PET monitoring of donepezil therapy in patients with Alzheimers

The 12th International Symposium on Radiopharmacolog

Tracer Conversion Rate and Accuracy of Compartmental Model Parameter in Irreversibly Trapped Radiotracer Method

Blood flow linitation of tracer delivery to tissues often affects accuracy and precision of kinetic parameter estimates, particularly in the K3 parameter (tracer conversion rate) of irreverisible tracers in tissues with high K3. As an example of such irreversible radiotracers,[11C] N-methylpiperidinyl-4-acetate, which is metabolically trapped in the brain, was used in the present study. The extent of PET data error in the scanning conditions employed was estimated by analyzing relationships in radioactivity count, standard error of pixel data, and observed PET data error in regiouns of inerest taken in emission images of a homogenous phantom and healthy human subjects. In several cerebral regions with different K3, standard time-radioactivity curves were obtained from one particular subject using three-compartment kinetic model analysis with nonlinear leaast-squares method.The standard time-radioactivity curve and the estimated PET data error were used to generate 100 different time-radioactivity data sets in each region. Two analytical methods for kinetic parameter estimation, i,e., conventional nonlinear least-squares method and shape analysis that estimtes K3 without using input function, were then applied to the sinulated data sets to evaluate the accuracy and precicion of K3 estimates. Both methods gave higher accuracy and precision of K3 in regions with lower K3. The dynamic range of K3 estimation was slightly Wider in the nonlinear least-squares method than in the shape analysis

Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates

A new method for quantitative measurement of brain acetylcholinesterase(AChE) activity in living human brain using positron emission tomography(PET) is described. We tested several radiolabeled lipophilic acetylcholine analogs, e.g., N-methylpiperidyl esters, which readily entered the brain via the blood-brain barrier, were hydrolyzed sselectively by AChE, and were then trapped in the brain. Among them, and tested and N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) was chosen as the tracer for PET. Quantitative measurement of cortical AChE was accomplished by fitting the time course of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies with a wide range in age(24-89 years) showed no decrease in AChE activity in the cerebral cortex with age. Studies on patients with Alzheimers disease demonstrated a widespread reduction of AChE activity in the cerebral cortex (more profound in early-onse than in late-onset Alzheimers disease). Parkinsons disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with [11C]MP4A/PET studies. Simple methods without using an arterial input function are also proposed. The method provides a quantitative measure ot the cholinergic aspect of brain function and proved to be useful in diagnosis of neurodegenerative disorders including Alzheimers disease

Synthesis of Piperidinyl and Pyrrolidinyl Butyrates for Potential In Vivo Measurement of Cerebral Butyrylcholinesterase Activity

Biochemical changes in postmortem brains of Alzheimer s diseaase patients include decreased acetylcholinesterase and choline acetyl transferase activity, indicating reduced activity of the central cholinergic system, while butyrylcholinesterase (BChE) activity increases. A method that can measure regional BChE activity in the brain in vivo may be useful for investigation the relationship between BChE and Alzheimer s disease. Seven compounds, either piperidinyl or pyrrolidinyl butyrates, were synathesized as BChE substrate radiotracers to map central BChE activity in vivo by positron emission tomography (PET). 14C-labeled compounds were assayed to determine their hydrolysis rates by BChE and the partition coefficient. The five esters of secondary alcohols had lipophilic properties sufficient to pass readily through the blood-brain barrier while the metabolites were sufficiently hydrophilic to be retained in the brain. The esters showed moderate hydrolysis rates by BChE and high specificity for BChE relaative to acetylcholinesterase, while two esters of primary alcohols were hydrolyzed too rapidly to estimate reliably the local cerebral BChE activity. From these results, we conclude that one or more of these five esters, when labeled with 11C, would be a useful racer for quantigication of BChE activity by PET

Piperidinyl and pirrolidinyl butyrates as radiotracers for measuring cerebral butyrylchilinesterase activity: Evaluation in rats.

The 14th International Symposium on Radiopharmaceutical Chemistr

N-methyl-3-hydroxy-3-(2-[123I]iodoethenyl)-4-eacetoxymethyl-piperidine:a novel acetylcholine radioanalog for SPECT.

The 14th International Symposium onn Radiopharmaceutical Chemistr