David M. Raffel

4-[18F]Fluoro-m-hydroxyphenethylguanidine: A radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography

4-[(18)F]Fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG, [(18)F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [(18)F]1 was developed in which the intermediate 4-[(18)F]fluoro-m-tyramine ([(18)F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [(18)F]fluorination. In PET imaging studies in rhesus macaque monkeys, [(18)F]1 demonstrated high quality cardiac images with low uptake in lungs and the liver. Compartmental modeling of [(18)F]1 kinetics provided net uptake rate constants Ki (mL/min/g wet), and Patlak graphical analysis of [(18)F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [(18)F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.

Kinetics of the norepinephrine analog [76Br]-metabromobenzylguanidine in isolated working rat heart☆

A related set of kinetic studies of the norepinephrine analog [76Br]-meta-bromobenzylguanidine (MBBG) were performed with an isolated working rat heart preparation. A series of constant infusion studies over a wide range of MBBG concentrations allowed estimation of the Michaelis-Menten constants for transport by the neuronal norepinephrine transporter (uptake1) and the extraneuronal uptake system (uptake2). Pharmacological blocking studies with inhibitors of uptake1, uptake2 and vesicular uptake were performed to delineate the relative importance of these norepinephrine handling mechanisms on the kinetics of MBBG in the rat heart. Bolus injection studies were done to assess the ability of compartmental modeling techniques to characterize the kinetics of MBBG. These studies demonstrate that MBBG shares many of the same uptake mechanisms as norepinephrine in the rat heart. PET imaging studies with MBBG would be useful for assessing sympathetic nerve status in the living human heart.

[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.