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Background: Postural instability and gait disturbances (PIGD) represent a significant cause of disability in Parkinson's disease (PD). Cholinergic system dysfunction has been implicated in falls in PD. The occurrence of falls typically results in fear of falling (FoF) that in turn may lead to poorer balance self-efficacy. Balance self-efficacy refers to one's level of confidence in their ability to balance while completing activities of daily living like getting dressed, bathing, and walking. Lower self-efficacy, or greater FoF during these activities is a function of motor, cognitive, and emotional impairments and may impact quality of life in PD. Unlike known cholinergic reduction, especially in the right lateral geniculate and caudate nuclei, little is known about the role of cholinergic transporters in FoF or mobility self-efficacy in PD. Methods: [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) positron emission tomography (PET) studies were conducted to assess vesicular acetylcholine transporter (VAChT) expression in 126 patients with PD (male (m) = 95, female (f) = 31). Participants had a mean age of 67.3 years (standard deviation (SD) = 7.1) and median Hoehn Yahr stage of 2.5. Patients also completed the Short Falls Efficacy Scale (sFES-I) as a survey measure of concerns about falling. [18F]FEOBV data were processed in Statistical Parametric Mapping (SPM) using a voxel-wise regression model with sFES-I scores as the outcome measure. Results: Reduced [18F]FEOBV binding in tectum, metathalamic (lateral more than medial geniculate nuclei), thalamus proper, bilateral mesiotemporal (hippocampal, parahippocampal, fusiform gyri and fimbriae), and right cerebellar lobule VI significantly associated with higher sFES-I scores (p < 0.05, family-wise error (FWE) correction after Threshold-Free Cluster Enhancement (TFCE)). Conclusions: Unlike the more limited involvement of the brainstem-thalamic complex and caudate nuclei cholinergic topography associated with falls in PD, cholinergic reductions in the extended connectivity between the thalamic complex and the temporal limbic system via the fimbriae associates with FoF. Additional cholinergic changes were seen in the cerebellum. The temporal limbic system plays a role not only in episodic memory but also in spatial navigation, scene and contextual (e.g., emotional) processing. Findings may augur novel therapeutic approaches to treat poor mobility self-efficacy in PD. [ABSTRACT FROM AUTHOR]

A new automated radiosynthesis of [11C]2‐(2,6‐difluoro‐4‐((2‐(N‐methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)‐compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on a linker–chelator complex attached to the 'inhibitor'. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake. Methods: [18F]FluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of [18F]FluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments. Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of [18F]FluroFAPI was demonstrated. [18F]FluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for [18F]FluroFAPI. Conclusions: With the successful development of an automated synthesis of [18F]FluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents. [ABSTRACT FROM AUTHOR]

An in‐loop 11C‐carbonylation process for the radiosynthesis of 11C‐carboxylic acids and esters from halide precursors has been developed. The reaction proceeds at room temperature under mild conditions and enables 11C‐carbonylation of both electron deficient and electron rich (hetero)aromatic halides to provide 11C‐carboxylic acids and esters in good to excellent radiochemical yields, high radiochemical purity, and excellent molar activity. The process has been fully automated using commercial radiochemistry synthesis modules, and application to clinical production is demonstrated via validated cGMP radiosyntheses of [11C]bexarotene and [11C]acetoacetic acid. [ABSTRACT FROM AUTHOR]

This report describes the development of a Zn(OTf)2‐mediated method for converting α‐tertiary haloamides to the corresponding fluorine‐18 labelled α‐tertiary fluoroamides with no‐carrier‐added [18F]tetramethylammonium fluoride. 1,5,7‐Triazabicyclo[4.4.0]dec‐5‐ene is an essential additive for achieving high radiochemical conversion. Under the optimised conditions, radiofluorination proceeds at sterically hindered tertiary sites in high radiochemical conversions, yields, and purities. This method has been successfully automated and applied to access >200 mCi (>7.4 GBq) of several model radiofluorides. Mechanistic studies led to the development of a new, nucleophilic C−H radiofluorination process using N‐sulphonyloxyamide substrates. [ABSTRACT FROM AUTHOR]

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABAAR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson's disease (PD). Little is known about how regional GABAAR availability affects motor symptoms. We investigated the relationship between regional availability of GABAAR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2–3) underwent [11C]flumazenil GABAAR benzodiazepine binding site and [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABAAR availability was selectively associated with axial motor scores (R2 = 0.55, F = 11.0, β = −6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABAAR availability (R2 = 0.47, β = −5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R2 = 0.30, β = −3.9, F = 9.1, p = 0.019; total model: R2 = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [11C]methyl-4-piperidinyl propionate cholinesterase PET and K1 flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABAAR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD. [ABSTRACT FROM AUTHOR]