4-[¹⁸F]Fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Regional Cardiac Sympathetic Nerve Density with Positron Emission Tomography

Abstract

4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]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 [18F]1 was developed in which the intermediate 4-[18F]fluoro-m-tyramine ([18F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [18F]fluorination. In PET imaging studies in rhesus macaque monkeys, [18F]1 demonstrated high quality cardiac images with low uptake in lungs and liver. Compartmental modeling of [18F]1 kinetics provided ‘net uptake rate’ constants Ki (mL/min/g wet) and Patlak graphical analysis of [18F]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 [18F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.

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

“…The N′,N′′ -bis-Boc-protected iodophenethylguanidine 7 was previously synthesized in our laboratory. 18 This compound was converted to the N,N′,N′′,N′′ -tetrakis-Boc-protected guanidine 8 by treatment with di- t -butyl dicarbonate in the presence of dimethylaminopyridine and triethylamine in THF. Reaction of 8 with bis(trimethyl)tin in the presence of tetrakis(triphenylphosphine)palladium provided the trimethylstannane compound 9 .…”

“…For these pilot studies, our initial approach to the preparation of [ 18 F] 1 was a multi-step automated radiosynthesis involving production of a 18 F-labeled intermediate using a diaryliodonium salt precursor followed by a deprotection step, an N -guanylation step, a second deprotection step and finally HPLC purification to provide [ 18 F] 1 . 18 Because of the multiple steps required, this initial method relied on the use of two automated radiosynthesis modules in adjacent hot-cells, linked in series, to provide the final product. While this approach was adequate for preclinical evaluations of [ 18 F] 1, it was poorly suited to routine production of the radiotracer for clinical studies in human subjects.…”

Preclinical Evaluation of 11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer

“…The biodistribution and organ kinetics of 11 C-sarcosine were measured in normal rats and used to estimate human radiation-absorbed doses according to previously described methods (17). Briefly, the organ distribution of 11 C-sarcosine was determined in 2 male and 2 female Sprague-Dawley rats at 5 time points (5,15,30,60, and 90 min) using injected doses of 7.4-28 MBq of 11 C-sarcosine.…”

Chemistry and Biology of Radiotracers That Target Changes in Sympathetic and Parasympathetic Nervous Systems in Heart Disease

“…The most recent attempt has been to find a radiotracer that has a lower extraction than MIBG or HED but is also transported at a slower rate into neurons and retained. The new lead compound is 4-18 F-fluoro-m-hydroxyphenethylguanidine ( 18 F-4-F-MHPG) (15). The compound was originally compared with norepinephrine and HED using the Michaelis-Menten enzyme Table 1).…”