Pharmacokinetics and Radiation Dosimetry of ¹⁸F-Fluorocholine

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 × 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 × 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 γ-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 × 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 × 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 C_FCH 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% × 1.44 × 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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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.

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.

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.

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.