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Journal of Nuclear Medicine Vol. 43 No. 1 92-96
© 2002 by Society of Nuclear Medicine

Basic Science Investigations

Pharmacokinetics and Radiation Dosimetry of 18F-Fluorocholine

Timothy R. DeGrado, PhD1, Robert E. Reiman, MD2, David T. Price, MD3, Shuyan Wang1 and R. Edward Coleman, MD1

1 Department of Radiology, Duke University Medical Center, Durham, North Carolina
2 Division of Radiation Safety, Duke University Medical Center, Durham, North Carolina
3 Department of Surgery, Duke University Medical Center, Durham, North Carolina


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
18F-Fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) has been developed as an oncologic probe for PET. This study evaluates the kinetics and radiation dosimetry of 18F-FCH using murine and human biodistribution data. Methods: The biodistribution of 18F-FCH was obtained at time points up to 10 h after administration in control and tumor-bearing anesthetized nude mice. Human biodistribution data within the first hour after injection were obtained from attenuation-corrected whole-body PET scans of male (n = 7) and female (n = 5) cancer patients. Radiation dosimetry estimates were calculated using the murine and human biodistribution data assuming no redistribution of tracer after 1 h. Results: Rapid pharmacokinetics were observed for 18F-FCH in mice and humans. The biodistribution is nearly static after 10 min. The dose-critical organ is the kidney, which receives 0.17 ± 0.05 and 0.16 ± 0.07 mSv/MBq (0.64 ± 0.18 and 0.55 ± 0.32 rad/mCi) for females and males, respectively. The effective dose equivalent (whole body) from administration of 4.07 MBq/kg (0.110 mCi/kg) is approximately 0.01 Sv for females and males. Conclusion: 18F-FCH is rapidly cleared from the circulation and its biodistribution changes very slowly at >10 min after administration. The kidney is the dose-critical organ and limits administration levels of 18F-FCH to 4.07 MBq/kg (0.110 mCi/kg) in human research studies.

Key Words: 18F-fluorocholine • PET • oncology


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Positron-labeled choline analogs are becoming increasingly useful as molecular probes for detection and localization of neoplasms in conjunction with PET (1–7). The avid transport of the choline analogs into malignant tissues and their rapid distribution kinetics are advantageous properties for clinical oncologic PET. However, high uptake of tracer in liver, kidney, and spleen may present limitations because of relatively high radiation doses to these tissues. This study evaluates the pharmacokinetics and biodistribution of the 18F-labeled choline analog fluoromethyl-dimethyl-2-hydroxyethylammonium (FCH) (6,7) in mice and humans and uses the data to calculate human radiation dosimetry estimates.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Synthesis of 18F-FCH
No-carrier-added 18F-FCH was synthesized through 18F-fluorobromomethane as described (7). The radiochemical purity was >99% by cation-exchange high-performance liquid chromatographic analysis. The final preparation consisted of 18F-FCH in sterile, isotonic saline solution.

Biodistribution Studies in Normal and Tumor-Bearing Mice
All animal experiments were conducted under a protocol approved by the Duke University Institutional Animal Care and Use Committee. Control 4- to 6-wk-old male athymic mice (BALB/c nu/nu; Comprehensive Cancer Isolation Facility, Duke University Medical Center, Durham, NC) were maintained in pathogen-free conditions (8) without interventions. In tumor-bearing groups of mice, human cancer cells (PC-3 androgen-independent prostate carcinoma or MCF7 estrogen receptor–positive breast carcinoma; Cell Culture Facility, Duke University Medical Center, Durham, NC) were suspended in Matrigel (Collaborative Research, Bedford, MA) at a concentration of 1 x 106 cells/100 µL and were injected subcutaneously into the flank of the mice. Body weight and tumor volume were measured weekly. Tumor volume (mm3) was calculated using the formula S2 x L/2, where S and L represent the large and small diameters of the tumor, respectively. After the tumor volume had surpassed 0.5 cm3, the mice were anesthetized with pentobarbital (75 mg/kg) before injection of radiotracer, and they remained anesthetized throughout the study. 18F-FCH (0.74–1.48 MBq [20–40 µCi]) was injected into a tail vein. A prescribed duration of time was allowed before procurement of organs and tissues. The tissues were weighed and 18F radioactivity was measured in a {gamma}-counter. For the bladder, the percentage of the injected dose in the urine was determined. For all other tissues, radiotracer uptake was calculated as:

(Eq. 1)
where cpm = counts per minute.

PET Studies in Patients with Prostate Cancer and Breast Cancer
The biodistribution of 18F-FCH was investigated in 7 male patients with prostate cancer and 5 female patients with breast cancer. The 18F-FCH PET studies were approved by the Duke University Medical Center Institutional Review Board and Cancer Research Committee. The subjects were informed of all risks associated with the study and written informed consent was obtained. The patients were requested to refrain from food intake for at least 4 h before scanning. No adverse events were observed in any of the patients after administration of 18F-FCH. Imaging was performed using an Advance PET scanner (General Electric Medical Systems, Milwaukee, WI) having an intrinsic spatial resolution of approximately 5 mm in all directions (9). Whole-body emission scans (6 or 7 bed positions x 4 min per bed position) were acquired beginning 10–20 min after administration of 18F-FCH (110–220 MBq [3–6 mCi]). Acquisition of transmission scans (6 or 7 bed positions x 3 min per bed position) followed emission imaging for correction of photon attenuation. Correction for emission activity during the transmission scan was performed using a commercially implemented algorithm. In 5 female patients, dynamic PET was performed over the heart in the first 10 min after injection to obtain time–activity curves of radioactivity in the left ventricular blood pool. Tissue concentrations of radioactivity (% dose/mL) were evaluated in various tissue regions using manual region definition on the PET images:

(Eq. 2)
where CFCH is the regional tissue concentration of radioactivity. To provide data for radiation dosimetry, the amount of radioactivity distributed to the whole organ was determined in liver, kidneys, spleen, and urinary bladder. Regions of interest around the whole organ were manually defined on the PET images by a skilled operator. For illustration purposes, the radioactivity concentration data were corrected for radioactive decay using a half-life of 109.8 min.

Radiation Dosimetry Calculations
Human radiation dosimetry estimates based on murine biodistribution of 18F-FCH were obtained as described (7). Although the human biodistribution data were derived from PET studies in cancer patients, uptake of 18F-FCH by neoplasms, if present, was not considered in the dosimetry calculations. Simulation studies showed that tumor uptake, which is typically <1% of the injected dose, has a negligible effect on the calculations of the effective dose equivalent. The mean tissue activity concentrations, or fraction of dose per whole organ, were computed for females (n = 5) and males (n = 7). For those tissues where total organ activity was unavailable, the organ weights derived from the Cristy–Eckerman (10) mathematic phantoms for the adult male and the adult female were used to estimate total tissue activity. For bone and skeletal muscle, 7.2% and 40.0% of average body weight were used to estimate tissue weight (11).

Because the murine biodistribution data (Table 1) showed a nearly static distribution of 18F-FCH in all tissues at >10 min after administration, and initial kinetic measurements in humans using dynamic 18F-FCH PET scans corroborated these murine measurements (Fig. 1), there was no basis for considering biologic clearance in the dose calculations. All uptake was assumed to be instantaneous, and the only clearance that was considered was the physical decay of 18F (half-life = 109.8 min). The total body residence time (100% x 1.44 x half-life) was 2.64 h. The individual organ residence times were computed by multiplying the total body residence time by the fraction of administered activity that was computed for each organ. To yield a conservative estimate of radiation dose to the bladder wall and gonads, the dynamic bladder model was not used; urinary radioactivity was assumed to be present immediately after injection and not voided during the decay period of the tracer. Bone uptake was assumed to be distributed at the bone surfaces. The calculated residence times were entered into the MIRDOSE 3.1 program (12) to calculate dose estimates.


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  		TABLE 1 Uptake (% Dose kg/100 g) of 18F-FCH in Tissues of Tumor-Bearing and Control Mice (male BALB/c nu/nu)

 


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  		FIGURE 1. Pharmacokinetics of 18F-FCH in left ventricular blood pool, liver, and lung of human subject. Data are corrected for radioactive decay. Blood-pool curve is fit by multiexponential model beginning at its peak (Table 2 summarizes parameter estimates).

 
Statistical Methods
Results are expressed as mean ± SD. Statistical analysis was performed using the Student t test and statistical significance was inferred at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Biodistribution of 18F-FCH in Normal and Tumor-Bearing Mice
Table 1 shows the biodistribution of 18F-FCH. The kidneys and liver were the primary sites of uptake for 18F-FCH, similar to previous findings with radiolabeled choline (1,13). No differences were observed in biodistribution patterns found in normal tissues of control and tumor-bearing groups of mice at 1 h after administration. Also, no significant difference was found in the biodistribution of 18F-FCH between the 2 groups of mice bearing breast cancer and prostate cancer xenografts. In the prostate cancer xenograft model, the kinetics were observed to be rapid and the distribution in the tissues was essentially static after 10 min. In control mice, no significant differences were found in the biodistribution of 18F-FCH between 1 and 10 h after administration, suggesting efficient metabolic sequestration of the radiolabel in tissues consistent with previously observed lipid incorporation of the radiolabel (7).

Pharmacokinetics of 18F-FCH in Human Subjects
Dynamic PET scanning that included the cardiac blood pool was performed on 5 breast cancer patients to evaluate the rapid pharmacokinetics of 18F-FCH in the blood. A region of interest was manually drawn within the left ventricular blood pool, and the dynamic PET data were evaluated from 0 to 30 min after administration (Fig. 1; Table 2). The use of image-derived blood radioactivity concentration has been validated previously against measurements using arterial blood sampling (14). The pharmacokinetics were fitted to a model that had 2 rapid exponential components plus a constant (Table 2). The 2 rapid phases, which were nearly complete by 3 min after administration, represented >93% of the peak radioactivity concentration. Thus, the tracer is extensively cleared in the first 5 min after administration. The concentration of 18F radioactivity in liver increased rapidly in the first 10 min and then increased slowly thereafter (Fig. 1). The concentration of 18F radioactivity in lung was relatively low at all times.


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  		TABLE 2 Exponential Model Parameter Estimates for 18F-FCH Arterial Blood Clearance Kinetics

 
Biodistribution of 18F-FCH in Human Subjects
Table 3 shows the uptake of 18F-FCH by various tissues in the human subjects derived from a whole-body PET scan beginning 10–20 min after administration. As noted previously (6), the biodistribution in humans is very similar to that in mouse with the exception of the lower lung and myocardial uptake in humans. The highest uptake was in the kidney followed by the liver and spleen. The mean activity in the bladder was 4.9% of the injected dose for females and 1.9% of the injected dose for males, although the difference was not statistically significant.


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  		TABLE 3 Biodistribution of 18F-FCH in Human Subjects at 10–55 Minutes After Injection

 
Radiation Dosimetry Estimates
Table 4 lists the estimated radiation doses for humans in mSv/MBq (rad/mCi) administered, with the doses derived from mouse data shown for comparison. Overall, the organ doses derived from human biodistribution data are comparable to those derived from rodent tissue distribution studies. The dose-critical organ is the kidney, which receives 0.17 and 0.16 mSv/MBq (0.64 and 0.55 rad/mCi) for females and males, respectively. To comply with the 0.05-Sv single-organ dose per study limit established by the Food and Drug Administration (FDA) for research subjects, it is required that the administered activity of 18F-FCH be limited to 4.07 MBq/kg (0.110 mCi/kg) for women and 4.14 MBq/kg (0.112 mCi/kg) for men. The effective dose equivalent for humans from administration of 4.07 MBq/kg (0.110 mCi/kg) is approximately 0.01 Sv for females and males, which is below the single-study FDA limit of 0.03 Sv for research subjects.


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  		TABLE 4 Radiation Dosimetry Estimates for Intravenous 18F-FCH Administration to Human Subjects on Basis of Murine and Human Biodistribution Data

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The rapid pharmacokinetics and long retention of 18F-FCH in tissues allow a conservative estimation of radiation doses from a model that assumes instantaneous distribution of tracer throughout the body followed by radioactive decay of 18F within the tissues. Consistent with previous 11C-choline data (1,3), blood clearance for 18F-FCH was found to be very rapid in humans with little change in the biodistribution pattern seen >10 min after administration.

Although a direct comparison of the pharmacokinetics of 18F-FCH and radiolabeled choline has not been performed in human subjects, comparison of the present data with those of Roivainen et al. (15) obtained with 11C-choline may suggest potential differences. Whereas 18F radioactivity concentration in arterial blood reaches a constant level >3 min after administration of 18F-FCH (6), the radioactivity concentration of 11C radioactivity continues to decline significantly after the early rapid clearance phase. The late clearance pattern with 11C-choline was attributed by Roivainen et al. to reflect metabolism of 11C-choline to 11C-betaine and subsequent clearance of the latter by the urinary system because most 11C in arterial plasma is in the form of 11C-betaine >5 min after administration. It is possible that 18F-FCH does not undergo similar metabolism through the oxidative pathway and therefore does not exhibit the later clearance pattern observed with 11C-choline. This notion is further supported by the finding of insignificant clearance of radiolabel in tissues of the mouse over a 10-h period after administration of 18F-FCH. Choline is known to undergo rapid oxidation in certain tissues with subsequent clearance of betaine from the tissue. For example, Haubrich et al. (13) observed radioactivity clearance half-lives in liver and kidney of 7–14 and 9–15 min, respectively, in guinea pigs after bolus intravenous administration of methyl-3H-choline. Liver clearance of radioactivity was also noted for 11C-choline in PET studies of normal rabbits (1). The lack of tissue clearance with 18F-FCH administration may reflect specific metabolic trapping of the tracer through phosphorylation and further incorporation of the radiolabel into phospholipids as recently shown in cultured prostate cancer cells (7). Further analytic studies in humans are needed to confirm the suggestion that the presence of the fluorine atom of FCH renders the molecule less susceptible for oxidation (and subsequent clearance) in human tissues than natural choline.

Our data show that men and women could receive a maximum injected dose of 4.07 MBq/kg (0.110 mCi/kg) and 4.14 MBq/kg (0.112 mCi/kg), respectively, and have an acceptable dose to the kidney (0.05 Gy [5 rad]) for research studies with 18F-FCH. Thus, when the doses are expressed per gram of body weight, the limiting doses are nearly equivalent for males and females. We have chosen to take the value of 4.07 MBq/kg (0.110 mCi/kg) as the limit for dose administration for our ongoing research studies.

The primary limitation of this study is the lack of information on the biodistribution of 18F-FCH in humans at times beyond 1 h after administration. Our assumption that there is no significant change in the tissue concentrations of tracer (correcting for decay) after a brief period is supported by the remarkably stable biodistribution of 18F-FCH in mice out to 10 h after administration. However, it is possible that species differences exist in tissue turnover of radiolabel in choline metabolite pools that we were not able to detect. A significant clearance of radiolabel from a tissue would result in a lower radiation dose in that tissue than is estimated in this study.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Preliminary dosimetry estimates were obtained from whole-body PET studies in human subjects acquired within the first hour after tracer administration. 18F-FCH is rapidly cleared from the circulation, and its biodistribution changes very slowly >10 min after administration. Mouse biodistribution data showed no significant change in tissue distribution from 1 to 10 h after administration. The kidney is the dose-critical organ and limits administration levels of 18F-FCH to 4.07 MBq/kg (0.110 mCi/kg body weight) in human research studies. Dynamic PET studies on human subjects over measurement periods exceeding 1 h may provide more accurate dosimetry estimates for 18F-FCH.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The authors thank technologists Mary Hawk and DeAndre Starnes for their excellent assistance and appreciate the clinical collaborations with Drs. P. Kelly Marcom, Matthew Ellis, Michael J. Kelley, Thomas Polascik, and Cary Robertson. The authors acknowledge helpful conversations with Drs. Barbara Croft, John Hoffman, Adaline Smith, Daniel Sullivan, and James Tatum of the National Cancer Institute’s Biomedical Imaging Program.


   FOOTNOTES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Received Mar. 19, 2001; revision accepted Sep. 21, 2001.

For correspondence or reprints contact: Timothy R. DeGrado, PhD, Department of Radiology, Duke University Medical Center, Box 3949, Durham, NC 27710.

E-mail: trd{at}petsparc.mc.duke.edu


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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  2. Shinoura N, Nishijima M, Hara T, et al. Brain tumors: detection with C-11 choline PET. Radiology 1997;202:497–503.[Abstract/Free Full Text]
  3. Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med 1998;39:990–995.[Abstract/Free Full Text]
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  5. Hara T, Inagaki K, Kosaka N, Morita T. Sensitive detection of mediastinal lymph node metastasis of lung cancer with 11C-choline PET. J Nucl Med 2000;41:1507–1513.[Abstract/Free Full Text]
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  7. DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers. J Nucl Med 2001;42:1805–1814.[Abstract/Free Full Text]
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  9. DeGrado TR, Turkington TG, Williams JJ, Stearns CW, Hoffman JM, Coleman RE. Performance characteristics of a whole body PET scanner. J Nucl Med 1994;35:1398–1406.[Abstract/Free Full Text]
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