Radiation Dosimetry and Biodistribution of the TSPO Ligand
11C-DPA-713 in Humans
Christopher J. Endres1, Jennifer M. Coughlin2, Kenneth L. Gage1, Crystal C. Watkins2, Michael Kassiou3–5,
and Martin G. Pomper1,2
1Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland;2Department of Psychiatry, Johns Hopkins
Medical Institutions, Baltimore, Maryland;3Brain and Mind Research Institute, University of Sydney, New South Wales, Australia;
4School of Chemistry, University of Sydney, New South Wales, Australia; and5Discipline of Medical Radiation Sciences, University of
Sydney, New South Wales, Australia
Whole-body PET/CT was used to characterize the radiation
dosimetry of11C-DPA-713, a specific PET ligand for the assess-
ment of translocator protein. Methods: Six healthy control sub-
jects, 3 men and 3 women, underwent whole-body dynamic
PET scans after bolus injection of11C-DPA-713. Subjects were
scanned from head to mid thigh with 7 passes performed, with
a total PET acquisition of approximately 100 min. Time–activity
curves were generated in organs with visible tracer uptake, and
tissue residence times were calculated. Whole-body dosimetry
was calculated using OLINDA 1.1 software, assuming no void-
ing. Results: The absorbed dose is highest in the lungs, spleen,
kidney, and pancreas. The lungs were determined to be the
dose-limiting organ, with an average absorbed dose of 2.01 ·
1022mSv/MBq (7.43 · 1022rem/mCi). On the basis of expo-
sure limits outlined in the U.S. Food and Drug Administration
Code of Federal Regulations (21CFR361.1), the single-dose
11C-DPA-713 radiotracer injection is 2,487.6 MBq
(67.3 mCi). Conclusion:11C-DPA-713 has an uptake pattern
that is consistent with the biodistribution of translocator protein
and yields a dose burden that is comparable to that of other
11C-labeled PET tracers.
Key Words: radiotracer tissue kinetics; dosimetry; microglia;
PET/CT; translocator protein
J Nucl Med 2012; 53:330–335
Translocator protein (TSPO), known formerly as the pe-
ripheral benzodiazepine receptor (PBR) (1), is established as
an important marker of neuroinflammation in central nervous
system disease or brain injury, as reviewed by various authors
(2–5). Historically, the TSPO ligand used most commonly
with PET is11C-R-PK11195. Although it has been used suc-
cessfully for numerous clinical studies,11C-R-PK11195 has
pharmacokinetic properties, such as high nonspecific bind-
ing, that are suboptimal for imaging. Given the importance of
TSPO as a molecular target, in recent years there has been
tremendous interest in developing an alternative radiotracer
for PET (6–9). One such ligand is11C-DPA-713 (10), which
has been shown to have greater uptake and higher affinity
than11C-R-PK11195 (11). However, it has also been shown
that11C-DPA-713 is susceptible to multiple-affinity state
binding (12,13). Nevertheless,11C-DPA-713 shows promise
as a prospective TSPO ligand; thus, we evaluated the radia-
tion dose burden in healthy human control subjects after
bolus tracer injection.
MATERIALS AND METHODS
Six healthy volunteers (3 women, 3 men) were included in this
study (Table 1). Subjects with a history of recent nosocomial in-
fection, central nervous system lymphoma, neurologic disorder,
structural central nervous system abnormality, head injury, or ac-
tive substance abuse were excluded from participating. Female
subjects were also screened and excluded for pregnancy. This
study was approved by the Johns Hopkins Institutional Review
Board. Subjects received an explanation of the purpose of the
study, the study procedure, and associated risks and provided writ-
ten informed consent before participation.
This study was performed under Investigational New Drug
78,283.11C-DPA-713 was synthesized according to the proce-
dures of Thominiaux et al. (14). Radiochemical purity was greater
than 95%. A Discovery Rx VCT scanner (GE Healthcare), equip-
ped with high-performance lutetium yttrium oxyorthosilicate PET
crystals and a 64-slice CT component, was used. Subjects were
positioned supine and imaged at rest. Before PET, a helical trans-
mission CT scan (120 kVp; 20–200 mA, automatically adjusted)
was acquired at each bed position. The CT scan was used for
attenuation correction of the PET data and to delineate organ
boundaries.11C-DPA-713 (injected dose, 668 6 21 MBq; specific
activity, 668 6 21 GBq/mmol; mass dose, 0.985 6 0.13 mg) was
delivered as a bolus via a catheterized vein over an approximately
30-s injection time. The catheter could not be accessed readily
with the subject positioned in the field of view. Thus, after the
Received Jun. 20, 2011; revision accepted Sep. 12, 2011.
For correspondence or reprints contact: Christopher J. Endres, Division of
Neuroradiology, Johns Hopkins University, 1550 Orleans St., CRB II Room
491, Baltimore, MD 21231.
Published online Jan. 12, 2012.
COPYRIGHT ª 2012 by the Society of Nuclear Medicine, Inc.
330THE JOURNAL OF NUCLEAR MEDICINE • Vol. 53 • No. 2 • February 2012
CT scan, the patient bed was positioned to allow access to the
catheter for radiotracer injection. The bed was then moved back
(;30 s) so that the PET acquisition was initiated about 1 min after
radiotracer delivery. PET was performed using a sequence of 7
passes. For each pass, 8 or 9 contiguous single-bed-position PET
images were acquired in 3-dimensional mode, with an 11-slice
(5-mm) overlap. The scan durations per bed position for the 7 passes
were 15, 30, 45, 60, 120, 240, and 240 s. PET images were recon-
structed as described previously (15) using a 3-dimensional ordered-
subset expectation maximization algorithm with 2 iterations, 21
subsets, a 3.0-mm postreconstruction gaussian filter, 4.7 · 4.7 mm
(in-plane), and 3.27-mm (transaxial) voxels. To obtain images in
Bq/mL, the scanner was calibrated with a 20-cm diameter, 20-cm-
long18F water phantom. The activity was measured using a dose
calibrator that had been previously calibrated for18F using a Na-
tional Institute of Standards and Technology–traceable source.
Regions of Interest (ROIs)
ROI analysis was performed using Analyze 10.0 (Mayo Clinic
Foundation) (16). Tissue ROIs were drawn on the standard regions
used by OLINDA 1.1 (Vanderbilt University) for dosimetry cal-
culation (17). To measure total disintegrations in gallbladder and
urinary bladder contents, large ROIs were drawn to encompass the
entire volume. For other organs, the regions were delineated by
subsampling the organ, with care taken to ensure that the ROI
included perceived regions of high radioactivity. Testes on male
subjects and uterus, breast tissue, and ovaries on female subjects
were identified. However, for 1 female subject (F2), ovaries could
not be identified. To ensure a conservatively high dose estimate,
the small intestine and stomach were subsampled by drawing
ROIs that encompassed the organ wall and contents in slices of
highest activity in each organ. Because11C-DPA-713 does not
accumulate in bone, it was assumed that all femoral radioactivity
was located in red marrow. ROIs were not drawn on muscle, skin,
or thymus. For the purpose of validating the use of subsampled
ROIs, whole-organ ROIs were drawn for 2 subjects (F2 and M3).
All ROIs were applied to the dynamic data to generate time–
activity curves. Time–activity curves were generated without decay
correction, and the acquisition time was taken to be the mid-
point time of the bed acquisition that contained the region. There
were 11 overlap slices for adjacent beds, in which case the acqui-
sition time was taken to be the average of the mid-point times
of the 2 beds. A complicating factor in determining the acquisi-
tion time precisely is that in some cases, particularly for whole-
organ ROIs, regions extended across both single-bed and overlap
regions, in which case the within-region radioactivity corresponds
to 2 or more different time points. In that case, if most (.90%) of
the region was located in a specific bed or overlap region, the
corresponding time was used to generate the time–activity curves.
If the region was split more evenly, then an average time weighted
by the number of voxels at each bed or overlap region was used. In
all subjects, we noticed that the catheter tubing and the site of
catheter insertion were clearly visible throughout the study. This
visibility indicates that some residual activity remained in the
catheter and thus did not effectively enter the circulatory system.
To determine the catheter residual, an ROI was drawn around the
tubing and injection site. The total radioactivity remaining in the
catheter was then compared with the total injected radioactivity,
accounting for radioactive decay. The mean percentage activity
remaining in the catheter was 2.4% 6 2.3%, with individual
values ranging from 0.5% to 6.2%. For the purpose of dose nor-
malization required for computing residence times, the injected
11C-DPA-713 radioactivity was adjusted by subtracting the mea-
sured catheter residual radioactivity. With subtraction of the cath-
eter activity, the percentage injected dose to all organs is increased
because the radiotracer uptake is attributed effectively to a smaller
Residence Times and Absorbed Dose Calculations
To compute residence times, time–activity curves were ex-
pressed as percentage of the injected dose and then multiplied
by the organ volume. We used sex-specific organ masses (adult
women, adult men) that were provided in OLINDA and are based
on a 56.9-kg woman and a 73.7-kg man. To convert standard organ
mass to standard volume, each organ mass was divided by organ-
specific tissue densities (18,19). After multiplying by the standard
volumes, time–activity curves were integrated using trapezoidal
integration up to the last measurement time point. Beyond the last
time point, the integral to infinity was computed assuming expo-
nential decay of11C with a half-life of 20.3 min. The total sum
integral for each organ is the residence time. For gallbladder con-
tents and urinary bladder contents, instead of normalizing to stan-
dard volumes, total disintegrations were estimated from the large
ROIs that were drawn about those regions. For dosimetry calcu-
lation, we made the most conservative assumption that the entire
dose was deposited in tissue, thus giving the maximum possible
residence time of 0.488 h (i.e., half-life/ln(2)) (ln(2) = 0.693 is the
natural log of 2). The remainder-of-body radioactivity was thus
computed as the sum of the residence times in all identified tissues,
subtracted from 0.488. For each subject, the residence times were
Summary of Subjects and Injected Dose of11C-DPA-713
Subject no.Age (y)Mass (kg) Height (m)
Body mass index
Mean 6 SD
36 6 4 82.0 6 8.41.67 6 0.1429.8 6 5.6 668 6 21
DOSIMETRY OF11C-DPA-713 IN HUMANS • Endres et al. 331
input to OLINDA using a sex-specific model (adult women, adult
men), and the effective dose equivalent was based on the tissue-
weighting factors recommended in International Commission on
Radiological Protection (ICRP) publication 60 (20). We report
mean 6 SD of residence times and effective dose equivalent values
averaged across all subjects. For comparison of dose estimates
obtained with whole-organ and subsampled ROIs, we take the
values obtained with whole-organ ROIs as the standard values
and compute the percentage difference in the dose estimates
obtained with subsampled ROIs.
The whole-body biodistribution of
shown in 2-dimensional coronal projections in Figure 1.
Tissue residence times are shown in Table 2, and the
absorbed dose estimates are in Table 3. Figure 2 shows
the whole-organ uptake curves expressed as a percentage
of the injected dose; these are the curves that are integrated
to compute residence times. The highest residence times
were obtained in the lungs, liver, red marrow, brain, kidney,
and small intestine. The highest absorbed doses were
obtained in the lungs, spleen, kidney, pancreas, heart, and
liver. For the 2 subjects (F2 and M3, Table 1) who had
whole-organ ROIs drawn, the total-body dose estimates
and the effective dose obtained using either whole-organ
or subsampled ROIs agreed to within 1%. The effective
dose equivalent obtained with either method agreed within
10% for both subjects (F2, 2.4%; M3, 9.0%), with subsam-
pling giving the larger dose estimate. The individual organ
dose estimates were also similar, with 75% of the organ
doses agreeing to within 10% with either whole-organ or
subsampled ROIs. Of particular importance to11C-DPA-
713 dosimetry is that the lungs were again determined to
be the critical dose-limiting organ, with dose estimates
11C-DPA-713 Residence Times in Measured Tissues (Hours)
Tissue or region Men (n 5 3) Women (n 5 3)Mean 6 SD (n 5 6)
Lower large intestine wall
Upper large intestine wall
Urinary bladder contents
Uterus or uterine wall
Remainder of body
3.56E–04 6 1.50E–04
1.18E–02 6 3.77E–03
1.09E–03 6 7.15E–04
1.36E–04 6 1.24E–04
1.22E–03 6 7.45E–04
1.06E–02 6 3.72E–03
3.01E–03 6 1.25E–03
3.01E–03 6 3.56E–03
3.63E–03 6 2.17E–03
6.39E–03 6 3.64E–03
1.08E–02 6 3.11E–03
4.10E–02 6 1.04E–02
6.62E–02 6 2.20E–02
8.90E–05 6 5.80E–05*
3.08E–03 6 1.41E–03
1.54E–02 6 9.16E–03
7.08E–03 6 2.19E–03
1.83E–04 6 2.52E–05
3.79E–04 6 1.52E–04
1.72E–04 6 1.21E–04
7.33E–04 6 1.75E–04
0.303 6 0.050
*Ovaries were not identified positively in 1 female subject (F2); thus, mean ovarian residence time is based on measurements from 2
subjects. Mean values for sex-specific regions, including breasts, uterus or uterine wall, and testes, are based on measurements from 3
subjects of each sex.
activity after bolus injection of11C-DPA-713. Seven whole-body
passes were performed as described. Images from left to right are
from passes 1, 3, and 5 and show tracer biodistribution from 1 to 3,
from 10 to 16, and from 28 to 42 min after injection, respectively.
Images are displayed to same maximum. Lung uptake is prominent
immediately after injection. Substantial tracer uptake is also ob-
served in kidneys, spleen, liver, and brain.
Summed coronal 2-dimensional projections of tracer
332THE JOURNAL OF NUCLEAR MEDICINE • Vol. 53 • No. 2 • February 2012
using whole or subsampled regions agreeing to within 3%
for both subjects (F2, 1.4%; M3, 2.3%).
The biodistribution of11C-DPA-713 was found to be
generally consistent with the known distribution of TSPO
(21–23). The dosimetry is also similar to that of the TSPO
ligand11C-PBR28 (24), which is expected because11C-
DPA-713 and11C-PBR28 have similar pharmacokinetics
(11,25). In particular, for both
PBR28, the highest residence times were in the lungs and
liver, and the highest absorbed doses were in the lungs,
kidney, and spleen. For11C-DPA-713, the lungs were de-
termined to be the dose-limiting organ. On the basis of
a single exposure limit of 5 rem (50 mSv), the single-
administration dose limit is 2.49 GBq, or 67.3 mCi. A typical
human PET study is performed with 555–740 MBq (15–20
mCi); thus, multiple tracer injections are possible, making
test–retest and longitudinal studies quite feasible. The
allowed dose limit is similar to that of other11C-labeled
radiotracers, and the effective dose of11C-DPA-713 (5.9
mSv/MBq) is virtually at the median of11C dosimetry val-
ues reported previously (as shown in Table 3 of Virta et al.
(26) and also in Table 3 of Hirvonen et al. (27)).
Regarding tissues that are more radiation-sensitive,
according to the Food and Drug Administration title 21
Code of Federal Regulations (CFR), part 361, only 3 rem
are allowed in a single-dose administration to the whole
body, active blood-forming organs, lens of the eye, and
gonads (28). When needed for dosimetry reports, it is rec-
ommended that the brain dose be used as an estimate of the
lens-of-eye dose. Even if the more stringent public lens-of-
eye exposure (15 mSv) recommended by ICRP publication
103 (29) is applied, the single-dose limit is 4.49 GBq (121
mCi); thus, the lens of the eye is not dose-limiting relative
to the lungs. The organ-weighting factors recommended in
ICRP 103 (29) were not applied here, but it was found for
11C-R-PK11195 that the effective dose estimates obtained
with either ICRP 60 or ICRP 103 weighting factors are
nearly identical (27).11C-DPA-713 is also nontoxic, be-
cause the no-observed-effect-limit dose is 49.3 mg/kg/d
according to the SRI international study (30). At typical
specific activity levels, approximately 1 mg is injected in
a human study.
Absorbed Dose Estimates After Bolus Injection of11C-DPA-713
coefficient of variation
Lower large intestine wall
Upper large intestine wall
Urinary bladder wall
Effective dose equivalent
Coefficient of variation is equal to SD divided by mean multiplied by 100. Values are averaged across all 6 subjects, except for breasts,
uterus or uterine wall, testes, and ovaries, which are sex-specific and thus averaged across 3 subjects. Although ovaries were not
identified in 1 female subject, OLINDA is still able to report absorbed dose estimate for that subject; estimate was included for computing
DOSIMETRY OF11C-DPA-713 IN HUMANS • Endres et al. 333
Drawing subsampled regions, as opposed to the time-
consuming method of delineating whole-organ boundaries,
is a practical approach to measuring activity in various
organs (31–33). For the 2 subjects who were examined (F2
and M3) with whole-organ ROIs, the total-body dose and
the effective dose were within 1% of the values obtained
from subsampled ROIs. The lung dose was also quite sim-
ilar, with subsampled ROIs yielding a 2% higher absorbed
dose estimate. To further assess if subsampling was suffi-
cient to quantify the dose to the critical organ, a whole-lung
region was created for all subjects using the semiautomated
ROI thresholding tool in Analyze (16). Lung residence
times using the whole-lung ROIs were 6.1% less than the
residence times obtained with subsampling; thus, the lung
dose was not underestimated by subsampling.
To simplify the labor-intensive procedure of generating
non–decay-corrected time–activity curves with acquisition
times corresponding to specific bed positions, we attempted
to perform the dosimetry with the time–activity curves de-
cay-corrected to the start of each pass. In principle, that will
yield the same residence time integral as non–decay-cor-
rected data if there is negligible tracer redistribution from
the start of the pass to the time of the specific bed acquisi-
tion. The benefit of decay correction to the start of each
pass is that the activity throughout the body corresponds to
the same time. That is, this procedure removes the ambi-
guity of the acquisition time when an organ is imaged in
adjacent beds. In general, the dosimetry values were quite
similar to those obtained without decay correction. How-
ever, for the lungs, performing the decay correction led to
a consistent underestimation (.10%) in absorbed dose. Be-
cause the lungs are the critical organ, the result was a cor-
responding increase in the allowed dose limit. Thus, we
used the non–decay-corrected results to ensure we obtained
the most conservative, as well as the most accurate, dose
The biodistribution of11C-DPA-713 is similar to that of
other TSPO ligands, as is evident when comparing whole-
body images of the present study (Fig. 1) with the corre-
sponding figures for11C-R-PK11195 (27) and11C-PBR28
(24). However, in contrast to the present study that found
the lungs to be the critical organ, for both11C-R-PK11195
and11C-PBR28 the critical organ was the kidneys, with the
spleen receiving the next highest dose. A comparison of
whole-body biodistribution showed that
has low lung uptake, compared with11C-PBR28 (34); thus,
it is not surprising that the lungs are not the critical organ
for11C-R-PK11195 dosimetry. On the other hand,11C-
PBR28 and11C-DPA-713 share some similar properties,
including similar affinity and lipophilicity (11).
PBR28 and11C-DPA-713 do, however, show differences
in protein binding (11), pharmacokinetics of labeled metab-
olites (25), and sensitivity to multiaffinity state binding
(12). Differences in methodology for dosimetry calculation
may also contribute to the determination of different critical
organs for11C-PBR28 and11C-DPA-713. For11C-PBR28,
it has been reported that the binding affinity affects dosim-
etry calculation (24). In particular, in a single subject with
low binding affinity binding, there was a large decrease in
dose to the spleen, kidney, and lungs, with a corresponding
increased dose to the liver, gallbladder wall, and urinary
bladder wall. Furthermore, the effective dose was reported
to be 28% less. PBR28 has a particularly large ratio in
TSPO binding affinity (50-fold) between low- and high-
affinity states (12).11C-DPA-713 has only a 4-fold ratio;
thus, the impact of affinity on dosimetry estimates should
be attenuated considerably. In the present study, on the
basis of the consistency of tracer uptake in the brain and
lungs, all subjects are believed to exhibit high-affinity bind-
ing. In principle,11C-DPA-713 and11C-PBR28 have favor-
able properties to be effective PETagents (11), although the
presence of multiple-affinity-state binding has confounded
efforts to demonstrate clearly that these tracers will im-
prove on11C-R-PK11195 for clinical investigation. Another
TSPO ligand that may affect the future use of11C-DPA-713
is the compound18F-DPA-714, which has a similar chem-
ical structure (35).18F-DPA-714 has an inherent advantage
for clinical use because of labeling with18F, whereas11C-
DPA-713 is amenable to research protocols that call for
multiple PET studies on the same day. Both11C-DPA-713
and18F-DPA-714 have been shown to give improved con-
11C-R-PK11195 in animal models of neuro-
inflammation (36,37). DPA-714 increases pregnenolone
synthesis, which is indicative of a TSPO agonist, whereas
DPA-713 has no effect and appears to be an antagonist (38).
In that case,11C-DPA-713 and18F-DPA-714 have the po-
tential to provide complementary information.
Absorbed dose estimates after11C-DPA-713 bolus injec-
tion reveal the lungs to be thecriticalorgan, yieldinga single-
713. Values are total organ activity expressed as percentage of
initial bolus activity. For each subject, 7 whole-body dynamic scans
were obtained, with 8–9 bed positions that proceeded from thigh to
head. Thus, brain was imaged in last bed position. Plot shows first 5
whole-body passes, and values reflect average of all 6 subjects.
Both axes are averaged, because the postinjection scan times are
slightly different for each subject.
Whole-organ uptake after bolus injection of11C-DPA-
334THE JOURNAL OF NUCLEAR MEDICINE • Vol. 53 • No. 2 • February 2012
injected-dose limit of 2,487.6 MBq (67.3 mCi). The dosim- Download full-text
etry is consistent with other11C tracers and indicates that
multiple injections per year are easily allowable under cur-
rent federal guidelines (21CFR361.1), especially given that
typical radiotracer injections are no more than 740 MBq
The costs of publication of this article were defrayed in
part by the payment of page charges. Therefore, and solely
to indicate this fact, this article is hereby marked “adver-
tisement” in accordance with 18 USC section 1734.
For radioisotope production, we thank the radiochemistry
staff at the Johns Hopkins Nuclear Medicine PET Center,
directed by Robert Dannals. We thank the PET/CT technol-
ogists for study preparation and image acquisition. We thank
George Sgouros and Srinivasan Senthamizhchelvan for
helpful comments and discussion. This study was supported
by the JHU NIMH Toxicological Evaluation of Novel
Ligands Program, NIH T32MH015330, NIH T32EB006351,
and NIH R21MH082277. No other potential conflict of
interest relevant to this article was reported.
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