Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

Abstract

A new cardiac sympathetic nerve imaging agent, [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [18F]4-fluoro-m-tyramine ([18F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH to afford [18F]4F-MHPG. Initial bioevaluations of [18F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [11C]4F-MHPG. The neuronal uptake rate of [18F]4F-MHPG into the isolated rat heart was 0.68 ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 > 13 h). A PET imaging study in a nonhuman primate with [18F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80–90 min after injection of 5-to-1. These initial kinetic and imaging studies of [18F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.

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

“…Recently, we reported on a multi-step radiosynthesis of [ 18 F] 1 which, while successful, only provided limited quantities of the final product. 12 Initial bioevaluation studies of [ 18 F] 1 provided results similar to those previously seen with [ 11 C] 1 , encouraging us to pursue first-in-human imaging studies with this new tracer. However, since the initial method of preparing [ 18 F] 1 was not practical for routine production, the goal of this study was to develop a new approach to the radiosynthesis of [ 18 F] 1 .…”

“…Specific activities (SA) were 1.2 ± 0.3 Ci/μmol at end of synthesis (EOS), significantly higher than those obtained with our initial radiolabeling approach. 12 However, these specific activities are lower than levels typically achieved in nucleophilic fluorine-18 labeling, partly due to the relatively long synthesis time.…”

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

“…[ 19 F]4F-MHPG and [ 19 F]3F-PHPG (standards for HPLC analysis) and N,N′ -bis( tert -butoxycarbonyl)- N -3-benzyloxy-4-iodophenethylguanidine ( 7 ) were prepared in our laboratory using previously reported methods. 18, 39 …”

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

“…Other 18 F-labeled MIBG analogues that lack an iodo substituent have been reported [28]. Radiofluorination by S N 2 substitution on a sp 3 carbon can be performed often in a single step, which motivated the development of 18 F-labeled MIBG analogues containing a fluoroalkyl side chain [29].…”