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Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

ABSTRACT: UNLABELLED:P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood-brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether (11)C-dLop is a substrate for P-gp at the blood-brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure. METHODS:Brain PET scans were acquired in 4 healthy subjects for 90 min and included concurrent measurements of the plasma concentration of unchanged radiotracer. Time-activity data from the whole brain were quantified using a 1-tissue-compartment model to estimate the rate of entry (K(1)) of radiotracer into the brain. Whole-body PET scans were acquired in 8 healthy subjects for 120 min. RESULTS:For brain imaging, after the injection of (11)C-dLop the concentration of radioactivity in the brain was low (standardized uptake value, approximately 15%) and stable after approximately 20 min. In contrast, uptake of radioactivity in the pituitary was about 50-fold higher than that in the brain. The plasma concentration of (11)C-dLop declined rapidly, but the percentage composition of plasma was unusually stable, with the parent radiotracer constituting 85% of total radioactivity after approximately 5 min. The rate of brain entry was low (K(1) = 0.009 +/- 0.002 mL.cm(-3).min(-1); n = 4). For whole-body imaging, as a measure of radiation exposure to the entire body the effective dose of (11)C-dLop was 7.8 +/- 0.6 muSv/MBq (n = 8). CONCLUSION:The low brain uptake of radioactivity is consistent with (11)C-dLop being a substrate for P-gp in humans and confirms that this radiotracer generates negligible quantities of brain-penetrant radiometabolites. In addition, the low rate of K(1) is consistent with P-gp rapidly effluxing substrates while they transit through the lipid bilayer. The radiation exposure of (11)C-dLop is similar to that of many other (11)C-radiotracers. Thus, (11)C-dLop is a promising radiotracer to study the function of P-gp at the blood-brain barrier, at which impaired function would allow increased uptake into the brain.

SUBMITTER: Seneca N

PROVIDER: S-EPMC2792991 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

Seneca Nicholas N Zoghbi Sami S SS Liow Jeih-San JS Kreisl William W Herscovitch Peter P Jenko Kimberly K Gladding Robert L RL Taku Andrew A Pike Victor W VW Innis Robert B RB

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20090416 5

<h4>Unlabelled</h4>P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood-brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The pu ...[more]

PMID: 19372478

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Project description:UnlabelledPermeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer (11)C-N-desmethyl-loperamide ((11)C-dLop). We examined the ability of (11)C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp.MethodsSeventeen healthy volunteers had a total of 23 PET scans with (11)C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with (15)O-H(2)O to measure cerebral blood flow. Brain uptake of (11)C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC(10-30)). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K(1)) and efflux from (k(2)) the brain.ResultsBrain uptake of radioactivity was negligible at baseline and increased only slightly (approximately 30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2- and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K(1)), because efflux (k(2)) and cerebral blood flow did not differ between tariquidar-treated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K(1) correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of (11)C-dLop. AUC(10-30) correlated linearly with K(1).ConclusionP-gp function at the blood-brain barrier in humans can be quantified using PET and (11)C-dLop. A simple measure of brain uptake (AUC(10-30)) may be used as a surrogate of the fully quantified rate constant for brain entry (K(1)) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).

Project description:UNLABELLED:11C-Loperamide is an avid substrate for P-glycoprotein (P-gp), but it is rapidly metabolized to 11C-N-desmethyl-loperamide (11C-dLop), which is also a substrate for P-gp and thereby contaminates the radioactive signal in the brain. Should further demethylation of 11C-dLop occur, radiometabolites with low entry into the brain are generated. Therefore, we evaluated the ability of 11C-dLop to quantify the function of P-gp at the blood-brain barrier in monkeys. METHODS:Six monkeys underwent 12 PET scans of the brain, 5 at baseline and 7 after pharmacologic blockade of P-gp. A subset of monkeys also underwent PET scans with 15O-water to measure cerebral blood flow. To determine whether P-gp blockade affected peripheral distribution of 11C-dLop, we measured whole-body biodistribution in 4 monkeys at baseline and after P-gp blockade. RESULTS:The concentration of 11C-dLop in the brain was low under baseline conditions and increased 5-fold after P-gp blockade. This increase was primarily caused by an increased rate of entry into the brain rather than a decreased rate of removal from the brain. With P-gp blockade, uptake of radioactivity among brain regions correlated linearly with blood flow, suggesting a high single-pass extraction. After correction for cerebral blood flow, the uptake of 11C-dLop was fairly uniform among brain regions, suggesting that the function of P-gp is fairly uniformly distributed in the brain. On whole-body imaging, P-gp blockade significantly affected distribution of radioactivity only to the brain and not to other visually identified source organs. The effective dose estimated for humans was approximately 9 microSv/MBq. CONCLUSION:PET with 11C-dLop can quantify P-gp function at the blood-brain barrier in monkeys. The single-pass extraction of 11C-dLop is high and requires correction for blood flow to accurately measure the function of this efflux transporter. The low uptake at baseline and markedly increased uptake after P-gp blockade suggest that 11C-dLop will be useful to measure a wide range of P-gp functions at the blood-brain barrier in humans.

Project description:Combined whole-body dual-tracer ((18)F-FDG and (11)C-acetate) PET/CT is increasingly used for staging hepatocellular carcinoma, with only limited studies investigating the radiation dosimetry data of these scans. The aim of the study was to characterize the radiation dosimetry of combined whole-body dual-tracer PET/CT protocols.Consecutive adult patients with hepatocellular carcinoma who underwent whole-body dual-tracer PET/CT scans were retrospectively reviewed with institutional review board approval. OLINDA/EXM 1.1 was used to estimate patient-specific internal dose exposure in each organ. Biokinetic models for (18)F-FDG and (11)C-acetate as provided by ICRP (International Commission on Radiological Protection) publication 106 were used. Standard reference phantoms were modified to more closely represent patient-specific organ mass. With patient-specific parameters, organ equivalent doses from each CT series were estimated using VirtualDose. Dosimetry capabilities for tube current modulation protocols were applied by integrating with the latest anatomic realistic models. Effective dose was calculated using ICRP publication 103 tissue-weighting coefficients for adult male and female, respectively.Fourteen scans were evaluated (12 men, 2 women; mean age ± SD, 60 ± 19.48 y). The patient-specific effective dose from (18)F-FDG and (11)C-acetate was 6.08 ± 1.49 and 1.56 ± 0.47 mSv, respectively, for male patients and 6.62 ± 1.38 and 1.79 ± 0.12 mSV, respectively, for female patients. The patient-specific effective dose of the CT component, which comprised 2 noncontrast whole-body scans, to male and female patients was 21.20 ± 8.94 and 14.79 ± 3.35 mSv, respectively. Thus, the total effective doses of the combined whole-body dual-tracer PET/CT studies for male and female patients were 28.84 ± 10.18 and 23.19 ± 4.61 mSv, respectively.Patient-specific parameters allow for more accurate estimation of organ equivalent doses. Considering the substantial radiation dose incurred, judicious medical justification is required with every whole-body dual-tracer PET/CT referral. Although radiation risks may have less impact for the population with cancer because of their reduced life expectancy, the information is of interest and relevant for both justification, to evaluate risk/benefit, and protocol optimization.

Project description:Background[18F]UCB-H was developed as a novel radiotracer with a high affinity for synaptic vesicle protein 2A, the binding site for the antiepileptic levetiracetam. The objectives of this study were to evaluate the radiation dosimetry of [18F]UCB-H in a preclinical trial and to determine the maximum injectable dose according to guidelines for human biomedical research. The radiation dosimetry was derived by organ harvesting and dynamic micro positron emission tomography (PET) imaging in mice, and the results of both methods were compared.MethodsTwenty-four male C57BL-6 mice were injected with 6.96 ± 0.81 MBq of [18F]UCB-H, and the biodistribution was determined by organ harvesting at 2, 5, 10, 30, 60, and 120 min (n = 4 for each time point). Dynamic microPET imaging was performed on five male C57BL-6 mice after the injection of 9.19 ± 3.40 MBq of [18F]UCB-H. A theoretical dynamic bladder model was applied to simulate urinary excretion. Human radiation dose estimates were derived from animal data using the International Commission on Radiological Protection 103 tissue weighting factors.ResultsBased on organ harvesting, the urinary bladder wall, liver and brain received the highest radiation dose with a resulting effective dose of 1.88E-02 mSv/MBq. Based on dynamic imaging an effective dose of 1.86E-02 mSv/MBq was calculated, with the urinary bladder wall and liver (brain was not in the imaging field of view) receiving the highest radiation.ConclusionsThis first preclinical dosimetry study of [18F]UCB-H showed that the tracer meets the standard criteria for radiation exposure in clinical studies. The dose-limiting organ based on US Food and Drug Administration (FDA) and European guidelines was the urinary bladder wall for FDA and the effective dose for Europe with a maximum injectable single dose of approximately 325 MBq was calculated. Although microPET imaging showed significant deviations from organ harvesting, the Pearson's correlation coefficient between radiation dosimetry derived by either method was 0.9666.

Project description:Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer 68Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of 68Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUVmax/organ SUVmean). Results: At all time points, average SUVmax was highest in the liver. Tumor and organ SUVmean decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Conclusion: 68Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Dataset Information

Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

Publications

Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

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