[18F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation.

Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of 18F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) and its structural isomer 3-[18F]fluoro-p-hydroxyphenethylguanidine ([18F]3F-PHPG, [18F]2) with good radiochemical yields. Preclinical evaluations of [18F]2 in nonhuman primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18F]1. The results of these studies have demonstrated that [18F]2 exhibits imaging properties comparable to those of [18F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18F]1 and [18F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

(-)-[(18) F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use.

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 ß2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (-)-[(18) F]flubatine, which was purified by semi-preparative HPLC. (-)-[(18) F]Flubatine was prepared in 25% radiochemical yield (formulated for clinical use at end of synthesis, n = 3), >95% radiochemical purity, and specific activity = 4647 Ci/mmol (171.9 GBq/µmol). Doses met all quality control criteria confirming their suitability for clinical use. Evaluation of (-)-[(18) F]flubatine in rhesus macaques was performed with a Concorde MicroPET P4 scanner (Concorde MicroSystems, Knoxville, TN). The brain was imaged for 90 min, and data were reconstructed using the 3-D maximum a posteriori algorithm. Image analysis revealed higher uptake and slower washout in the thalamus than those in other areas of the brain and peak uptake at 45 min. Injection of 2.5 µg/kg of nifene at 60 min initiated a slow washout of [(18) F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min.

125I-labeled gold nanorods for targeted imaging of inflammation.

For better examination of inflammation, we designed inflammation-targeted nuclear and optical dual-modality contrast agents prepared by I-125 radiolabeling of gold nanorods (GdNRs) conjugated with anti-intercellular adhesion molecule 1 (ICAM-1) antibody. The bioactivity and specific binding of the PEGylated (125)I-ICAM-GdNR conjugates to the ICAM-1 was validated through ELISA testing. Inflammation-targeted imaging was then conducted on an adjuvant-induced arthritic rat model which demonstrated an elevation of ICAM-1 level in the affected ankle joints. Facilitated by the I-125 radioisotope and the whole-body imaging via the Gamma camera, the time-dependent distribution of the systemically injected agent as well as the uptake of the agent in the inflammatory articular tissues could be examined conveniently and quantitatively. The success in targeted delivery of gold nanoparticles to inflammatory tissue enables both nuclear and optical imaging of inflammation at molecular or cellular level. Other than diagnosis, radiolabeled gold nanoparticles also hold promise for targeted therapy of a variety of disorders.