A copper-mediated radiofluorination of aryl- and vinylboronic acids with K18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [18F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes [18F]KF to access 18F-labeled electron-rich, -neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-[18F]fluorophenylalanine and 6-[18F]fluoroDOPA.

The last 2–3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.

Objective: We investigated dopaminergic and cholinergic correlates of gait speed in Parkinson disease (PD) and non-PD control subjects to test the hypothesis that gait dysfunction in PD may result from multisystem degeneration.Methods: This was a cross-sectional study. Subjects with PD but without dementia (n 5 125, age 65.6 6 7.3 years) and elderly subjects without PD (n 5 32, age 66.0 6 10.6 years) underwent [ 11 C]dihydrotetrabenazine dopaminergic and [11 C]methyl-4-piperidinyl propionate acetylcholinesterase PET imaging, and cognitive and clinical testing, including an 8.5-m walk in the dopaminergic "off" state. The fifth percentile of cortical cholinergic activity in the elderly without PD was used to define normal-range activity in the subjects with PD.Results: Normal-range cortical cholinergic activity was present in 87 subjects with PD (69.6%).Analysis of covariance using gait speed as the dependent variable demonstrated a significant model (F 5 6.70, p , 0.0001) with a significant group effect (F 5 3.36, p 5 0.037) and significant slower gait speed in the low cholinergic PD subgroup (0.97 6 0.22 m/s) with no significant difference between the normal-range cholinergic PD subgroup (1.12 6 0.20 m/s) and control subjects (1.17 6 0.18 m/s). Covariate effects were significant for cognition (F 5 6.58, p 5 0.011), but not for striatal dopaminergic innervation, sex, or age. Conclusion:Comorbid cortical cholinergic denervation is a more robust marker of slowing of gait in PD than nigrostriatal denervation alone. Gait speed is not significantly slower than normal in subjects with PD with relatively isolated nigrostriatal denervation. The cardinal motor symptoms of Parkinson disease (PD) often develop at different times during disease progression. Upper extremity bradykinesia and rigidity typically precede axial and bilateral lower extremity motor changes, such as limitations in gait.1,2 Imaging studies show that nigrostriatal denervation is already severe in early clinical stage PD.3 Increased activity of other brain systems may compensate for nigrostriatal degeneration. 4,5 If gait speed functions are not prominently affected in early PD despite significant dopaminergic losses, subsequent slowing of gait speed implicates later degeneration of nondopaminergic pathways. A recent study suggested that cholinergic dysfunction is an important contributor to gait dysfunction in PD. 6 We reported previously that subjects with PD with combined basal forebrain cholinergic and dopaminergic deficits had lower global cognitive performance, more severe nigrostriatal denervation, and a trend toward more severe motor impairments, including slower gait, when compared to subjects with PD with normal-range cortical cholinergic innervation. 7 In our prior study, there was no comparison with a non-PD control group and findings were not corrected for the degree of nigrostriatal denervation.

A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [18F]F-phenylalanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.

The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent (11)C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (β = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information.

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IMPORTANCELittle is known about the relative contributions of multisystem degenerative processes across the spectrum of predemented cognitive decline in Parkinson disease (PD).OBJECTIVE To investigate the relative frequency of caudate nucleus dopaminergic and forebrain cholinergic deficits across a spectrum of cognitively impaired patients with PD to explore their relative, individual, and combined contributions to cognitive impairment in PD. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional study at an academic movement disorders clinic that included a predominantly nondemented cohort of 143 patients with PD. The mean (SD) age of patients was 65.5 (7.4) years and the mean (SD) Hoehn and Yahr stage was 2.4 (0.6). MAIN OUTCOMES AND MEASURESBinary classification of carbon 11-labeled [ 11 C]PMP acetylcholinesterase and caudate nucleus [ 11 C]DTBZ monoaminergic positron-emission tomography imaging based on normative data. The frequency of significant degenerative processes based on normative values was determined for consecutive intervals of cognitive impairment, ranging from no or minimal (z > −0.5) to more severe (z Յ −2) cognitive impairment.RESULTS Across the spectrum from minimal (z > −0.5) to more severe (z Յ −2) global cognitive impairment scores, caudate nucleus dopaminergic denervation was relatively frequent in individuals with minimal or no cognitive changes (51.1%) and increased in patients with more severe cognitive impairments (χ 2 = 12.8; P = .01). Cortical cholinergic denervation frequency increased monotonically with increasing cognitive impairment from 24.7% (z > −0.5) to 85.7% (z Յ −2); χ 2 = 23.2; P = .001). Eighty-seven percent of patients with neocortical cholinergic deficits had caudate nucleus dopaminergic deficits. Multiple regression analysis (F = 7.51; P < .001) showed both independent cognitive predictions for caudate nucleus dopaminergic (F = 7.25; P = .008) and cortical cholinergic (F = 7.50; P = .007) degenerations as well as interaction effects (F = 5.40; P = .02). CONCLUSIONS AND RELEVANCECortical cholinergic denervation is a major neurodegeneration associated with progressive declines across the spectrum of cognitive impairment in PD and typically occurs in the context of significant caudate nucleus dopaminergic denervation. Our findings imply that dopaminergic and cholinergic degenerations exhibit both independent and interactive contributions to cognitive impairment in PD.