PET-Derived Biodistribution and Dosimetry of the Benzodiazepine Receptor-Binding Radioligand ¹¹C-(R)-PK11195 in Children and Adults

MATERIALS AND METHODS

PET Procedure

The PK tracer was produced at Children's Hospital of Michigan using a synthesis module designed and built in-house (6). Both the radiochemical and chemical purities of the product were greater than 98%. The specific activity of ¹¹C-(R)-PK11195 was 47.2 ± 6.4 GBq/μmol at the end of synthesis and 37.2 ± 4.8 GBq/μmol at the time of administration. PET studies were performed using the CTI/Siemens EXACT/HR whole-body positron tomograph after 6–8 h of fasting. Before tracer injection, two 15-min transmission scans were acquired to correct for photon attenuation, one for the brain and the other for the torso (body) at the level of the liver or the urinary bladder. Coinciding with the tracer (17 MBq/kg) injection, a dynamic image sequence was initiated, alternating between the brain (0–20, 30–40, and 50–60 min) and the torso (20–30, 40–50, and 60–70 min), with 60-s periods interleaved for patient repositioning (Fig. 1). Torso imaging was performed at the level of liver, starting from the sixth rib (around nipples), in such a way that the heart and lower lobes of the lungs were included in the field of view (16 cm). In each age group, 2 subjects were scanned at the level of the urinary bladder instead of the liver, starting below the umbilicus. As a result, some organs—such as the lungs, heart, and intestines—were only partially included in the field of view, depending on the age and length of the subject. Although it is difficult to quantify the exact percentage represented in the region of interest (ROI), because of different subject sizes, approximately one fourth of the lungs and two thirds of the heart were usually included in the ROIs. Emission data were acquired in 3-dimensional mode, and measured attenuation corrections and scatter and decay corrections were applied to all PET images. In 2 adults, 3 sequential whole-body scans from head to thigh (5 bed positions, each of 4-min duration) were obtained in 3-dimensional mode using the GE Discovery STE PET/CT scanner. The PET scan was preceded by the CT scan of the same area, which was used both for attenuation correction and organ localization. Pulse oximetry, heart rate, respiratory rate, and temperature were monitored throughout the study.

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FIGURE 1. 

Interleaved PET protocol used for acquisition of dynamic PET scan. Short 1-min interval was used to reposition patient between 2 bed positions. Subset of patients was scanned at level of urinary bladder instead of liver.

RESULTS

The time-dependent distribution of PK in the body is shown in Figures 2A–2C. Immediately after the injection, PK was most prominently taken up by the liver and heart wall and, to a lesser extent, by the salivary gland, red marrow, stomach wall, thyroid gland, and spleen. Subsequently, the activity increased in the red marrow and salivary glands, with persisting tracer uptake in the liver, heart wall, and stomach wall. PK also began to accumulate in the gallbladder, pelvis of the kidney, urinary bladder, and stomach lumen (probably from salivary and gastric secretion). Over time, PK cleared from most of the organs and finally, after about 1 h after injection, most of the remaining activity was concentrated in the 2 main excretory organs—the gallbladder and urinary bladder. Lungs showed minimal PK uptake throughout the study period. The brains in healthy adults showed low uptake and rapid washout. Some of the brains of the children (n = 11) also showed low uptake.

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FIGURE 2. 

Three sequential whole-body ¹¹C-(R)-PK11195 PET/CT scans showing time-dependent biodistribution of PK at 20 min after injection (A), 40 min after injection (B), and 60 min after injection (C). PK uptake was highest in gallbladder and urinary bladder, followed by liver, kidney, bone marrow, salivary gland, and heart wall, with minimal localization in all other organs including normal brain and lungs.

Figure 3A shows representative decay-corrected time–activity curves for the pelvis of the kidneys, liver, brain, urinary bladder, and gallbladder in a 5-y-old child with low brain uptake. There was a fast initial uptake of tracer activity in the liver and the pelvis of the kidneys, subsequently reaching a constant level. In contrast, there was a steady increase of tracer activity in both the gallbladder and the urinary bladder during the initial 60 min after tracer injection. Finally, tracer activity in the brain reached a maximum within the first 2 min and then decreased exponentially. Non–decay-corrected time–activity curves of the same organs are shown in Figure 3B. These curves were extrapolated to 240 min (12 half-lives), applying only physical decay of the tracer, and were subsequently used to calculate the cumulated activity for each organ.

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FIGURE 3. 

Decay-corrected (A) and non–decay-corrected (B) time–activity curves for kidneys, liver, brain, urinary bladder, and gallbladder in 5-y-old subject. Tracer activity in brain reached maximum within first 2 min and then decreased exponentially (inset of A). Non–decay-corrected time–activity curves were extrapolated to 240 min (12 half-lives), applying only physical decay of tracer (inset of B).

Table 1 shows the calculated residence times derived from PET for the various age groups. Radiation doses, calculated from these residence times, are reported in Table 2; Table 3 summarizes the EDE in each age group. Both the EDE and the organ doses per unit injected activity decreased with age. The administration of a 17 MBq/kg (0.45 mCi/kg) dose of PK for PET studies resulted in a total EDE of 3.94 mSv for children aged 4–7 y, 4.32 mSv for children aged 8–12 y, and 5.13 mSv for adolescents (aged 13–17 y). In comparison, the total EDE to the adults was 5.47 mSv. The gallbladder received the maximum radiation dose in the 2 youngest pediatric groups, whereas the urinary bladder received the highest radiation in adolescents and adults. No effect of sex was found on the residence times or on the EDE values.

DISCUSSION

The results of our study suggest that the radiation dose from PK PET is comparable to doses from other clinically used ¹¹C-labeled PET tracers. Specifically, 17 MBq/kg of administered activity of PK resulted in good image quality and a total effective dose of about or less than 5 mSv for all age groups.

A rapid increase in PK uptake in the normal brain followed by rapid clearance suggested the free passage of PK through the intact blood–brain barrier but a relatively low level of PBRs in the brain, consistent with previous findings (9,10). In the body, PK uptake was mostly concentrated in the gallbladder, urinary bladder, liver, kidneys, and bone marrow. In humans, ¹¹C-PK11195 is metabolized into 2 main radioactive metabolites—¹¹C-formaldehyde and ¹¹C-N-methyl-sec-butylamine (11,12)—which may contribute to the high liver and gallbladder uptake. PK binding to PBRs located on hepatocytes and biliary epithelial tissue may also contribute to the liver and gallbladder tracer uptake. Salivary gland and heart wall also showed a relatively high PK uptake. Although microarray data show the highest expression of PBRs in the lung (13,14), the lung showed low PK localization. The local formation of ¹¹CO₂ from ¹¹C-PK11195 through decarboxylation and its rapid elimination may be the possible reason for low uptake in the lungs (15). We did not find high activity in the adrenal glands, ovaries and testes, and other organs with previously reported high PBR uptake (16). The reason could be a combination of partial-volume effects because of the small size of these organs and their proximity to larger organs with high PK uptake, such as the liver, kidneys, and urinary bladder. Highest PK uptake was determined in the gallbladder, which is consistent with reports that the highest activity of ¹²³I-iodo-PK11195 was in the bile of dogs (17) and in adult volunteers (16). Sex analysis did not reveal any difference in the biodistribution or dosimetry between men and women.

The biodistribution and dosimetry of other PBR radioligands has been performed previously in animals (9,18–23) and healthy adult human volunteers (16,18,24). Hashimoto et al. (21) studied the biodistribution of ³H-PK 11195 in mice and found high accumulations of radioactivity in the heart, lung, spleen, kidneys, and adrenals. In ex vivo rat biodistribution and inhibition studies, the fluoromethyl derivative of 2-quinolinecarboxamide (a PBR radioligand) rapidly accumulated in PBR-rich tissues such as the heart, lung, kidneys, spleen, and adrenals and at a lower level in the brain, which was further confirmed by PET (19). Radiation doses of ¹¹C-PBR28, based on biodistribution data in monkeys and humans, showed that the highest organ doses were received by kidneys, spleen, and lungs, with an overall effective dose of 6.6 μSv/MBq (18), similar to that reported in the present study. Moreover, low uptake of ¹¹C-PBR28 was reported in the brain of healthy human subjects, compared with monkeys (24). In human SPECT studies, ¹²³I-iodo-PK11195 was rapidly cleared from the blood, mainly by the hepatobiliary system; approximately 20% was excreted in urine by 48 h in healthy adults (16). The effective dose was 40.3 μSv/MBq and the effective dose for the study was 7.46 mSv after an administration of 185 MBq of ¹²³I-iodo-PK11195. Recently, Roivainen et al. (15) studied the whole-body distribution and metabolism of ¹¹C-PK11195 in 10 patients with Alzheimer disease and 4 healthy adults. Similar to our findings, they reported high uptake in urinary bladder, liver, kidneys, vertebral column, heart, and salivary gland and low uptake in lungs and brain.

An effective dose range of 4–14 μSv/MBq in adults has been reported for various ¹¹C tracers used for brain imaging including radioligands used for inflammation imaging (18). Therefore, the current results show that ¹¹C-(R)-PK11195 radiation doses are comparable to those of other radiotracers. Although children received a higher EDE per unit administered activity (i.e., mSv/MBq) than adults, the total EDE for the administered activity used (17 MBq/kg) was lower in children.

One of the limitations of the present study is that most of the children were taking some medications for their brain disorders, and these medications might have affected the kinetics and biodistribution of ¹¹C-PK11195. PBRs show a wide range of specificity for some organic compounds and drugs, such as dipyridamole, disulfiram, lidocaine, pyrethroid insecticides, porphyrins, steroids, and lindane (the γ-isomer of the compound hexachlorocyclohexane) (25). The histidine-modifying reagent diethylpyrocarbonate also noncompetitively inhibits the binding of PK11195, observed in rats but not in bovine PBRs. Imidazopyridines and arylindoleamines also have subnanomolar affinity to PBRs. Another limitation is that all of the children were studied for brain disorders associated with neuroinflammation. It is not clear whether the actions of medications or possible systemic changes associated with their brain disorders might be responsible for the apparent differences in elimination of the tracer.

CONCLUSION

The present study shows that PK uptake is mostly concentrated in the gallbladder and urinary bladder, followed by the liver, kidney, bone marrow, salivary gland, and heart wall, with minimal localization in other organs including brain and lungs. Moreover, PK is excreted through both the hepatobiliary and the renal systems. At clinically practical administered activities, the radiation dose from ¹¹C-PK11195 in both children and adults is comparable to that from other clinical PET tracers and diagnostic radiopharmaceuticals in routine clinical use.