independent AUC-based brain-to-blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modeling. The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUC brain/blood), and the volume of distribution (V T) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11–13% lower AUC brain/blood ratio and brain V T generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18–20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8–9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUC brain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling. [Display omitted] [ABSTRACT FROM AUTHOR]

• [18F]SynVesT-1 PET shows synaptic density to be stable during aging, .... • ...except at a very old age when a small decrease is seen in healthy C57BL/6 J mice. • Acquisition time of 60 min together with 1TCM gave robust pharmacokinetic parameter estimates. Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [18F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice. Wild type C57BL/6 mice divided into three age groups (4–5 months (n = 7), 12–14 months (n = 11), 17–19 months (n = 7)) were PET scanned with [18F]SynVesT-1. Brain retention of [18F]SynVesT-1 expressed as the volume of distribution (V IDIF) was calculated using an image-derived input function. Estimates of V IDIF were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [18F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers. We found that [18F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [18F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age-dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed. [ABSTRACT FROM AUTHOR]