Human Biodistribution and Dosimetry of 11C-CUMI-101, an Agonist Radioligand for Serotonin-1A Receptors in Brain

As a reported agonist,11C-CUMI-101 is believed to selectively bind the G-protein-coupled state of the serotonin-1A (5-HT1A) receptor, thereby providing a measure of the active subset of all 5-HT1A receptors in brain. Although 11C-CUMI-101 has been successfully used to quantify 5-HT1A receptors in human and monkey brain, its radiation exposure has not previously been reported. The purpose of this study was to calculate the radiation exposure to organs of the body based on serial whole-body imaging with positron emission tomography (PET) in human subjects

Image-Derived Input Function for Human Brain Using High Resolution PET Imaging with [11C](R)-rolipram and [11C]PBR28

The aim of this study was to test seven previously published image-input methods in state-of-the-art high resolution PET brain images. Images were obtained with a High Resolution Research Tomograph plus a resolution-recovery reconstruction algorithm using two different radioligands with different radiometabolite fractions. Three of the methods required arterial blood samples to scale the image-input, and four were blood-free methods. values was quantified using a scoring system. Using the image input methods that gave the most accurate results with Logan analysis, we also performed kinetic modelling with a two-tissue compartment model.)-rolipram, which has a lower metabolite fraction. Compartment modeling gave less reliable results, especially for the estimation of individual rate constants.C]PBR28), the more difficult it is to obtain a reliable image-derived input function; and 4) in association with image inputs, graphical analyses should be preferred over compartmental modelling

Macrophage-Specific ApoE Gene Repair Reduces Diet-Induced Hyperlipidemia and Atherosclerosis in Hypomorphic Apoe Mice

Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account for up to 10% of plasma apoE levels. This study examined the contribution of macrophage-derived apoE expression levels in diet-induced hyperlipidemia and atherosclerosis.Hypomorphic apoE (Apoe(h/h)) mice expressing wildtype mouse apoE at ∼2-5% of physiological levels in all tissues were derived by gene targeting in embryonic stem cells. Cre-mediated gene repair of the Apoe(h/h) allele in Apoe(h/h)LysM-Cre mice raised apoE expression levels by 26 fold in freshly isolated peritoneal macrophages, restoring it to 37% of levels seen in wildtype mice. Chow-fed Apoe(h/h)LysM-Cre and Apoe(h/h) mice displayed similar plasma apoE and cholesterol levels (55.53±2.90 mg/dl versus 62.70±2.77 mg/dl, n = 12). When fed a high-cholesterol diet (HCD) for 16 weeks, Apoe(h/h)LysM-Cre mice displayed a 3-fold increase in plasma apoE and a concomitant 32% decrease in plasma cholesterol when compared to Apoe(h/h) mice (602.20±22.30 mg/dl versus 888.80±24.99 mg/dl, n = 7). On HCD, Apoe(h/h)LysM-Cre mice showed increased apoE immunoreactivity in lesional macrophages and liver-associated Kupffer cells but not hepatocytes. In addition, Apoe(h/h)LysM-Cre mice developed 35% less atherosclerotic lesions in the aortic root than Apoe(h/h) mice (167×10(3)±16×10(3) µm(2) versus 259×10(3)±56×10(3) µm(2), n = 7). This difference in atherosclerosis lesions size was proportional to the observed reduction in plasma cholesterol.Macrophage-derived apoE raises plasma apoE levels in response to diet-induced hyperlipidemia and by such reduces atherosclerosis proportionally to the extent to which it lowers plasma cholesterol levels

Population-based input function modeling for [(18)F]FMPEP-d 2, an inverse agonist radioligand for cannabinoid CB1 receptors: validation in clinical studies.

BACKGROUND: Population-based input function (PBIF) may be a valid alternative to full blood sampling for quantitative PET imaging. PBIF is typically validated by comparing its quantification results with those obtained via arterial sampling. However, for PBIF to be employed in actual clinical research studies, its ability to faithfully capture the whole spectrum of results must be assessed. The present study validated a PBIF for [(18)F]FMPEP-d 2, a cannabinoid CB1 receptor radioligand, in healthy volunteers, and also attempted to utilize PBIF to replicate three previously published clinical studies in which the input function was acquired with arterial sampling. METHODS: The PBIF was first created and validated with data from 42 healthy volunteers. This PBIF was used to assess the retest variability of [(18)F]FMPEP-d 2, and then to quantify CB1 receptors in alcoholic patients (n = 18) and chronic daily cannabis smokers (n = 29). Both groups were scanned at baseline and after 2-4 weeks of monitored drug abstinence. RESULTS: PBIF yielded accurate results in the 42 healthy subjects (average Logan-distribution volume (V T) was 13.3±3.8 mL/cm(3) for full sampling and 13.2±3.8 mL/cm(3) for PBIF; R(2) = 0.8765, p<0.0001) and test-retest results were comparable to those obtained with full sampling (variability: 16%; intraclass correlation coefficient: 0.89). PBIF accurately replicated the alcoholism study, showing a widespread ∼20% reduction of CB1 receptors in alcoholic subjects, without significant change after abstinence. However, a small PBIF-V T bias of -9% was unexpectedly observed in cannabis smokers. This bias led to substantial errors, including a V T decrease in regions that had shown no downregulation in the full input function. Simulated data showed that the original findings could only have been replicated with a PBIF bias between -6% and +4%. CONCLUSIONS: Despite being initially well validated in healthy subjects, PBIF may misrepresent clinical protocol results and be a source of variability between different studies and institutions

The positron emission tomographic radioligand 18F-FIMX images and quantifies metabotropic glutamate receptor 1 in proportion to the regional density of its gene transcript in human brain

A recent study from our laboratory found that (18)F-FIMX is an excellent positron emission tomography (PET) radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake (VS) and nondisplaceable uptake (VND) in each brain region.METHODS: After injection of 189 ± 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 minutes. In six of them, images were acquired until 210 minutes. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects had whole-body scans to estimate radiation exposure.RESULTS: (18)F-FIMX uptake into human brain was high (SUV = 4-6 in cerebellum), peaked at about 10 minutes, and washed out rapidly. An unconstrained two-tissue compartment model fitted the data well, and distribution volume (VT) (mL • cm-3) values ranged from 1.5 in caudate to 11 in cerebellum. A 120-minute scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 minutes was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL • cm-3). This measure of VND in humans was very similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 µSv/MBq.CONCLUSION: (18)F-FIMX can quantify mGluR1 in human brain with a 120 - 170 minute scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacological doses of a blocking agent