Introduction

Although several studies have demonstrated that positron emission tomography (PET) myocardial perfusion imaging (MPI) is the gold standard for diagnosis of coronary artery disease (CAD), utilization remains low.1,2,3 Challenges preventing more widespread adoption of PET MPI include limited production of strontium-82 (Sr-82), limited Sr-82/rubidium-82 (Rb-82) generator manufacturing capacity, and Sr-82 break through events leading to significant unintentional patient radiation exposures. Nitrogen-13 (N13)-ammonia has been shown to be valuable in prognosis and diagnosis of CAD.4,5 While it has several favorable properties compared to Rb-82, including (1) improved spatial and defect contrast resolution,6 (2) decreased patient doses,7 and (3) ability to perform exercise MPI,8 it has been difficult to use clinically due to the need for an onsite cyclotron. Because Rb-82 is a generator product, implementation has been substantially simpler than for N13–ammonia. Furthermore, the ultra-short half-life of Rb-82 (76 seconds) enables rapid rest-stress protocols which can be completed in as little as 30 minutes of scanner time per patient whereas standard N13-ammonia protocols require an hour or longer to allow for isotope decay.3

Advances in superconducting cyclotron design and automated multi-use purification unit have enabled development of a highly automated minimally shielded mini-cyclotron system. We report the initial clinical experience with such a system.

Materials and Methods

Due to disruption in the Sr-82/Rb-82 generator supply chain, over approximately one month (January 14th to February 14th, 2019), 97 patients referred for clinical PET MPI underwent imaging using N13-ammonia as the sole radiotracer.

N13-ammonia was manufactured by technicians trained by the cyclotron manufacturer to safely and effectively operate the production system. The system consists of the ION-12SC (Ionetix, Inc, San Francisco, CA), which produced in-target Ammonia N 13, and an automated multi-use purification system, which purified and formulated the final drug product. The first dose (quality control sub-batch) was inspected daily for appearance (visual inspection), pH, radiochemical purity/identity through thin layer chromatography (Figure 1), radioactive concentration, bacterial endotoxin, filter integrity test (bubble point), and sterility. The patient sub-batches were evaluated for appearance (visual inspection), radioactive concentration and a filter integrity test (bubble point).

Figure 1
figure 1

An example of thin layer chromatography from a batch of N13-ammonia produced Feb 8, 2019. Radiochemical purity was > 99% in all samples

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For imaging, patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) N13-ammonia (Medrad® Spectris Solaris® EP Injection System modified to with tungsten shield, 20 mL at 1 mL/s followed by a 10 mL normal saline flush). List mode imaging was performed for 10 minutes beginning at tracer injection. For stress testing, after a minimum of five minutes post rest imaging (15 minutes post tracer injection), 0.4 mg of regadenoson was injected intravenously. At peak hyperemia, 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) N13-ammonia was injected (20 mL at 1 mL/s followed by a 10 mL normal saline flush). List mode imaging was performed for 9 minutes, beginning one minute prior to tracer injection (Figure 2). Static, ECG-gated, and dynamic images were unlisted. Images were interpreted clinically for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality using 4DM (INVIA Medical Imaging Solutions, Ann Arbor, MI). The studies were interpreted by three board certified nuclear cardiologists and were scored as poor, fair, good, or excellent based on overall image quality including noise, contrast, patient motion and quality of tracer bolus administration. Patients were monitored for a minimum of 20 minutes for adverse reactions.

Figure 2
figure 2

Graphic representation of protocol described in “Methods.” CTAC, CT-based attenuation correction; CAC, coronary artery calcium scan (*where clinically indicated). The estimated radiation exposure is reported for rest/stress scan

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Results

N13-ammonia was produced in approximately 4-mL with > 95% yield (decay corrected). Quality control procedures aligned with the N13-ammonia USP monograph, and no quality control failures occurred during the operational period. Radiochemical purity analysis of all manufactured batches was found to be greater than 99% with potential anionic impurity levels being below the analytical limit of detection. An example can be seen in Figure 1. The ION12-SC was collocated within a shielded vault with a GE PETtrace cyclotron (GE Healthcare); therefore, radiation from the ION-12SC could not be independently measured. Daily microbiologic testing for sterility was negative. Beam current was 10µA for each run, and average activity per run was 52.4 ± 2.3mCi.

In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). The majority of patients were men (56.7%). Further baseline characteristics can be seen in Table 1. Eighteen patients had prior PET/CT MPI performed. Image quality was 91.8% good or excellent, 6.1% good, and 2.0% fair. None were poor/non-diagnostic. Study durations were acceptable: 16.5 (IQR 15.8-18.0) minutes for rest only, 48.1 (IQR 47.0-60.9) minutes for rest-stress, and 29 minutes for stress only. Time between rest and stress scans was 22.3 ± 10.3 minutes. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress).9 Subjects per day averaged 4.1 ± 1.0. There were no major complications. There were no adverse reactions observed during rest infusions. All symptoms during stress infusion were similar in quality, frequency, and severity to those described for the stress agent (regadenoson).

Table 1 Describing baseline characteristics of our 97-patient cohort
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Example images are presented in Figures 3, 4. Figure 3 highlights the advantages of using N13-ammonia in assessing perfusion defects. In this image, there is excellent visualization of a partially reversible anterior and anteroseptal defect, as well as completely reversible lateral and anterolateral defects. Figure 4 showcases the ability of N13-ammonia to visualize cardiac sub-structures such as the moderator band with excellent definition.

Figure 3
figure 3

N13-ammonia PET/CT myocardial perfusion scan of a 59-year-old female with an anterior and anteroseptal, partially reversible, as well as completely reversible lateral and anterolateral defects. SA, short axis; HLA, horizontal long axis; VLA, vertical long axis

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Figure 4
figure 4

N13-ammonia PET/CT myocardial perfusion scan of a 76-year-old male with dilated, non-ischemic cardiomyopathy and severe left ventricular hypokinesis. The right ventricular wall and moderator band can be appreciated especially in the short axis (SA). HLA, horizontal long axis; VLA, vertical long axis

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Discussion

We found that N13-ammonia produced by the Ionetix ION-12SC delivered high quality myocardial PET perfusion images in a safe and reliable manner with a rapid protocol. To our knowledge, this is the first study assessing the clinical performance of an automated N13–ammonia production system. Consequently, we are hopeful that this option may improve availability of cardiac PET MPI.

Importantly, this system does have several tradeoffs relative to Rb-82. Because of differences in half-life of the tracers, at present Rb-82 rest/stress scans are still slightly shorter in duration than N13-ammonia studies. This could potentially be improved as time between rest and stress scans was greater than intended in some cases (22.3 ± 10.3 minutes). Furthermore, given excellent count rates during stress imaging, shorter stress acquisitions may be feasible. At present the minimum duration of a N13-ammonia protocol is 23 minutes plus time for patient preparation and recovery from stress as compared to 17 minutes for Rb-82 protocols. Although daily volumes were limited during this initial experience, there are no intrinsic limitations preventing extended scanning at the current levels of hourly throughput which would enable 8-10 scans per business day. Further, we believe there is substantial opportunity for further process optimization enabling further improved patient throughput.

Conclusion

N13-ammonia can be safely and efficiently produced for clinical PET MPI using an automated mini-cyclotron system.