mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG.

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall's W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results.

The adenosine A(2A) receptor in the basal ganglia is involved in the control of movement and plays a role in movement disorders such as Parkinsonism. Developing ligands to evaluate that receptor by noninvasive methods such as positron emission tomography has a high priority. In vitro radioligand binding guides the selection of ligands for in vivo application. This study measured the binding of the adenosine A(2A) receptor antagonist [(3)H]MSX-2 (3-(3-hydroxypropyl)-8-m-methoxystyryl)-7-methyl-1-propargylxanthine) to rat, mouse and pig brain by autoradiography. Other studies measured binding to membranes from PC12 pheochromocytoma cells. Those binding parameters were compared to those of the adenosine A(2A) receptor antagonist [(3)H]ZM241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino)ethyl)phenol), the adenosine A(2A) receptor agonist [(3)H]CGS21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine) and the unselective adenosine receptor agonist [(3)H]NECA (5'N-ethylcarboxamido)adenosine). The potency order (K(d)) in the three species was [(3)H]ZM241385<[(3)H]MSX-2<[(3)H]NECA<[(3)H]CGS21680. The density of [(3)H]MSX-2 binding sites was greater in the striatum than in the cortex. Preliminary ex vivo experiments showed that by 10min after iv injection, [(3)H]MSX-2 and [(3)H]CGS21680 crossed the blood-brain barrier to the extent of almost 1% ID/g brain tissue, but [(3)H]NECA and [(3)H]ZM241385 to only 0.2% ID/g. The prior administration of unlabeled ZM241385 significantly lowered brain uptake of [(3)H]MSX-2. In conclusion, [(3)H]MSX-2 has a high affinity and sufficient selectivity for the adenosine A(2A) receptor. It penetrates the blood-brain barrier. Sensitivity to photoisomerization is a limitation. Further investigations assess its suitability as a ligand for imaging the brain adenosine A(2A) receptor.

High molar activity of [11C]TCH346 via [11C]methyl triflate using the "wet" [11C]CO2 reduction method.

[(11)C]TCH346, a compound acting on the glycolytic enzyme, glycerol-aldehyde-3-phosphate dehydrogenase, was produced under optimised conditions by methylation of the desmethyl compound with no-carrier added (n.c.a.) [(11)C]methyl triflate. An i.v. injectable solution of n.c.a. [(11)C]TCH346 containing 4040+/-1550 MBq (n=6) containing a molar activity between 40 and 5700 GBq/micromol and a radiochemical purity of >99% was obtained within 30 min (after EOB) by irradiation of nitrogen gas containing 0.5% oxygen with 16.5 MeV protons at 45 microA for 30 min. The alkylation reagent [(11)C]methyl triflate was prepared via on-line conversion of [(11)C]methyl iodide. For the formation of [(11)C]methyl iodide, [(11)C]carbon dioxide from the target chamber was reduced by a lithium aluminium hydride solution, and the methanol obtained on-line was converted using triphenylphosphine diiodide. The molar activity of [(11)C]TCH346 could be improved from 40 up to nearly 5700GB q/micromol during the optimisation of the synthesis using the same stock solution of lithium aluminium hydride solution in tetrahydrofuran.

Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2A adenosine receptor antagonists for positron emission tomography (PET).

The brain A2A adenosine receptor (A2AAR) participates with the dopamine D2 receptor in the control of movement and also might influence behavior. Because PET is an important tool for studying the roles of receptors in disease, a ligand for imaging the brain A2AAR is desirable. This report describes the synthesis and A2AAR antagonist activities of a panel of phenyl-substituted 7-amino-2-(2-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines, 11aa-af, and their 3-furyl congeners, 11ba-bd. In competitive binding studies all compounds displaced [3H]CGS21680 from the A2AAR with Ki values of 14-33 nM with selectivity for the A2AAR over the A1AR of 5- to 94-fold. Autoradiography of brain sections showed a high level of unspecific binding that obscured specific binding. Thus, these compounds are not promising PET ligands.