Mali Pratap

99mTc Hexamethyl-Propylene-Aminoxime Single-Photon Emission Computed Tomography Prediction of Conversion From Mild Cognitive Impairment to Alzheimer Disease

OBJECTIVE To examine the utility of single-photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). DESIGN Longitudinal, prospective study. SETTING University-based memory disorders clinic. PARTICIPANTS One hundred twenty seven patients with MCI and 59 healthy comparison subjects followed up for 1-9 years. MEASUREMENTS Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, magnetic resonance imaging, and brain Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done. RESULTS Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fishers exact test p = 0.013). Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% confidence interval: 1.16-7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% confidence interval: 1.14-8.56, p = 0.027). In the 3-year follow-up sample, low parietal (p <0.05) and medial temporal (p <0.01) flow predicted conversion to AD, with or without controlling for age, Mini-Mental State Examination, and apolipoprotein E ε4 genotype. These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal, and entorhinal cortex volumes. CONCLUSIONS SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.

In vivo biodistribution of a radiotracer for imaging serotonin-1a receptor sites with pet: [11C]Ly274601

LY274601 [R-(+)8-thiomethyl-2-(di-n-propyl-amino)tetralin], a full agonist of the 5-HT1A receptor with high affinity and selectivity, was labeled with 11C and 3H, and its in vivo behavior was studied to evaluate [11C]LY274601 as a PET radiotracer for imaging 5-HT1A receptor sites in living brain. Following intravenous tail injection into mice, [11C]LY274601 showed high blood-brain barrier permeability and accumulated in regions known to have high densities of 5-HT1A receptor sites such as the brain stem including the raphe nuclei. The binding of the radiotracer in target tissues is blocked by pre-injection of the 5-HT1A receptor selective ligand 8-OH-DPAT (1 mg/kg, s.c.), suggesting that the binding is specific to 5-HT1A receptor sites. Using ex vivo autoradiography, the target tissues such as hippocampus CA1-4 fields, piriform cortex, dorsal raphe nucleus and lateral septum were visualized as hot spots. These tissues were observed to have binding 2-2.7 times greater than the cerebellum. The distribution of the radiotracer agrees well with the distribution of 5-HT1A receptors revealed by in vitro autoradiography with [3H]8-OH-DPAT. However, the radiotracer was metabolized quickly and cleared from target tissues with a half life of approximately 15 min. [11C]LY274601 showed high non-specific binding in regions with low number of 5-HT1A receptor sites such as cerebellum.

Radiosynthesis and in Vivo Evaluation of Neuropeptide Y5 Receptor (NPY5R) PET Tracers

Neuropeptide Y receptor type 5 (NPY5R) is a G-protein coupled receptor (GPCR) that belongs to the subfamily of neuropeptide receptors (NPYR) that mediate the action of endogenous neuropeptide Y (NPY). Animal models and preclinical studies indicate a role for NPY5R in the pathophysiology of depression, anxiety, and obesity and as a target of potential therapeutic drugs. To better understand the pathophysiological involvement of NPY5R, and to measure target occupancy by potential therapeutic drugs, it would be advantageous to measure NPY5R binding in vivo by positron emission tomography (PET). Four potent and selective NPY5R antagonists were radiolabeled via nucleophilic aromatic substitution reactions with [(18)F]fluoride. Of the four radioligands investigated, PET studies in anesthetized baboons showed that [(18)F]LuAE00654 ([(18)F]N-[trans-4-({[4-(2-fluoropyridin-3-yl)thiazol-2-yl]amino}methyl)cyclohexyl]propane-2-sulfonamide) penetrates blood brain barrier (BBB) and a small amount is retained in the brain. Slow metabolism of [(18)F]LuAE00654 was observed in baboon plasma. Blocking studies with a specific NPY5R antagonist demonstrated up to 60% displacement of radioactivity in striatum, the brain region with highest NPY5R binding. Our studies suggest that [(18)F]LuAE00654 can be a potential PET radiotracer for the quantification and occupancy studies of NPY5R drug candidates.