Robotic preparation of Sodium Acetate C 11 Injection for use in clinical PET

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Abstract

Sodium Acetate C 11 Injection is a radiopharmaceutical commonly used for clinical studies with positron emission tomography (PET). We have designed a fully-automated robotic system for the compounding of this 20-minute half-lived tracer in the clinical setting. The system is comprised of five modular workstations that are configured in a flexible manner to accommodate all of the steps in the production of the labeled drug. The Trapping Station isolates cyclotron-produced [11C]CO2 gas from the target and directs carbonation of methylmagnesium Grignard in diethyl ether. The Heating Station hydrolyzes the intermediate, and removes ether and unreacted [11C]CO2 from the mixture. The Extraction Station removes ionic and organic contaminants from the drug using solid-phase extraction (AG 11A8 and C18 resin). The Filtration Station sterilizes the radiopharmaceutical, and tests membrane patency post filtration. The Assay Station measures the weight and radioactivity content of the Final Product Container, facilitating calculation of activity concentration in a remote manner. Rapid quality control methodology has also been developed that is suitable for pre-release analysis of the drug product. For a 7.5 min irradiation with a 40 μA proton beam, 223–300 mCi of Acetate C 11 Injection with purity meeting USP standards is produced within 23 min. This robotic system is a reliable method for producing Sodium Acetate C 11 Injection, USP in the clinical setting with minimal personnel exposure. Moreover, its design flexibility permits synthesis of additional 11C- or 18F-labeled PET tracers within the same shielded hot cell.

Introduction

Positron emission tomography (PET) is a noninvasive diagnostic technique with significant utility in the clinical management of disease. Two particular applications of PET in the area of cardiology are detection and estimation of coronary artery disease severity, and assessment of myocardial viability [5]. Viability studies are especially useful because maintenance of oxidative metabolism is a critical determinant of the heart’s capacity for functional recovery in ischemic myocardium. Detection of viable myocardium that has intact metabolic activity in the presence of underperfusion has great prognostic and therapeutic value, since it identifies those subjects in whom interventional procedures such as percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) are indicated.

[1-11C]Acetate has ideal characteristics as a PET tracer of myocardial viability. The direct relationship between the turnover rate constant and myocardial oxygen consumption has been validated [1], [11] and, because acetate enters the Krebs cycle in a substrate-independent manner, standardization of the substrate environment of the subject is not necessary [10]. Due to these useful characteristics, clinical experience with [1-11C]acetate is extensive. The tracer is applied for measurement of myocardial oxidative metabolic reserve [20] and to evaluate changes in oxidative metabolism in patients with recent myocardial infarction [38]. [1-11C]Acetate is also utilized for PET measurement of functional recovery in patients treated with thrombolytic agents [19] as well as revascularization procedures like CABG or PTCA [15], [16], [17], [32]. In these studies, measurement of oxidative metabolism has proven to be a more accurate predictor of functional myocardial recovery than measurement of either myocardial perfusion or glucose utilization.

In addition to PET measurement of myocardial viability, [1-11C]acetate has further indications as an imaging agent. The PET tracer has been shown to be a suitable marker for estimation of myocardial perfusion [13], [18], [33]. Also, oncological studies suggest that the in vivo behavior of [1-11C]acetate is favorable for clinical detection and evaluation of prostate cancer by PET [29], [34].

Because of these numerous diagnostic applications, [1-11C]acetate has evolved into a popular radiopharmaceutical for clinical PET studies, and regulatory agencies have developed purity standards for the radiopharmaceutical. The United States Pharmacopeia defines these in the monograph Sodium Acetate C 11 Injection, USP [26], [35], and European bodies have also established guidelines for production and quality control procedures [37]. There is great demand in clinical PET facilities for the routine compounding of [1-11C]acetate with a purity that meets these official standards.

We have previously shown the utility of microprocessor-controlled robotic systems for the production of several clinically-used PET radiopharmaceuticals [6], [7], [8], [9], [27]. With this work, we have extended this concept to include the robotic preparation of Sodium Acetate C 11 Injection. The methodology described here facilitates rapid and reliable production of the labeled PET drug, with radiochemical yield and purity suitable for application in human subjects within the clinical setting.

Section snippets

Apparatus

The preparation of Sodium Acetate C 11 Injection was accomplished using the same Zymate Laboratory Automation System (Zymark; Hopkinton, MA) robotic system utilized for compounding Fludeoxyglucose F 18 Injection [8], [27], 16-α-[18F]fluoroestradiol-17β [9], as well as several other PET tracers [4], [6], [7]. The key component of the system is a Zymate Laboratory Automation System (Zymark Corporation, Hopkinton, MA). The Power and Event controller for the Zymate Laboratory Automation Station is

Results and discussion

Like other PET radiopharmaceuticals, the production of [1-11C]acetate for routine clinical purposes is fraught with challenging laboratory requirements. To promote scheduling ease in the busy clinical setting, drug radiosynthesis must be efficient and reliable in order to assure timely delivery of the labeled drug to the clinician, with minimal demands for preliminary preparation. Besides this radiosynthetic constraint, production methodologies must be standardized so that preparation of each

Conclusions

A robotic system has been developed for the fully-automated compounding of over 200 mCi of Sodium Acetate C 11 Injection, USP within 23 minutes and minimum radiation burden to personnel. A rapid HPLC method for determination of the radiochemical purity has been developed that facilitates pre-release testing of the labeled drug. Validation studies show that the radiopharmaceutical produced with this system meets or exceeds standards [35] set by the USP for this drug. Based on the production of

Acknowledgements

This work was supported by NIH grant HL13851. We thank W. Margenau for equipment construction and radioisotope production, D. Ficke for radioisotope production, and K. Lechner for assistance with quality control procedures.

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