Evaluating N-difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [18 F]fluoroform.

The trifluoromethyl group is a prominent motif in biologically active compounds and therefore of great interest for the labeling with the positron emitter fluorine-18 for positron emission tomography (PET) imaging. Multiple labeling strategies have been explored in the past; however, most of them suffer from low molar activity due to precursor degradation. In this study, the potential of 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate as precursor for the synthesis of the [18 F]trifluoromethylation building block [18 F]fluoroform with high molar activity was investigated. The triazolium precursor was reacted under various conditions with [18 F]fluoride, providing [18 F]fluoroform with radiochemical yields (RCY) and molar activities (Am ) comparable and even superior with already existing methods. Highest molar activities (Am = 153 ± 14 GBq/µmol, dc, EOS) were observed for the automated procedure on the Neptis® perform module. Due to its easy handling and good RCY and Am in the [18 F]fluoroform synthesis, the triazolium precursor is a valuable alternative to already known precursors.

Fluorine-18 Labeled Fluorofuranylnorprogesterone ([18F]FFNP) and Dihydrotestosterone ([18F]FDHT) Prepared by "Fluorination on Sep-Pak" Method.

To further explore the scope of our recently developed "fluorination on Sep-Pak" method, we prepared two well-known positron emission tomography (PET) tracers 21-[18F]fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione furanyl norprogesterone ([18F]FFNP) and 16ß-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT). Following the "fluorination on Sep-Pak" method, over 70% elution efficiency was observed with 3 mg of triflate precursor of [18F]FFNP. The overall yield of [18F]FFNP was 64-72% (decay corrected) in 40 min synthesis time with a molar activity of 37-81 GBq/µmol (1000-2200 Ci/mmol). Slightly lower elution efficiency (~55%) was observed with the triflate precursor of [18F]FDHT. Fluorine-18 labeling, reduction, and deprotection to prepare [18F]FDHT were performed on Sep-Pak cartridges (PS-HCO3 and Sep-Pak plus C-18). The overall yield of [18F]FDHT was 25-32% (decay corrected) in 70 min. The molar activity determined by using mass spectrometry was 63-148 GBq/µmol (1700-4000 Ci/mmol). Applying this quantitative measure of molar activity to in vitro assays [18F]FDHT exhibited high-affinity binding to androgen receptors (Kd~2.5 nM) providing biological validation of this method.

Cu(II)-Mediated direct 18F-dehydrofluorination of phosphine oxides in high molar activity.

BACKGROUND: The 18F/19F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous 18F-labeling of peptides and proteins. However, the molar activity (Am) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [18F]F-. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct 18F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the 18F-labeled product from the phosphine oxide precursors, aiming to primarily increase Am. RESULTS: Through a 19F-dehydrofluorination efficiency test, Cu(OAc)2 was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the Am of an activated ester, [18F]4, sees an impressive nearly 15-fold increase compared to the 18F/19F-isotope exchange, with the same initial activity of [18F]F-. Furthermore, this Cu(II)-mediated 18F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of 18F-labeled water-soluble molecules under non-drying conditions. CONCLUSIONS: The direct 18F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high Am via Cu(II)-mediated oxidative addition and reductive elimination.

Influence of the Molar Activity of 203/212Pb-PSC-PEG2-TOC on Somatostatin Receptor Type 2-Binding and Cell Uptake.

(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [177Lu]Lu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴,-tetraacetic acid-[Tyr3,Thr8]-octreotide (177Lu-DOTA-TOC) and, more recently, by a lead specific chelator (PSC) containing 203/212Pb-PSC-PEG2-TOC (PSC-TOC). The molar activity (AM) can play a crucial role in tumor uptake, especially in receptor-mediated uptake, such as in NETs. Therefore, an investigation of the influence of different molar activities of 203/212Pb-PSC-TOC on cell uptake was investigated. (2) Methods: Optimized radiolabeling of 203/212Pb-PSC-TOC was performed with 50 µg of precursor in a NaAc/AcOH buffer at pH 5.3-5.5 within 15-45 min at 95° C. Cell uptake was studied in AR42 J, HEK293 sst2, and ZR75-1 cells. (3) Results: 203/212Pb-PSC-TOC was radiolabeled with high radiochemical purity >95% and high radiochemical yield >95%, with AM ranging from 0.2 to 61.6 MBq/nmol. The cell uptake of 203Pb-PSC-TOC (AM = 38 MBq/nmol) was highest in AR42 J (17.9%), moderate in HEK293 sstr (9.1%) and lowest in ZR75-1 (0.6%). Cell uptake increased with the level of AM. (4) Conclusions: A moderate AM of 15-40 MBq/nmol showed the highest cell uptake. No uptake limitation was found in the first 24-48 h. Further escalation experiments with even higher AM should be performed in the future. It was shown that AM plays an important role because of its direct dependence on the cellular uptake levels, possibly due to less receptor saturation with non-radioactive ligands at higher AM.

The Influence of Specific Activity on the Biodistribution of 18F-rhPSMA-7.3: A Retrospective Analysis of Clinical PET Data.

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal-organ and tumor uptake of the PSMA ligand 18F-rhPSMA-7.3 in patients with prostate cancer. Methods: The biodistribution of 18F-rhPSMA-7.3 on PET/CT scans obtained with a high specific activity (median, 178.9 MBq/µg; n = 42) and a low specific activity (median, 19.3 MBq/µg; n = 42) was compared. Results: Tracer uptake by the parotid gland, submandibular gland, and spleen was moderately but significantly lower in the low-specific-activity group than in the high-specific-activity group (median SUVmean, 16.7 vs. 19.2; 18.1 vs. 22.3; and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. Conclusion: A 10-fold decrease in specific activity has only minor effects on the biodistribution of 18F-rhPSMA-7.3. These findings suggest that 18F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to 18F-FDG.

Optimization of Precursor Preparation in PSMA-11 Radiolabeling to Obtain a Highly Reproducible Radiochemical Yield.

[68Ga]Ga-PSMA-11 PET/CT plays a pivotal role in the diagnosis and staging of prostate cancer because of its higher sensitivity and detection rate compared with traditional choline PET/CT. A highly reproducible radiochemical yield of the radiopharmaceutical to be used in the clinical routine is an important parameter for planning and optimization of clinical activity. During radiometallation of PSMA-11, the presence of metal ion contaminants in the peptide precursor may cause a decrease in the [68Ga]Ga-PSMA-11 radiochemical yield because of metal ion contaminants competition with gallium-68. To optimize the radiochemical yield of [68Ga]Ga-PSMA-11 radiosynthesis, data obtained by preparing the solution of the PSMA-11 precursor with three different methods (A, B, and C) were compared. Methods A and B consisted of the reconstitution of different quantities of precursor (1000 µg and 30 µg, respectively) to obtain a 1 µg/mL solution. In Method A, the precursor solution was aliquoted and stored frozen, while the precursor solution obtained with Method B was entirely used. Method C consisted of the reconstitution of 1000 µg of precursor taking into account net peptide content as described in European Pharmacopoeia. Radiosynthesis data demonstrated that reconstitution methods B and C gave a consistently higher and reproducible radiochemical yield, highlighting the role of metals and precursor storage conditions on the synthesis performance.

Demystifying solid targets: Simple and rapid distribution-scale production of [68Ga]GaCl3 and [68Ga]Ga-PSMA-11.

BACKGROUND: As the demand for 68Ga continues to grow, there is increasing interest in single-to-multi-Curie production quantities of both [68Ga]GaCl3 and tracers such as [68Ga]Ga-PSMA-11. While such quantities are possible with solid targets, this implementation is often challenging as it typically requires significant site expertise for solid target processing and careful operator-dependent synchronization of multiple independent time-sensitive chemistry steps. Herein we focus on a fully automated solid target production and purification process whereby we avoid the need for tongs/tele-pliers, and have simplified the chemistry by implementing a single sequence (i.e. "time-list") to execute cassette-based dissolution, purification, and labeling. METHODS: Electroplated 68Zn was irradiated in a PETtrace prototype automated solid target system. Following irradiation, and using a single FASTlab time-list, the 68Zn was automatically dissolved with HCl/H2O2 and purified as [68Ga]GaCl3 using a combination of resins (ZR/TK400, A8, TK200: Triskem). For select experiments, [68Ga]Ga-PSMA-11 was also produced on the same cassette/single time-list (N = 4), or, by kit labeling (N = 1). Efforts focused towards on-cassette production of [68Ga]GaCl3 strived to maximize activity and quality, whereas efforts focused towards on-cassette production of [68Ga]Ga-PSMA-11 aimed at limiting the entire production cycle to 1 h including the irradiation time (i.e. start-of-bombardment âž” end-of-synthesis [EOS]). RESULTS: For the high activity triplicate [68Ga]GaCl3 productions (i.e. 80 µA, 102 min, 216 ± 10 mg), [68Ga]GaCl3 was purified (end-of-bombardment âž” end-of-purification [EOP]) in ~28 min with activity yields of 181 ± 8 GBq at EOP and average radiochemical yields of 66 ± 5%. Average AMAs of 2.26 ± 0.16 TBq/µmol using DOTA (N = 3) and 12.00 TBq/µmol using HBED (PSMA-11) (N = 1) at EOP were measured. For the single kit test, (80 µA, 120 min, 263 mg 68Zn) for which 18 mg ascorbic acid was added to the buffer, 199 GBq of [68Ga]Ga-PSMA-11 was successfully produced (thin layer chromatography-based radiochemical purity >99% at 6 h EOS). Finally, for efforts focused at expedient [68Ga]Ga-PSMA-11, up to 42 GBq [68Ga]Ga-PSMA-11 with a radiochemical yield of 51.2% was produced in 63 min, including beamtime, using 220 mg of 68Zn as target material. CONCLUSION: With the goal of simplifying solid target production and purification efforts, automated methods using single-use, cassette-based approaches for rapid, large-scale, single time-list production of [68Ga]GaCl3 and [68Ga]Ga-PSMA-11 were developed. These methods were simple to execute and yielded high quality multi-Curie levels of both [68Ga]GaCl3 and [68Ga]Ga-PSMA-11.

The effects of molar activity on [18F]FDOPA uptake in patients with neuroendocrine tumors.

BACKGROUND: 6-[18F]fluoro-L-3,4-dihydroxyphenyl alanine ([18F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [18F]FDOPA is decarboxylated to [18F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [18F]FDOPA has been developed, [18F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([18F]FDOPA-L). AIMS: This study aimed to investigate whether the difference in molar activity affects the [18F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [18F]FDOPA-H would be equal to or higher than [18F]FDOPA-L. METHODS: We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [18F]FDOPA-H and [18F]FDOPA-L within a time span of 5 years. A total of 98 [18F]FDOPA scans (49 [18F]FDOPA-L and 49 [18F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1-2 lesions) and higher tumor load (3-10 lesions). RESULTS: Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [18F]FDOPA-H compared to [18F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [18F]FDOPA-H group with 3-10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L. CONCLUSION: [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV's, with slight increases in uptake of [18F]FDOPA-H in comparison to [18F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [18F]FDOPA.

Determination of molar activity of [18F]fluoride by HPLC via sulfonyl derivatization.

The molar activity of [18F]fluoride was determined by HPLC of sulfonyl fluorides, which have high UV absorbance and are formed exclusively from sulfonyl chlorides and [18F]fluoride in aqueous solution. The measurable limit of sulfonyl fluorides is as low as 0.1 ppm, allowing measurements up to the theoretical molar activity of [18F]fluoride. The method was validated with standard solutions of fluoride, and provides a convenient way to measure molar activity of [18F]fluoride using only HPLC without specialized equipment.

GMP-Automated Purification of Copper-61 Produced in Cyclotron Liquid Targets: Methodological Aspects.

BACKGROUND: Expanding the range of metal-based PET radiopharmaceuticals that can be produced by the widely available network of biomedical cyclotrons is a major priority. Copper- 61 is a positron emitter with very favourable physical (61.5% ß+, 1.22 MeV max.) and chemical properties, which emerged as a promising PET imaging agent. OBJECTIVES: This work aimed to develop and optimise a GMP-automated purification method for copper-61 produced in a cyclotron using a natural zinc liquid target. METHODS: The automated purification process was performed using a commercially available Synthera ® Extension module (IBA, Louvain-la-Neuve, Belgium) using a three-column method: two extraction chromatographic resins and a strong anion exchange resin. The final product was evaluated using HPGe and ICP-MS analysis, to assess the radionuclidic and chemical purity of the final copper- 61 solution. RESULTS: The automated purification process was completed within 1 h of processing time, with an average yield of 63.0 ± 15.0%, in a maximum volume of 5 mL. The radionuclidic purity of copper- 61 in the final solution was over 95% for 7 h after EOB. ICP-MS analysis revealed 4.8 ± 2.4 µg of natural zinc in the final purified sample, and the copper-61 molar activity was 230.5 ± 139.3 GBq/µmol. CONCLUSION: The described purification process allows for the production of a highly radionuclidically and chemically pure, GMP compliant copper-61 solution, ready to be used for the development of copper-61 based radiopharmaceuticals for routine clinical use.

EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality.

This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed.

Molar activity of [18F]FP-(+)-DTBZ radiopharmaceutical: Determination and its effect on quantitative analysis of VMAT2 autoradiography.

[18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) is a rising positron tracer for imaging vesicular monoamine transporter II (VMAT2) in the central nervous system. The present work was to develop a novel chromatographic method capable of the molar activity (Am) determination of [18F]FP-(+)-DTBZ. As a complement work of the Am measurement, we also investigated the effect of Am on the quantitative analysis of VMAT2 autoradiography with [18F]FP-(+)-DTBZ. The Am determination was performed by high performance liquid chromatography (HPLC) using the non-radioactive standard (FP-(+)-DTBZ) for calibration plot of peak area against concentration. Based on this correlation, the Am of [18F]FP-(+)-DTBZ was calculated and corrected to the end of synthesis. In the quantitative analysis of in vitro VMAT2 autoradiography, the striatum radioactivity uptake together with the uptake ratio of striatum versus cortex reduced along with the decrease of Am and the increase of the FP-(+)-DTBZ content. Therefore, the Am and the corresponding FP-(+)-DTBZ content have a significant effect on the quantitative analysis of VMAT2 autoradiography using [18F]FP-(+)-DTBZ.

A simple and efficient automated microvolume radiosynthesis of [18F]Florbetaben.

BACKGROUND: Current automated radiosynthesizers are generally optimized for producing large batches of PET tracers. Preclinical imaging studies, however, often require only a small portion of a regular batch, which cannot be economically produced on a conventional synthesizer. Alternative approaches are desired to produce small to moderate batches to reduce cost and the amount of reagents and radioisotope needed to produce PET tracers with high molar activity. In this work we describe the first reported microvolume method for production of [18F]Florbetaben for use in imaging of Alzheimer's disease. PROCEDURES: The microscale synthesis of [18F]Florbetaben was adapted from conventional-scale synthesis methods. Aqueous [18F]fluoride was azeotropically dried with K2CO3/K222 (275/383 nmol) complex prior to radiofluorination of the Boc-protected precursor (80 nmol) in 10 µL DMSO at 130 °C for 5 min. The resulting intermediate was deprotected with HCl at 90 °C for 3 min and recovered from the chip in aqueous acetonitrile solution. The crude product was purified via analytical scale HPLC and the collected fraction reformulated via solid-phase extraction using a miniature C18 cartridge. RESULTS: Starting with 270 ± 100 MBq (n = 3) of [18F]Fluoride, the method affords formulated product with 49 ± 3% (decay-corrected) yield,> 98% radiochemical purity and a molar activity of 338 ± 55 GBq/µmol. The miniature C18 cartridge enables efficient elution with only 150 µL of ethanol which is diluted to a final volume of 1.0 mL, thus providing a sufficient concentration for in vivo imaging. The whole procedure can be completed in 55 min. CONCLUSIONS: This work describes an efficient and reliable procedure to produce [18F]Florbetaben in quantities sufficient for large-scale preclinical applications. This method provides very high yields and molar activities compared to reported literature methods. This method can be applied to higher starting activities with special consideration given to automation and radiolysis prevention.

Optimization of the Automated Synthesis of [11C]mHED-Administered and Apparent Molar Activities.

The tracer [[11C]meta-Hydroxyephedrine ([[11C]mHED) is one of the most applied PET tracers for cardiac imaging, whose radiosynthesis was already reported in 1990. While not stated in the literature, separation difficulties and an adequate formulation of the product are well known challenges in its production. Furthermore, the precursor (metaraminol) is also a substrate for the norepinephrine transporter, and can therefore affect the image quality. This study aims at optimizing the synthetic process of [[11C]mHED and investigating the effect of the apparent molar activity (sum of mHED and metaraminol) in patients and animals. The main optimization was the improved separation through reverse phase-HPLC by a step gradient and subsequent retention of the product on a weakly-cationic ion exchange cartridge. The µPET/µCT was conducted in ten rats (ischemic model) and the apparent molar activity was correlated to the VOI- and SUV-ratio of the myocardium/intra-ventricular blood pool. Moreover, nine long-term heart transplanted and five Morbus Fabry patients underwent PET and MRI imaging for detection of changes in the sympathetic innervation. In summary, the fully-automated synthesis and optimized purification method of [[11C]mHED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality.

Impact of 18F-PSMA-1007 Uptake in Prostate Cancer Using Different Peptide Concentrations: Preclinical PET/CT Study on Mice.

PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/µmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/µmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/µmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.

Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET).

BACKGROUND: Conventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. Using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), we demonstrate that simple microvolume radiosynthesis techniques can improve the efficiency of production by consuming tiny amounts of precursor, and maintaining high molar activity of the tracers even with low starting activity. PROCEDURES: The synthesis was carried out in microvolume droplets manipulated on a disposable patterned silicon "chip" affixed to a heater. A droplet of [18F]fluoride containing TBAHCO3 was first deposited onto a chip and dried at 100 °C. Subsequently, a droplet containing 60 nmol of precursor was added to the chip and the fluorination reaction was performed at 90 °C for 5 min. Removal of protecting groups was accomplished with a droplet of HCl heated at 90 °C for 3 min. Finally, the crude product was collected in a methanol-water mixture, purified via analytical-scale radio-HPLC and formulated in saline. As a demonstration, using [18F]FET produced on the chip, we prepared aliquots with different molar activities to explore the impact on preclinical PET imaging of tumor-bearing mice. RESULTS: The microdroplet synthesis exhibited an overall decay-corrected radiochemical yield of 55 ± 7% (n = 4) after purification and formulation. When automated, the synthesis could be completed in 35 min. Starting with < 370 MBq of activity, ~ 150 MBq of [18F]FET could be produced, sufficient for multiple in vivo experiments, with high molar activities (48-119 GBq/µmol). The demonstration imaging study revealed the uptake of [18F]FET in subcutaneous tumors, but no significant differences in tumor uptake as a result of molar activity differences (ranging 0.37-48 GBq/µmol) were observed. CONCLUSIONS: A microdroplet synthesis of [18F]FET was developed demonstrating low reagent consumption, high yield, and high molar activity. The approach can be expanded to tracers other than [18F]FET, and adapted to produce higher quantities of the tracer sufficient for clinical PET imaging.

Molar activity - The keystone in 11C-radiochemistry: An explorative study using the gas phase method.

INTRODUCTION: Radiochemists/radiopharmacists, involved in the preparation of radiopharmaceuticals are regularly confronted with the requirement of continuous high quality productions in their day-to-day business. One of these requirements is high specific or molar activity of the radiotracer in order to avoid e.g. receptor saturation and pharmacological or even toxic effects of the applied tracer for positron emission tomography. In the case of 11C-labeled radiotracers, the reasons for low molar activity are manifold and often the search for potential 12C-contaminations is time-consuming. METHODS: In this study, diverse 12C-contaminations were analyzed and quantified, which occurred during >450 syntheses of six PET tracers using [11C]CO2 or [11C]CH3I generated via the gas phase method in a commercially available synthesizer. Additionally, non-radioactive syntheses were performed in order to identify the origins of carbon-12. RESULTS: The manifold contributions to low molar activity can be attributed to three main categories, namely technical parameters (e.g. quality of target gases, reagents or tubings), inter/intralaboratory parameters (e.g. maintenance interval, burden of the module, etc.) and interoperator parameters (e.g. handling of the module). CONCLUSION: Our study provides a better understanding of different factors contributing to the overall carbon load of a synthesis module, which facilitates maintenance of high molar activity of carbon-11-labeled radiopharmaceuticals.