3AcFNP-59 for Positron Emission Tomography Imaging of Cholesterol Trafficking and Utilization

Cholesteryl ester analogues of [18F]FNP-59 have the ability to provide information on cholesterol trafficking and utilization at earlier time points than those of [18F]FNP-59 or [131I]NP-59. It is well-known that free cholesterol and cholesteryl esters have differing distribution profiles and that they can be interconverted enzymatically. Substitution of the ester influences the rate of cholesterol ester hydrolysis and the subsequent mixing of cholesterol esters with the lipid pool in the body. This can be utilized by preparing esters that are more readily taken up by lipoprotein, are quickly hydrolyzed and mixed with the endogenous lipid pool and delivered to tissues of interest more quickly than free cholesterol analogues that require esterification for lipoprotein association. The acetyl ester of FNP-59 demonstrated the preferred uptake properties and response to adrenal cortical manipulation, indicating its ability to image hormone production. Finally, dosimetry studies were conducted in preparation for the clinical translation of [18F]3AcFNP-59

Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure–activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[¹¹C]­methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood–brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [¹⁸F]­fluoride was used to prepare the desired candidate radiotracer (<i>R</i>,<i>E</i>/<i>Z</i>)-1-(2-((4-fluoro-2-(4-[¹⁸F]­fluorobenzoyl)­styryl)­oxy)­ethyl)­piperidine-3-carboxylic acid ((<i>R</i>,<i>E</i>/<i>Z</i>)-<b>[</b>^<b>18</b><b>F]­10</b>). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of (<i>R</i>,<i>E</i>/<i>Z</i>)-[^<b>18</b><b>F]­10</b> in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of (<i>R</i>,<i>E</i>/<i>Z</i>)-<b>[</b>^<b>18</b><b>F]­10</b>. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood–brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres

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