Our previous dosimetry studies have demonstrated that for dopaminergic radiotracers, 18F-FDOPA and 18F-FPCIT, the urinary bladder is the critical organ. As these tracers accumulate in the basal ganglia (BG) with high affinity and long residence times, radiation dose to the BG may become significant, especially in normal control subjects. We have performed dynamic PET measurements using 18F-FPCIT in 16 normal adult subjects to determine if in fact the BG, although not a whole organ, but a well-defined substructure, receives the highest dose. Regions of interest were drawn over left and right BG structures. Resultant time-activity curves were generated and used to determine residence times for dosimetry calculations.
Neurology and psychiatry PET research has focused on compounds that localize in the basal ganglia (BG) and trace different functions of the dopaminergic pathway. We have studied three of these compounds: 18F-FDOPA, 11C-raclopride, and 18F-FPCIT. All of them localize in the BG with varying affinity. Published dosimetry has demonstrated that whole brain is not limiting for these compounds, but the BG substructures may be [
Our previous paper in
This particular study of 18F-FPCIT was undertaken to determine if, in subjects for which dynamic PET data was available, the BG structures were dose-limiting. With increasing clinical use of longer half-life labeled dopamine transporter radioligand, 123I-FPCIT (DatScan), this issue has become even more relevant. Previous dosimetry work has been focused on anatomically well-defined organs while the current work takes into account both anatomy and significant functional differences within the organs themselves. Uptake of dopaminergic radiotracers is a case in point where uptake, as well as the residence time, is far greater in BG (a well-defined substructure within the brain) compared to the rest of the brain. This observation leads us to believe that the radiation burden to BG will be higher than the rest of the brain. The same logic can, in the future, be used to treat renal cortex as distinct from the kidneys if new radiotracers were to specifically target these locations. The principle is similar to that of labeled monoclonal antibody therapy where the radionuclide binds to the tumor surface sites and delivers the required therapeutic radiation dose. The tumor can be small or large, homogeneously or heterogeneously distributed. This is in contrast to the BG, which is anatomically well-delineated and homogeneous at least as far as dopaminergic radiotracer uptake is concerned in normal subjects. The uptake of dopaminergic tracers in normal control subjects provides the worst-case scenario for dosimetry. All these studies were conducted under Radioactive Drug Research Committee approved protocols where the dose limits are organ-based. Finally, another issue that needs to be addressed is the question of radiosensitivity of brain compared to other organs. We do not yet have any data to suggest that BG is more radiosensitive than the rest of the brain (which itself is not very radiosensitive compared to reproductive organs) [
Dynamic PET scans of the brain were acquired in 16 normal adult subjects. Data were acquired in 3D mode on a GE Advance tomograph (General Electric, Milwaukee, WI). Scanning protocol included 21 frames: 5 × 1 min, 5 × 2 min, 5 × 5 min, and 6 × 10 min. Ethical permission for the procedures was obtained from the Institutional Review Board of North Shore University Hospital. Written consent was obtained from each participant following a detailed explanation of the procedures. Thirty-five slices parallel to the orbital-meatus were collected over an axial field of view of 15 cm so that the entire brain was covered. Emission data were corrected for attenuation using a rotating Ge-68 source. Image reconstruction was performed using filtered backprojection with a cutoff resolution of 8 mm. All brain slices that included the BG were added to form a composite image. Regions of interest (ROI) were drawn over the left caudate, left putamen, right caudate, and right putamen, and time-activity curves were generated over the duration of the scan. No MRI scans were available for these normal subjects. Also, it was assumed that for dosimetry purposes, the ROI drawn on PET scans was sufficient without an MRI coregistration. Activity concentrations (kBq/cc) were computed using a calibration scan of a cylindrical phantom of known activity concentration. Time-activity curves for the four BG regions were fit to a nonlinear regression model of exponential uptake and clearance and analytical integration was employed to estimate the area under the curve (AUC). Units for AUC are (kBq/cc)
We did not have individual MRI images available for estimating BG volumes. Therefore, BG structures were assumed to be spherical regions of mass 3.7 and 4.4 grams for caudate nuclei and putamen, respectively, in each brain hemisphere; these were derived from average masses of BG structures from seven published MRI datasets [
Figure
Dynamic 18F-FPCIT PET regions of interest data from basal ganglia fitted to extract residence times. Data from four regions of interest is presented (caudate and putamen on left and right hemispheres). A multiexponential curve fit to the right putamen data is also shown. Analytical area under the curve was obtained from this fitted curve and dose estimated using (
Figure
Table
Radiation absorbed doses to basal ganglia.
Sex | Age | Dose (mGy/MBq) | Average BG dose | BG fractional | |||
---|---|---|---|---|---|---|---|
L Cau | R Cau | L Put | R Put | (mGy/MBq) | Dose* | ||
m | 53 | 0.0444 | 0.0404 | 0.0390 | 0.0406 | 0.0411 | 0.6966 |
f | 52 | 0.0749 | 0.0489 | 0.0576 | 0.0482 | 0.0574 | 0.9728 |
f | 23 | 0.0501 | 0.0535 | 0.0431 | 0.0607 | 0.0518 | 0.8785 |
m | 50 | 0.0304 | 0.0301 | 0.0281 | 0.0283 | 0.0292 | 0.4954 |
f | 28 | 0.0577 | 0.0559 | 0.0538 | 0.0529 | 0.0551 | 0.9336 |
f | 23 | 0.0435 | 0.0428 | 0.0410 | 0.0392 | 0.0417 | 0.7060 |
m | 69 | 0.0688 | 0.0719 | 0.0696 | 0.0670 | 0.0693 |
|
f | 65 | 0.0359 | 0.0364 | 0.0343 | 0.0345 | 0.0353 | 0.5977 |
f | 39 | 0.0301 | 0.0734 | 0.0260 | 0.0518 | 0.0453 | 0.7681 |
f | 56 | 0.0265 | 0.0324 | 0.0345 | 0.0275 | 0.0302 | 0.5125 |
f | 55 | 0.0479 | 0.0413 | 0.0403 | 0.0381 | 0.0419 | 0.7099 |
f | 73 | 0.0532 | 0.0423 | 0.0736 | 0.0412 | 0.0526 | 0.8915 |
m | 47 | 0.0582 | 0.0552 | 0.0556 | 0.0414 | 0.0526 | 0.8914 |
m | 70 | 0.0479 | 0.0453 | 0.0394 | 0.0380 | 0.0426 | 0.7228 |
f | 53 | 0.0725 | 0.0725 | 0.0534 | 0.0528 | 0.0628 |
|
f | 76 | 0.0655 | 0.0657 | 0.0544 | 0.0519 | 0.0594 |
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Mean |
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|
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|
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SD | 0.0147 | 0.0138 | 0.0134 | 0.0107 | 0.0112 | 0.1890 |
Caudate (Cau); putamen (Put); basal ganglia (BG). *Fractional dose is calculated by dividing the BG dose by bladder dose of 0.059 mGy/MBq taken from [
Figure
Ratio of basal ganglia and bladder dose as a function of age. In three out of 16 subjects, basal ganglia (BG) dose exceeded that of the critical organ (urinary bladder) for 18F-FPCIT. In half of the subjects (
PET studies utilizing radiopharmaceuticals that localize in the BG have become very useful in patients with movement disorders. Radiation dosimetry using the MIRD techniques has traditionally evaluated whole organ doses. Using standard dosimetry in humans with F-18 PET compounds, the urinary bladder is the critical organ. Neuroleptic compounds localize in the BG, and although the whole brain might not be critical, BG may be. We have used the MIRDOSE 3 software and the ability to determine lesion doses to evaluate BG dosimetry. Even though BG structures are not perfect spheres, this approximation may be sufficient for dosimetry purposes. This enabled us to calculate self-dose from BG uptake and determine if injected dosages should be modified to account for these structures. As the maximum dose to BG in one subject exceeded bladder dose by 18%, we are changing our guidelines to limit the maximum permissible injected dosage for 18F-FPCIT from 23 mCi to 19 mCi [
Even though we use 5 mCi for routine brain imaging with 18F-FPCIT, we think that it is not a question of 23 versus 5 mCi, but whether the limit of 23 mCi should be based upon bladder dose or BG dose [
It is likely that F-18 labeled tracers, which take a long time to achieve BG equilibrium as opposed to C-11 labeled tracers, may need special focus on BG dosimetry. For tracers with long half-life, such as I-131 (half-life: 8 days), thyroid dose is high enough to limit the diagnostic (not therapeutic) injection to 4 mCi, which is a suboptimal dose for imaging. Similarly, Mn-52 and Sc-46 (half-lives: 5.6 days and 84 days, resp.), which have been recently considered for nonhuman imaging studies, will have serious limitations as to the injected dose for human diagnostic studies because of long residence times.
In our laboratory, we perform multitracer multiday protocols on the same subject and have to often limit the injected activity well below maximum allowable limit for 18F-FPCIT, 18F-FDG, and H2 15O in order to remain within radiation exposure guidelines. This compromise forces us to extend the scan time for 18F-FDG studies to keep signal-to-noise acceptable.
There are two limitations of the study: (1) no individual MRI estimates of caudate and putamen; and (2) bladder doses for individual subjects not being available. Nonetheless, these two issues are expected to have minor influence on our findings.
From the 16 normal subjects studied, BG appears to be the critical organ for dosimetric consideration in three subjects. In a total of eight subjects, BG dose exceeded 85% of the bladder dose and in three subjects BG dose actually exceeded the bladder dose. As new compounds with high affinity or for similar tracers with long half-life radionuclide label are developed, BG dosimetry should be considered in the development process.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the National Institutes of Health (P50 NS 38370 and K24 NS 02101 to David Eidelberg). The authors acknowledge the valuable assistance of Ms. Toni Fitzpatrick and Ms. Yoon Young Choi in the preparation of this paper.