Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone.

(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer's disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[11C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc)3 as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100 °C for 10 min gave (R,S)-[11C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield. HPLC separation using a strong cation exchange column, followed by pharmaceutical formulation in the presence of d/l-tartaric acid, afforded (R,S)-[11C]isoproterenol with a total radioactivity of 2.0 ±â€¯0.2 GBq, a decay-corrected radiochemical yield of 19 ±â€¯2%, chemical and radiochemical purities of 71% and >99%, respectively, and a molar activity of 100 ±â€¯13 GBq/µmol (n = 3). The overall synthesis time from the end of the bombardment to pharmaceutical formulation was 48 min. A preliminary preclinical PET study in a rat demonstrated the potential of the radioligand for the evaluation of the penetration of (R,S)-isoproterenol in human brain.

An atlas-based image registration method for dopamine receptor imaging with PET in rats.

For analysis of in vivo dopamine receptor binding in the rat brain by positron emission tomography (PET), a convenient method to obtain precise anatomical registration for striatum and cerebellum on the PET image was developed. On the PET measurements, a control, an anesthetized rat was positioned in a stereotaxic holder so that the horizontal plane of the PET image would be parallel to the horizontal plane of the brain atlas. After the positioning, [11C]raclopride was intravenously injected into the rats and scanned to obtain PET images of dopamine D2 receptor in the brain. The striatum was bilaterally identified in the obtained PET image. The atlas-based regions of interest (ROIs) of the whole brain were preliminarily created according to the atlas, and were superimposed on an early phase PET image. The early phase PET image was compatible to the whole brain ROI in the atlas, which enabled determination of striatal and cerebellar ROI difficult to determine by the PET image alone. Using the cerebellar radioactivity as a reference input function, rate constants between the free/nonspecific compartment and the receptor bound compartment (k3 and k4) were calculated by a two-parameter compartment model, and the binding potential (k3/k4) was estimated. The binding potential and its coefficients of variation were 1.56+/-0.30, 19.3% in Wistar rats, 1.05+/-0.14, 13.4% in Sprague-Dawley (SD) rats, and 1.29+/-0.07, 5.2% in Fischer F344 rats, in which binding potential in Wistar rats was significantly higher than that in SD rats. This method is objective and convenient in routine use for PET studies in rats, regardless of differences in the rat strains.

Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain.

Positron emission tomography (PET) measurements in 6-month-old F344/N rats were performed in the conscious state and the influence of chloral hydrate, ketamine, and pentobarbital anesthesia on dopamine D(1) (DA-D(1)) receptor binding was evaluated using [(11)C]SCH23390, a selective DA-D(1) receptor ligand. To perform the PET study in conscious rats, an original fixation apparatus was developed and the animals were trained to acclimate to the scanning atmosphere for 3 h. This training was carried out twice a day for 2 weeks. PET measurements in conscious rats were successful, since the trained rats scarcely moved during the scanning (as monitored by video camera) and since highly reproducible measurements of binding potential (BP) were derived from their scanning. Chloral hydrate and ketamine anesthesia significantly increased the striatal BP of DA-D(1) receptors by 36% and 46%, respectively, compared to that observed in the conscious state. In contrast, pentobarbital markedly decreased the BP by 41%. These BP values of DA-D(1) receptors were calculated using a curve-fitting method. Our results indicate that PET studies in rats should be performed in the conscious state since the anesthetics dramatically modified ligand-receptor bindings, such as DA-D(1) receptor binding, in rat brain.

Cognitive- and motor-related regions in Parkinson's disease: FDOPA and FDG PET studies.

OBJECTIVE: Using 6-[(18)F]fluoro-L-dopa (FDOPA) and [(18)F]fluorodeoxyglucoce (FDG) positron emission tomography (PET), multiple regression analyses were performed to determine the specific brain regions that are related to cognitive and motor symptoms in nondemented patients with Parkinson's disease. METHODS: Spatially normalized images of FDOPA influx rate constant (Ki) values and relative regional cerebral metabolic rates for glucose (rrCMRglc) were created. Raven's Coloured Progressive Matrices (RCPM) scores and the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were used to determine the patients' cognitive and motor functions, respectively. Multiple correlation analyses between the FDOPA and FDG images and the cognitive and motor scores were performed for each voxel. RESULTS: RCPM score was significantly positively correlated with the FDOPA Ki in the left hippocampus and with the rrCMRglc in the left middle frontal gyrus and right retrosplenial cortex. Motor function was significantly positively correlated with the FDOPA Ki in the bilateral striatum and with the rrCMRglc in association areas and primary visual cortex. The level of motor function was significantly inversely correlated with the FDOPA Ki in the anterior cingulate gyrus and with the rrCMRglc in bilateral primary motor cortex and right putamen. CONCLUSIONS: Changes of striatal FDOPA uptake and rrCMRglc in the primary motor cortex likely represent dysfunction in the motor system involving the corticobasal ganglia-thalamocortical loop. Change of FDOPA uptake in the anterior cingulate gyrus may be related to up-regulation of dopamine synthesis in surviving dopamine neurons. The regions where correlation with cognitive function was observed belong to a cognitive frontoparietal-hippocampal network.

Direct electrophilic radiofluorination of a cyclic RGD peptide for in vivo alpha(v)beta3 integrin related tumor imaging.

The association of the alpha(v)beta(3) integrin with tumor metastasis and tumor related angiogenesis has been suggested. Therefore, by imaging the alpha(v)beta(3) receptor with PET, information concerning the tumor status could be obtained. Cyclic peptides including the RGD sequence, were radiolabeled by direct electrophilic fluorination with [(18)F]AcOF. In tumor-bearing mice, the labeled peptides accumulated at the tumor with a high tumor to blood ratio. These findings suggest that an assessment of tumor characteristics may be obtained by using these (18)F-labeled peptides.

Synthesis and evaluation of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-[11C]ethyl-1,3-dihydro-2H-benzimidazol-2-one as a brain ORL1 receptor imaging agent for positron emission tomography.

1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-[(11)C]ethyl-1,3-dihydro-2H-benzimidazol-2-one ([(11)C]CPEB) was synthesized by [(11)C]N-ethylation and evaluated as a potential brain ORL1 receptor imaging agent by positron emission tomography. The uptake of [(11)C]CPEB in the mouse brain was 1.9% dose/g, 2 min post-injection, and gradually decreased with time. Receptor-specific binding was observed, however, the contribution of other receptors was observed and the non-specific binding of [(11)C]CPEB was too high for imaging receptors in vivo. Therefore, [(11)C]CPEB is not a suitable tracer for in vivo ORL1 receptor imaging.

Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-L-dopa PET study.

We investigated the relative differences in dopaminergic function through the whole brain in patients with Parkinson's disease without dementia (PD) and with dementia (PDD) using 6-[18F]fluoro-L-dopa (18F-dopa) PET and a voxel-by-voxel analysis. The 10 PD and 10 PDD patients were equivalently disabled, having mean scores of 3.2 +/- 0.6 and 3.2 +/- 0.7, respectively, on the Hoehn and Yahr rating scale. 18F-dopa influx constant (Ki) images of those patients and 15 normal age-matched subjects were transformed into standard stereotactic space. The significant differences between the groups (expressed in mean regional Ki values) were localized with statistical parametric mapping (SPM) on a voxel-by-voxel basis. Compared with the normal group, SPM localized declines of the 18F-dopa Ki bilaterally in the putamen, the right caudate nucleus and the left ventral midbrain for the PD group (P < 0.01, corrected). Compared with the normal group, the PDD group showed reduced 18F-dopa Ki bilaterally in the striatum, midbrain and anterior cingulate area (P < 0.01, corrected). A relative difference in 18F-dopa uptake between PD and PDD was the bilateral decline in the anterior cingulate area and ventral striatum and in the right caudate nucleus in the PDD group (P < 0.001, corrected). Accordingly, we conclude that dementia in PD is associated with impaired mesolimbic and caudate dopaminergic function.