4-18F-Fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis. The aim of this study was to evaluate their performance in cardiomyopathy patients. Eight cardiomyopathy patients were scanned with 18F-4F-MHPG and 18F-3F-PHPG. Also, regional resting perfusion was assessed with 13N-ammonia. 18F-4F-MHPG and 18F-3F-PHPG kinetics were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as measures of regional nerve density. Patlak slope polar maps were used to evaluate the pattern and extent of cardiac denervation. For comparison, “retention index” (RI) values (mL blood/min/mL tissue) were also calculated and used to assess denervation. Perfusion polar maps were used to estimate the extent of hypoperfusion. Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all subjects, ranging from 25 to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion. The two tracers provided comparable metrics of regional nerve density and the extent of left ventricular denervation. 18F-4F-MHPG exhibited faster liver clearance than 18F-3F-PHPG, reducing spillover from the liver into the inferior wall. 18F-4F-MHPG was also metabolized more consistently in plasma, which may allow application of population-averaged metabolite corrections. The advantages of 18F-4F-MHPG (more rapid liver clearance, more consistent metabolism in plasma) make it the better imaging agent to carry forward into future clinical studies in patients with cardiomyopathy. Trial registration: Registered at the ClinicalTrials.gov website (NCT02669563). URL: https://clinicaltrials.gov/ct2/show/NCT02669563

BackgroundIn the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing.ResultsThe University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees.ConclusionsThe data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.

Although N13-ammonia has favorable properties among FDA approved radiotracers, complexity of implementation has limited its use. We describe the initial patient experience of N13-ammonia PET imaging using a compact N13-ammonia production system. N13 was produced using the ION-12SC, a 12MeV, 10uA superconducting minimally shielded cyclotron, and reduced to N13-ammonia in an automated multi-use purification unit. Patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) of N13-ammonia for rest imaging, and 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) of N13-ammonia was injected at peak hyperemia for stress testing. Images were interpreted for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality. In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). Image quality was 91.8% good or excellent. None were poor/non-diagnostic. Study durations were acceptable. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress). Clinical N13-ammonia production by the Ionetix ION-12SC delivers high quality myocardial PET perfusion images in a rapid protocol.

Background: Disease-induced damage to cardiac autonomic nerve populations is associated with an increased risk of sudden cardiac death. The extent of cardiac sympathetic denervation, assessed using planar scintigraphy or positron emission tomography, has been shown to predict the risk of arrhythmic events in heart failure patients staged for implantable cardioverter defibrillator therapy. The goal of this study was to perform first-in-human evaluations of 4-[ 18 F]fluoro-meta-hydroxyphenethylguanidine and 3-[ 18 F]fluoro-para-hydroxyphenethylguanidine, 2 new positron emission tomography radiotracers developed for quantifying regional cardiac sympathetic nerve density. Methods and Results: Cardiac positron emission tomography studies with 4-[ 18 F]fluoro-meta-hydroxyphenethylguanidine and 3-[ 18 F]fluoro-para-hydroxyphenethylguanidine were performed in normal subjects (n=4 each) to assess their imaging properties and organ kinetics. Patlak graphical analysis of their myocardial kinetics was evaluated as a technique for generating nerve density metrics. Whole-body biodistribution studies (n=4 each) were acquired and used to calculate human radiation dosimetry estimates. Patlak analysis proved to be an effective approach for quantifying regional nerve density. Using 960 left ventricular volumes of interest, across-subject Patlak slopes averaged 0.107±0.010 mL/min per gram for 4-[ 18 F]fluoro-meta-hydroxyphenethylguanidine and 0.116±0.010 mL/min per gram for 3-[ 18 F]fluoro-para-hydroxyphenethylguanidine. Tracer uptake was highest in heart, liver, kidneys, and salivary glands. Urinary excretion was the main elimination pathway. Conclusions: 4-[ 18 F]fluoro-meta-hydroxyphenethylguanidine and 3-[ 18 F]fluoro-para-hydroxyphenethylguanidine each produce high-quality positron emission tomography images of the distribution of sympathetic nerves in human heart. Patlak analysis provides reproducible measurements of regional cardiac sympathetic nerve density at high spatial resolution. Further studies of these tracers in heart failure patients will be performed to identify the best agent for clinical development. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02385877.

232 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: Kpat = 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

Positron emission tomography (PET), in combination with myocardial blood flow tracers, allows highly accurate diagnosis of coronary artery disease using visual data interpretation. To increase the objectivity of data analysis and to reduce interobserver variability, we developed an automated analysis method for the three-dimensional definition of myocardial activity, which includes true volumetric data extraction and mathematical constraints of activity sampling to the expected shape of the left ventricle. Data are displayed in a standardized polar map or three-dimensional format for comparison with a normal database. The first clinical evaluation of this method in 52 patients using receiver operating characteristics (ROC) curve analysis demonstrated high diagnostic accuracy for detection as well as localization of coronary artery stenosis in predefined vascular territories. The interobserver and intraobserver agreement for localization of disease was excellent, with correlation coefficients varying from 0.85 to 0.99 for individual vascular territories. Thus, this automated quantitative analysis program provides highly accurate and reproducible evaluation of cardiac PET flow studies. Definite determination of its diagnostic accuracy requires a prospective multicenter trial in a larger patient population employing the criteria for abnormality established in this initial clinical evaluation.

Glucose metabolism was examined by positron emission tomographic scanning with F-2-fluoro-2-deoxy-D-glucose in 29 persons at risk for Huntington's disease (HD), 28 age-matched controls, nine patients with stage I, and eight patients with stage II symptomatic HD. Absolute caudate metabolic rates and normalized indexes of caudate metabolism for at-risk persons were normal compared with controls. No at-risk person had caudate indexes outside two SDs of the controls' mean. Caudate metabolism in the earliest HD cases was significantly reduced compared with controls and at-risk persons, but within the 99% confidence levels of both groups. Stage II patients had caudate measures that were significantly depressed compared with those of stage I HD patients. Measurement of caudate glucose hypometabolism is unlikely to be sufficiently sensitive to serve as a presymptomatic marker of heterozygote status, although it will provide a sensitive marker for progressive caudate dysfunction in HD.