First-in-human studies of ¹⁸F-hydroxyphenethylguanidines: PET radiotracers for quantifying cardiac sympathetic nerve density.

Objectives To perform first-in-human evaluations of 4-[¹⁸F]fluoro-m-hydroxyphenethylguanidine ([¹⁸F]4F-MHPG) and 3-[¹⁸F]fluoro-p-hydroxyphenethylguanidine ([¹⁸F]3F-PHPG), two new PET tracers developed for quantifying regional cardiac sympathetic nerve density.

Methods All studies were performed in healthy subjects (8 female, 8 male, ages 18-49y) using a Siemens ECAT Exact/HR+ PET scanner. Kinetics of [¹⁸F]4F-MHPG (n = 4) and [¹⁸F]3F-PHPG (n = 4) in heart, liver and blood were assessed in dynamic PET studies (240-260 MBq, 90 min, 27 frames). Radiometabolites were measured in plasma from six venous blood samples drawn during each study (HPLC, radiation detection). Radiometabolite data and ratios of activity in plasma over whole-blood were used to convert the whole-blood time-activity curve into an input function for kinetic analyses. Myocardial time-activity curves for 480 left ventricular regions were analyzed using compartmental modeling and Patlak graphical analysis to evaluate the ability of these methods to provide quantitative estimates of regional cardiac sympathetic nerve density. Also, biodistribution studies of the tracers (n = 4 each) were performed to acquire data for human dosimetry calculations (4 whole-body scans, start times: 5, 60, 150, and 360 min). Heart rate (HR) and blood pressure (BP) were continuously monitored and safety lab tests (blood chemistry, urinalysis, EKG) were acquired before and after each imaging session.

Results [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG each provided high quality cardiac PET images with negligible lung uptake and acceptably low liver uptake. [¹⁸F]4F-MHPG breaks down more rapidly in plasma than [¹⁸F]3F-PHPG, with 50% of parent tracer intact at 4.1 ± 0.6 min and 8.6 ± 2.6 min, respectively. [¹⁸F]4F-MHPG clears from liver more rapidly, providing better heart-to-liver contrast. Heart-to-liver ratios at 55 min were 2.3 ± 0.3 for [¹⁸F]4F-MHPG and 1.1 ± 0.3 for [¹⁸F]3F-PHPG. Uptake of [¹⁸F]4F-MHPG into cardiac sympathetic neurons peaked by 30-50 min, while neuronal uptake of [¹⁸F]3F-PHPG continued for the entire dynamic PET study. At 55 min, heart-to-blood ratios for [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG were 3.6 ± 0.6 and 5.4 ± 0.4, respectively. Kinetic analyses of both tracers were successful, with the most robust results obtained with Patlak analysis of the data from 5 to 55 min. Within individual subjects, the coefficient of variation (CV) of the Patlak slopes ranged from 11-14%. Across subjects, the mean Patlak slope was consistent: K_pat = 0.105 ± 0.009 mL/min/g for [¹⁸F]4F-MHPG and 0.122 ± 0.008 mL/min/g for [¹⁸F]3F-PHPG. Biodistribution studies showed uptake of both tracers was highest in heart, liver, and renal collecting system with elimination primarily by urinary excretion to the bladder. [¹⁸F]4F-MHPG had significant uptake in the gut which was not observed with [¹⁸F]3F-PHPG. Human dosimetry calculations are in progress. Tracer injections (masses ranging 0.7 - 4.0 μg) had no effects on HR, BP or safety lab measures, and no adverse events were observed.

Conclusions [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG possess excellent imaging properties in human subjects and analyses of their myocardial kinetics can provide regional measures of cardiac sympathetic nerve density. Additional PET studies directly comparing the two tracers in heart failure patients are underway and the results of these studies will be used to select a lead radiotracer for further clinical development. Research Support: NIH/NHLBI SMARTT Program, University of Michigan MTRAC Kickstart Award