The receptor for advanced glycation endproducts (RAGE) is a 35kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer’s disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-β into the brain as well as amplify Aβ-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary pre-clinical evaluation of [18F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies propose a likely binding interaction between RAGE and RAGER, [18F]RAGER autoradiography showed co-localization with RAGE identified by immunohistochemistry in AD brain samples, and [18F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This 1st generation radiotracer represents initial proof-of-concept and a promising first step towards quantifying CNS RAGE activity using PET. However, there were high levels of non-specific [18F]RAGER binding in vitro, likely due to its high logP (experimental logP = 3.5), and rapid metabolism of [18F]RAGER in rat liver microsome studies. Therefore development of 2nd generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies.

Synthetic high-density lipoprotein nanoparticles (sHDL) are a valuable class of nanomedicines with established animal safety profile, clinical tolerability and therapeutic efficacy for cardiovascular applications. In this study we examined how the scavenger receptor B-I-mediated (SR-BI) tumor-targeting ability of sHDL, long plasma circulation half-life, and small particle size (9.6 ± 0.2 nm) impacted sHDL accumulation in SR-BI positive colorectal carcinoma cells, 3D tumor spheroids, and in vivo xenografts. We compared tumor accumulation of sHDL with that of liposomes (LIP, 130.7 ± 0.8 nm), pegylated liposomes (PEG-LIP, 101 ± 2 nm), and pegylated sHDL (12.1 ± 0.1 nm), all prepared with the same lipid components. sHDL penetrated deep (210 μm) into tumor spheroids and exhibited 12- and 3-fold higher in vivo solid tumor accumulation, compared with LIP and PEG-LIP (p < 0.05), respectively. These results suggest that sHDL with established human safety possess promising intrinsic tumor-targeted properties.

Glioblastoma multiforme (GBM) is the deadliest type of brain tumor, affecting approximately three in 100,000 adults annually. Positron emission tomography (PET) imaging provides an important non-invasive method of measuring biochemically specific targets at GBM lesions. These powerful data can characterize tumors, predict treatment effectiveness, and monitor treatment. This review will discuss the PET imaging agents that have already been evaluated in GBM patients so far, and new imaging targets with promise for future use. Previously used PET imaging agents include the tracers for markers of proliferation ([11C]methionine; [18F]fluoro-ethyl-L-tyrosine, [18F]Fluorodopa, [18F]fluoro-thymidine, and [18F]clofarabine), hypoxia sensing ([18F]FMISO, [18F]FET-NIM, [18F]EF5, [18F]HX4, and [64Cu]ATSM), and ligands for inflammation. As cancer therapeutics evolve toward personalized medicine and therapies centered on tumor biomarkers, the development of complimentary selective PET agents can dramatically enhance these efforts. Newer biomarkers for GBM PET imaging are discussed, with some already in use for PET imaging other cancers and neurological disorders. These targets include Sigma 1, Sigma 2, programmed death ligand 1, poly-ADP-ribose polymerase, and isocitrate dehydrogenase. For GBM, these imaging agents come with additional considerations such as blood–brain barrier penetration, quantitative modeling approaches, and nonspecific binding.

In this Review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging.