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3 November 2026

12 Pages

Optimization of [11C]Choline Synthesis on the TracerMaker Module for Primary Hyperparathyroidism PET Imaging

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Department of Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, DK-2730 Herlev, Denmark
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Radiation2026, 6(4), 44;https://doi.org/10.3390/radiation6040044
This article belongs to the Section Radiation in Medical Imaging
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Simple Summary

[11C]choline positron emission tomography (PET) is essential for localizing autonomous adenomas in primary hyperparathyroidism (PHPT), but carbon-11’s short physical half-life (t½ = 20.34 min) restricts production yield. In this study, in-house [11C]choline synthesis on a TracerMaker module was optimized using a single higher-mass sorbent cartridge (360 mg) and a higher precursor load. This strategy doubled the end-of-synthesis (EOS) yield from 3.19 ± 0.69 GBq to 6.46 ± 0.31 GBq while maintaining low residual precursor levels, addressing the growing clinical demand for PHPT PET imaging.

Abstract

Positron emission tomography (PET) using [11C]choline has recently gained clinical importance for localizing autonomous adenomas in primary hyperparathyroidism (PHPT), offering superior diagnostic accuracy and sensitivity compared to conventional [99mTc]sestamibi scintigraphy. To meet rising clinical demand using existing infrastructure, this study evaluated three key parameters to optimize the in-house [11C]choline synthesis on a TracerMaker module using [11C]CH4 as the radioactive precursor, which originally yielded 3.19 ± 0.69 GBq at end of synthesis (EOS). Three critical synthesis steps were systematically evaluated: (1) cyclotron irradiation time, (2) precursor (dimethylaminoethanol, DMAE) loading volume across Sep-Pak Accell CM cartridges, and (3) purification wash volumes. Extending irradiation time from 25 to 42 min produced no significant increase in EOS yield. Increased DMAE loading volumes up to 300 µL across 1–3 serially connected 130 mg sorbent cartridges doubled the EOS yield but elevated residual DMAE levels in the final product. Increased wash volumes of ethanol and water failed to improve purification efficiency; however, substituting the multi-cartridge system with a single higher-mass sorbent cartridge (360 mg) achieved effective DMAE removal while maintaining high EOS yield (6.46 ± 0.31 GBq). These findings demonstrate a practical route for [11C]choline synthesis optimization to meet the growing clinical demand for PET imaging of PHPT.

1. Introduction

The radiopharmaceutical [11C]choline has recently regained attention as a positron emission tomography (PET) tracer for localizing hyperactive adenomas in patients with primary hyperparathyroidism (PHPT) [1,2]. This resurgence follows a period of declining clinical use for its original application in prostate cancer imaging.
Originally, [11C]choline was developed in 1998 as an alternative to [18F]fluorodeoxyglucose ([18F]FDG) for prostate cancer PET imaging [3]. [11C]Choline is a 11C-labeled version of the biomolecule choline, which is an essential component in phospholipid membrane synthesis. Here, [11C]choline capitalizes on the elevated choline uptake and phospholipid turnover in prostate cancer cells [3,4], unlike [18F]FDG, which undergoes urinary excretion and causes a high background signal in the pelvic region that limits diagnostic accuracy [5,6]. [11C]choline is cleared predominantly by the liver [7]. Hepatic clearance results in radioactivity accumulation in the bile duct, significantly reducing pelvic signal interference and making [11C]choline a valuable tool for localizing primary prostate tumors when [18F]FDG is suboptimal [8,9]. However, following several years of clinical use, [11C]choline was gradually supplanted by prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals—such as [68Ga]PSMA-11 [10,11] and [18F]PSMA-1007 [12,13]—which exhibit higher affinity for prostate tumor tissue [14].
Recently, studies have highlighted a renewed diagnostic role for [11C]choline in patients with PHPT, a condition characterized by excessive secretion of parathyroid hormone (PTH) due to overactive parathyroid glands [15,16]. In most cases, this hyperfunction results from benign adenomas, though malignant tumors within or adjacent to the thyroid lobes are responsible in rare instances. Parathyroidectomy (PTX) remains the definitive treatment for PHPT; however, achieving optimal surgical outcomes while minimizing morbidity requires precise preoperative localization of the adenoma.
Although [99mTc]sestamibi ([99mTc]MIBI) scintigraphy has traditionally served as the first-line method for detecting primary parathyroid adenomas (PTA), it lacks sensitivity and frequently yields false-negative results [17,18]. In contrast, [11C]choline PET demonstrates markedly higher sensitivity and specificity for detecting primary hyperparathyroid adenomas (PHPTA) [2,19], as well as superior performance in identifying ectopic adenomas compared with [99mTc]MIBI SPECT imaging [20]. In patients being evaluated for PTX, [11C]choline PET is now utilized both for primary localization and as a second-line modality when [99mTc]MIBI scintigraphy fails to identify the adenoma [21]. This shift is already reflected at our production facility, where two weekly productions (2–3 patients per production) resulted in approximately 100 patients with PHPT being scanned annually in 2023–2025 at the Department of Nuclear Medicine, Herlev Hospital (shown in a typical clinical case, Figure S1; further details on clinical usage are provided in Section S1 of the electronic Supplementary Information (ESI)).
A major limitation of [11C]choline PET/CT is the short physical half-life of carbon-11 (t½ = 20.34 min), which necessitates an on-site cyclotron. Furthermore, efficient radiopharmaceutical production requires rapid and straightforward synthesis procedures capable of delivering high radioactive yields to meet clinical demand. Thus, the growing demand for [11C]choline, combined with the decay constraints of carbon-11, highlights the critical need for optimized synthesis protocols.
In the original synthesis reported in 1998, [11C]choline was synthesized via a one-step bimolecular nucleophilic substitution (SN2) reaction between [11C]methyl iodide ([11C]CH3I) and dimethylaminoethanol (DMAE), shown in Figure 1 [3]. This synthesis was performed in a reaction vial followed by purification on a cation-exchange cartridge [3].
Figure 1. One-step synthesis of [11C]choline.
The radioactive precursor, [11C]CH3I, is obtained via the 14N(p,α)11C nuclear reaction by proton bombardment of either 14N + 5–10% H2 gas (“CH4 target”) or 14N + 0.5–1.0% O2 gas (“CO2 target”), yielding [11C]CH4 or [11C]CO2, respectively. [11C]CH4 is converted directly to [11C]CH3I through reaction with iodine (I2) at >700 °C. In contrast, [11C]CO2 must first be reduced to [11C]CH4 before reacting with I2 at 360 °C to form [11C]CH3I (Figure 2a) [22,23,24,25].
Figure 2. Schematic overview of [11C]choline synthesis at Herlev Hospital. The radioactive precursor [11C]CH4 can be produced via two distinct pathways, both utilizing the 14N(p,α)11C nuclear reaction through proton bombardment of either 14N+O2 or 14N+H2 target gas. Pathway (a) [11C]CO2 is initially generated and subsequently reduced to [11C]CH4 using a nickel catalyst at 360 °C. Pathway (b) [11C]CH4 is produced directly from 14N2 and H2. (c) The [11C]CH3I then reacts with dimethylaminoethanol (DMAE) preloaded on a cation-exchange cartridge to yield [11C]choline, followed by purification with ethanol and then water. Finally, the product is eluted with saline. All synthesis steps are performed automatically using a TracerMaker module.
Direct [11C]CH4 production from the CH4 target is less time-consuming than the CO2-based route and generally yields high molar activities by avoiding inadvertent atmospheric carbon dioxide contamination during [11C]CO2 trapping and processing [26]. However, the CO2-route is typically preferred in the literature due to its higher overall radioactive yields, which in practical settings outweigh both the faster 11C-production and high molar activity of the CH4-route (except for production of tracers targeting low-density biological receptors, e.g., neuroimaging applications [27]). The [11C]choline productions reported in the literature [28,29,30,31,32], where the CO2-route is the preferred method, are no exception, affording end-of-synthesis (EOS) yields of approximately 10–30 GBq, compared to approximately 3 GBq (this work) using the CH4-route. At our facility, hardware constraints—specifically a single [11C]CH4 gas target on an IBA 18/9 cyclotron and a single TracerMaker module—prevent us from using a [11C]CO2 target or multi-module configurations. Consequently, optimizing the direct CH4-route on this specific setup establishes a practical, reproducible workflow for clinical centers with similar equipment limitations.
To address the growing clinical demand through improved radiosynthesis and comparative methodology, this study evaluates parameter optimization for in-house [11C]choline synthesis on a TracerMaker module using a [11C]CH4 gas target installed on an IBA 18/9 cyclotron (Figure 2b). The synthesis adapts the original literature protocols by loading DMAE directly onto the cation-exchange cartridge (Figure 2c). Three key parameters—irradiation time, precursor loading volume across single versus stacked cartridges, and purification efficiency—were systematically investigated to enhance EOS yield and product purity beyond previously published methods while maintaining product specifications.

2. Results and Discussion

The synthesis of [11C]choline is divided into three key steps. The first step is the formation of [11C]CH3I, the second is the reaction of DMAE with [11C]CH3I on the cation-exchange cartridge, and the third is purification of the product. The parameters of the validated standard synthesis for clinical use at the Department of Nuclear Medicine, Herlev Hospital, are summarized in Table 1. These serve as the basis for optimization. Moreover, the product specifications for human use are included in Table S1 (ESI, Section S2).
Table 1. Conditions for validated [11C]choline synthesis. EOB: end-of-bombardment, i.e., theoretical starting activity of the radioactive precursor, [11C]CH4. EOS, i.e., measured activity of the final product, [11C]choline.

2.1. Cyclotron [11C]CH4 Target Irradiation Times

Routine [11C]choline synthesis utilizes target irradiation times of 20–25 min, corresponding roughly to one half-life of carbon-11 (t½ = 20.34 min). The radioactive decay of the produced isotope leads to diminishing returns as irradiation time increases. Thus, irradiating for one half-life results in a maximum theoretical activity produced (saturation yield) of 50%, and two half-lives result in a 75% yield, etc. [33]. Extending irradiation to 42 min produced no significant increase in EOS yield of [11C]choline on our setup (Figure 3a).
Figure 3. (a) EOS yield [GBq] of [11C]choline when irradiating for roughly one (25 min, blue bar) and two (42 min, orange bar) half-lives. (b) The EOS yield of [11C]choline when increasing the temperature of HayeSep D (n = 3).
This plateau suggests saturation of the HayeSep D column during [11C]CH4 trapping, supported by the built-in radioactivity detectors on the TracerMaker module placed at the HayeSep D trap and the solid phase extraction (SPE) cartridge (ESI Section S3, Figure S2). Although these detectors are not calibrated and are only used to follow the activity through the system, the HayeSep D trap detector shows that similar radioactivity levels are achieved after both 25 min and 42 min of bombardment (ESI, Figure S2c).
Because [11C]CH4 is present in trace quantities relative to carrier N2, competitive absorption occurs. Studies show adsorption of gas species like [11C]CH4 and N2 on HayeSep D is correlated to the trapping temperature. Lower temperatures favor [11C]CH4 adsorption but simultaneously increase N2 retention [34]. Adjusting column trapping temperatures to −145 °C and −100 °C (compared to standard −125 °C) failed to improve performance. The experiment at −145 °C yielded similar activity trapping and EOS yields (3.25 ± 0.32 GBq; Figure 3b), whereas −100 °C reduced trapping by ~75% and significantly lowered EOS yield (1.87 ± 0.05 GBq; Figure 3b).
A possible solution would be to increase the amount of HayeSep D to improve the trapping. However, since the TracerMaker module is used for routine clinical production, this solution is not considered practical. Furthermore, packing a HayeSep D column is both time-consuming and technically challenging. Given this limitation, we therefore pursued alternative approaches to enhance the radioactive yield.

2.2. Number of SPE Cartridges and Amount of DMAE

The reaction of [11C]CH3I with DMAE takes place directly on the cation-exchange SPE cartridge through an SN2 nucleophilic substitution mechanism. In the validated [11C]choline synthesis, a single SPE cartridge is loaded with 50 µL of DMAE (Table 1). It was hypothesized that the EOS yield would increase proportionally with the amount of precursor. To evaluate this hypothesis, experiments were conducted by increasing DMAE volumes from 50 µL to 300 µL across 1–3 stacked SPE cartridges. Furthermore, a commercially available cartridge containing a larger amount of sorbent mass (360 mg) was evaluated. The parameters and resulting yields for the various [11C]choline synthesis configurations are summarized in Table S2 (ESI, Section S4 and illustrated in Figure 4).
Figure 4. On-cartridge reaction of DMAE and [11C]CH3I with increasing load of DMAE. Activities are measured at the EOS as soon as possible and not decay corrected (initial EOB activities across all test batches remained highly stable, averaging 34.8 ± 2.5 GBq). (a) Experiments with 1 × 130 mg adsorbent SPE cartridge (n = 3), (b) with 2 × stacked 130 mg adsorbent SPE cartridges (n = 3), (c) with 3 × stacked 130 mg adsorbent SPE cartridges (n = 3), and (d) with 1 × SPE cartridge containing 360 mg adsorbent (n = 3).
As shown in Figure 4a, utilizing a single 130 mg SPE cartridge loaded with 50 µL of DMAE afforded 3.19 ± 0.69 GBq (n = 143). Increasing the DMAE volume from 75 µL to 150 µL improved the yield to approximately 4.4–4.6 GBq. However, no significant increase in activity was observed between a loading volume of 100–150 µL, indicating that the maximum precursor loading capacity for a single 130 mg cartridge is up to 150 µL of DMAE.
Based on these findings, two 130 mg SPE cartridges stacked in series were loaded with 150 µL of DMAE per cartridge (Figure 4b), which increased the EOS yield to 5.85 ± 0.64 GBq. Notably, dividing 50 µL of DMAE across two cartridges (25 µL/cartridge) afforded an EOS yield of 3.73 ± 0.75 GBq, which is higher than the average EOS yield for routine productions (3.19 GBq). This enhancement suggests that lower precursor volumes (<50 µL/cartridge) achieve superior spatial distribution within the sorbent bed, expanding the effective surface area available for alkylation with [11C]CH3I. This trend was further supported by experiments performed with 50, 75 and 100 µL/cartridge, which resulted in yields comparable to those obtained at 150 µL/cartridge (Figure 4b).
For the experiments with three cartridges, a total loading volume of 150 µL of DMAE (50 µL/cartridge) was evaluated (Figure 4c), matching the volume per cartridge used in routine productions. This composition also increased EOS yield compared to routine productions (5.20 ± 0.59 GBq vs. 3.19 ± 0.69 GBq). However, no improvement was observed when compared to two cartridges loaded with 50 µL per cartridge (5.50 ± 0.26 GBq). This plateau indicates sorbent saturation, prompting us to forgo higher loading volumes with three cartridges. Instead, a single SPE cartridge containing a larger sorbent mass (360 mg) was evaluated (Figure 4d). Loading 150 µL and 300 µL of DMAE onto a 360 mg cartridge afforded 4.77 ± 0.12 GBq and 6.46 ± 0.31 GBq, respectively. The 150 µL load on the 360 mg cartridge yielded results comparable to a single 130 mg cartridge with 150 µL of DMAE (4.60 GBq). However, the yield was lower than an equivalent 150 of µL of DMAE distributed across two or three stacked 130 mg cartridges (5.71 GBq and 5.20 GBq), reinforcing the premise that precursor distribution across smaller sorbent beds enhances yield. The highest average EOS yield of all tested conditions was achieved when loading 300 µL on a single 360 mg cartridge (6.46 ± 0.31GBq), outperforming 300 µL of DMAE distributed across two 130 mg cartridges (5.85 GBq).
Overall, these findings confirm that higher precursor loads increase EOS yields, though the relationship remains nonlinear due to sorbent bed saturation at high DMAE volumes.
Residual DMAE concentrations in the final formulation were monitored across all experiments. As presented in Figure 5 and Table S2 (ESI, Section S4), an increase in the precursor load elevated residual DMAE levels in the final formulation. Although the DMAE concentration remained within clinical product specification (≤200 µg/mL), optimization strategies were explored to minimize residual precursor contamination.
Figure 5. Residual DMAE content in the final product. (a) DMAE content with 1 cartridge. (b) DMAE content with 2 cartridges. The DMAE content in the final product was analyzed by HPLC.
In the routine production, the product is washed with 5 mL of ethanol to remove unreacted DMAE, followed by 5 mL of water to flush residual ethanol. To improve clearance, washing volumes were doubled (2 × 5 mL ethanol, 2 × 5 mL H2O) on two stacked cartridges loaded with 150 µL of DMAE (75 µL per cartridge). This modification yielded no significant reduction in residual DMAE (Figure 6a), suggesting that the connection between the stacked cartridges introduces fluidic dead space where unreacted precursor accumulates during purification.
Figure 6. (a) Experiments with two stacked cartridges (150 µL DMAE load) using single (1 × 5 mL) and doubled (2 × 5 mL) washing volumes. (b) Absolute residual DMAE concentration in µg/mL (blue bars) compared directly against the clinical safety limit (threshold < 200 µL/mL, dashed line) and corresponding EOS yields in GBq (orange bars) across routine production (1 × 130 mg cartridge), stacked setup (2 × 130 mg cartridges), and a single 360 mg absorbent SPE cartridge (n = 3). These experiments were purified with double washing volumes (2 × 5 mL).
Evaluating the single 360 mg sorbent cartridge demonstrated superior DMAE clearance while preserving high EOS [11C]choline yields (Figure 6b). Doubling the precursor load on the 360 mg cartridge from 150 µL to 300 µL resulted in a minor increase in absolute residual DMAE (14.7 ± 0.67 µL/mL), remaining well below the clinical safety limit (<200 µL/mL). In contrast, equivalent precursor loads across stacked 130 mg cartridges resulted in higher residual DMAE levels (29.3 ± 21.5 µL/mL). These findings confirm that elimination interface connection dead space minimizes precursor retention in the final product.

3. Materials and Methods

The DMAE, sterilizing filter (Millex-GS, 0.22 µm, SLGSV255F) and ventilation filter (Millex-PVDF, 0.22 µm, SLGV004SL) were obtained from Sigma-Aldrich/Merck Life Science A/S, Vandtaarnsvej 62, 2860 Soeborg, Denmark. Both types of cation-exchange SPE cartridges—Sep-Pak Accell CM Plus Light 130 mg sorbent (WAT023531) and Accell Plus CM Plus Short 360 mg sorbent (WAT020550)—were obtained from WatersTM, Dybendalsvaegent 2, Prague 4, 2630 Taastrup, Denmark. Standard reagents such as ethanol, sterile water (water for injection), and isotonic saline were supplied by the Herlev Hospital Pharmacy, Marielundvej 25, 2730 Herlev, Denmark. The raw materials were stored at room temperature. The [11C]CH4 was obtained by bombardment of a 95% N2 + 5% H2 target gas through the 14N(p,α)11C nuclear reaction using an IBA 18 MeV cyclone 18/9 cyclotron (beam current: 27 µA, irradiation time: 20–25 min, Louvain-la-Neuve, Belgium). The synthesis and product purification were performed on a TracerMaker (software version 1.0) module from Scansys Laboratorieteknik ApS, Ravnehusvej1, 3500 Vaerloese, Denmark and executed by an automated sequence of operations. A detailed description and schematic overview of the radiosynthesis setup on TracerMaker are depicted in Figure S3 (ESI, Section S5). The quality of the final product was verified by various analytical tools. The DMAE content and radiochemical purity were quantified by high-performance liquid chromatography (HPLC) (Table S3 and Figure S4; ESI Section S6.1), the precursor purity was examined by gas chromatography (GC) (Table S4 and Figure S5; ESI Section S6.2), and ethanol content was quantified similarly (Table S5 and Figure S6; ESI Section S6.3). Finally, the pH level was determined by pH indicator strips (Figure S7; ESI Section S6.4). All quality controls must be within the site-specific approved specifications before the product can be utilized in patients. The full list of specifications is shown in Table S1 (ESI, Section S2). A detailed description for each method can be found in the ESI Section S6.

3.1. Product Quality Control and Analysis

All batches for human use were subjected to quality control (QC) testing prior to release in compliance with compassionate use permits issued by the Danish Medicines Agency. The analytical methods used for QC are generally validated in line with the European Pharmacopoeia (Ph. Eur. 11.0; monograph 04/2018:2462). Details on the QC procedures, equipment (dose calibrator, endotoxin test, GC, HPLC, and pH), and drug specifications are described in the ESI (Sections S2 and S6). Based on a 5 mL final product formulation containing an average cold choline concentration of 3.17 µg/mL and an EOS activity yield of 3.19–6.46 GBq, the resulting EOS molar activity was calculated to be 28.1–56.9 GBq/µmol, which is sufficient for diagnostic PET imaging.

3.2. Statistical Methods

Data are reported as mean ± standard deviation (SD). Data processing and statistical evaluations were performed in Microsoft Excel using the built-in statistical functionalities and were visualized with the Matplotlib 3.9 package in Python 3.12.7.

4. Conclusions

Optimization of [11C]choline synthesis on the TracerMaker module was evaluated for three parameters to improve the EOS yield. (1) Extended target irradiation time (42 min vs. 25 min) of the 14N + H2 target in the production of [11C]CH4 did not increase EOS yield, indicating saturation of the HayeSep D column. Increasing trapping temperature to minimize competitive N2 adsorption did not improve EOS yield either. (2) Increased precursor loading across 1–3 stacked cation-exchange cartridges (130 mg sorbent) produced up to a twofold EOS yield increase. The highest yield for stacked configurations (5.85 ± 0.64 GBq) was obtained using 300 µL of DMAE split equally across two cartridges; however, this increased residual precursor concentration in the final formulation (160 µg/mL vs. 6 µg/mL). (3) Doubling wash volumes (2 × 5 mL EtOH, 2 × 5 mL water) did not improve precursor clearance.
Conversely, replacing stacked cartridges with a single 360 mg sorbent cartridge loaded with 300 µL of DMAE effectively reduced residual DMAE (14.7 ± 0.67) while achieving higher radioactive yield (6.46 ± 0.31 GBq). The baseline yield of 3.19 ± 0.69 GBq at EOS was insufficient for multi-patient decay management. Our target yield threshold of > 5.0 GBq was achieved with the single 360 mg cartridge setup (6.46 ± 0.31 GBq), directly solving this clinical bottleneck. Consequently, an optimized synthesis protocol was established using a single 360 mg SPE cartridge loaded with 300 µL of DMAE, doubling the baseline production yield.
These results could serve as potential inspiration for other radiopharmaceutical production sites seeking to optimize their existing [11C]choline production efficiency, especially with [11C]CH4 as the radioactive precursor, or establish a [11C]choline production line.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/radiation6040044/s1: Section S1: Clinical use of [11C]choline. Section S2: Site-specific specifications of [11C]choline for human use. Section S3: Radioactivity signals during trapping and release of [11C]choline. Section S4: Synthesis information and results. Section S5: Radiosynthesis of [11C]choline on TracerMaker. Section S6: Quality control of [11C]choline. Table S1: Specifications for [11C]choline. Table S2: Synthesis parameters and results. Table S3: HPLC product quality control parameters. Figure S4: HPLC chromatogram of DMAE and Choline. Table S4: GC parameters for DMAE purity. Table S5: GC product quality control parameters for ethanol. Figure S1: Examples of [11C]choline PET images. Figure S2: Graphs of radioactivity signals. Figure S3: Schematic overviews of TracerMaker module. Figure S5: GC chromatogram of DMAE purity. Figure S6: GC product quality control chromatogram of ethanol. Figure S7: pH product quality control with pH indicator strips.

Author Contributions

Conceptualization, T.H.V.H.; data curation, T.H.H., A.B.A.A., C.B.C. and L.T.J.; visualization, T.H.H., A.B.A.A. and C.B.C.; writing—original draft preparation, T.H.H., A.B.A.A. and T.H.V.H.; writing—review and editing, T.H.H., A.B.A.A., V.L.A., C.B.C. and T.H.V.H.; Supervision, T.H.H. and T.H.V.H.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

All data generated or analyzed during this study are included in this published article and its Supplementary Information Files.

Acknowledgments

The authors thank the staff members involved in the production and quality analysis of [11C]choline and for the PET scanning of patients at the Department of Nuclear Medicine, Copenhagen University Hospital Herlev and Gentofte Hospital.

Conflicts of Interest

The authors declare no conflicts of interest.

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