Highly efficient solid phase supported radiosynthesis of [11 C]PiB using tC18 cartridge as a "3-in-1" production entity.

Pittsburgh compound B ([11 C]PiB) is the gold standard positron emission tomography (PET) tracer for the in vivo imaging of amyloid plaques. Currently, it is synthesized by either solution chemistry or using a "dry loop" approach followed by HPLC purification within 30 minutes starting from [11 C]CO2 . Here, we report a novel, highly efficient solid phase supported carbon-11 radiolabeling procedure using commercially available disposable tC18 cartridge as a "3-in-1" entity: reactor, purifier, and solvent replacement system. [11 C]PiB is synthesized by passing gaseous [11 C]CH3 OTf through a tC18 cartridge preloaded with a solution of precursor. Successive elution with aqueous ethanol solutions allows for nearly quantitative separation of the reaction mixture to provide chemically and radiochemically pure PET tracer. [11 C]PiB suitable for human injection is produced within 10 minutes starting from [11 C]CH3 OTf (20 min from [11 C]CO2 ) in 22% isolated yield not corrected for decay and molar activity of 190 GBq/µmol using 0.2 mg of precursor. This technique reduces the amount of precursor and other supplies, avoids use of preparative HPLC and toxic solvents, and decreases the time between consecutive production batches. Solid phase supported technique can facilitate [11 C]PiB production compliant with Good Manufacturing Practice (GMP) and improve synthesis reliability.

The cell adhesion molecule Sdk1 shapes assembly of a retinal circuit that detects localized edges.

Nearly 50 different mouse retinal ganglion cell (RGC) types sample the visual scene for distinct features. RGC feature selectivity arises from their synapses with a specific subset of amacrine (AC) and bipolar cell (BC) types, but how RGC dendrites arborize and collect input from these specific subsets remains poorly understood. Here we examine the hypothesis that RGCs employ molecular recognition systems to meet this challenge. By combining calcium imaging and type-specific histological stains, we define a family of circuits that express the recognition molecule Sidekick-1 (Sdk1), which include a novel RGC type (S1-RGC) that responds to local edges. Genetic and physiological studies revealed that Sdk1 loss selectively disrupts S1-RGC visual responses, which result from a loss of excitatory and inhibitory inputs and selective dendritic deficits on this neuron. We conclude that Sdk1 shapes dendrite growth and wiring to help S1-RGCs become feature selective.

New Optical Tools to Study Neural Circuit Assembly in the Retina.

During development, neurons navigate a tangled thicket of thousands of axons and dendrites to synapse with just a few specific targets. This phenomenon termed wiring specificity, is critical to the assembly of neural circuits and the way neurons manage this feat is only now becoming clear. Recent studies in the mouse retina are shedding new insight into this process. They show that specific wiring arises through a series of stages that include: directed axonal and dendritic growth, the formation of neuropil layers, positioning of such layers, and matching of co-laminar synaptic partners. Each stage appears to be directed by a distinct family of recognition molecules, suggesting that the combinatorial expression of such family members might act as a blueprint for retinal connectivity. By reviewing the evidence in support of each stage, and by considering their underlying molecular mechanisms, we attempt to synthesize these results into a wiring model which generates testable predictions for future studies. Finally, we conclude by highlighting new optical methods that could be used to address such predictions and gain further insight into this fundamental process.

Identification of [18F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging.

Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads while displaying high on-target affinity and human kinome selectivity.