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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 20, 2003 as doi:10.1096/fj.02-0492fje. |
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NIDA Intramural Research Program; Baltimore, Maryland, USA;
* Neuropsychiatric Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA; and
NIMH Intramural Research Program, Bethesda, MD, USA
2Correspondence: Neuroimaging Research Branch, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. E-mail: akimes{at}intra.nida.nih.gov
SPECIFIC AIMS
Noninvasive imaging of nicotinic acetylcholine receptors (nAChRs) in the human brain in vivo is extremely important for elucidating the role of these receptors in normal brain function and in the pathogenesis of brain disorders. To date, [11C]nicotine is the only nAChR radioligand used for positron emission tomography (PET) studies in humans. Unfortunately, this ligand has some drawbacks, such as rapid dissociation of the receptor–ligand complex, high nonspecific binding, and a strong dependency of its cerebral accumulation on cerebral blood flow. Although modeling approaches have been developed to improve the analysis of PET data obtained using [11C]nicotine, it continues to be a suboptimal radioligand for imaging brain nAChRs. The goal of this study was to determine whether 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine, commonly known as 2-[18F]F-A-85380, (2-[18F]FA), a recently developed radioligand, could be used to image nAChRs in human brain with PET within radiation dose limits and to confirm the safety of the no carrier-added radiolabeled drug.
PRINCIPAL FINDINGS
1. Visualizing nAChRs in the brain
To evaluate the usefulness of this radioligand for imaging human cerebral nAChRs, we acquired PET scans of the brains of three healthy nonsmoking volunteers after i.v. bolus administration of 2-[18F]FA (1.6±0.1 MBq/kg or 0.043±0.002 mCi/kg, 1.3–10 pmol/kg). The total accumulation of radioactivity in the human brain reached a maximum of 2.5 ± 0.2% of the injected dose (ID) between 50 and 80 min after 2-[18F]FA administration. Using coregistered PET and MRI images, we identified structures having the greatest accumulation of radioactivity as thalamus, midbrain, and pons, consistent with moderate to high densities of nAChRs in these regions (Fig. 1
). Less accumulation of radioactivity was observed in the cerebral cortices, caudate, putamen, and cerebellum. White matter, especially the corpus callosum, accumulated the least radioactivity. With the dose of radioligand administered in our studies, visualization of brain regions in which the densities of nAChRs are moderate to high was possible for up to 5 h after injection. The accumulation of radioactivity in the thalamus was relatively homogeneous. Activity in the midbrain could not be unambiguously assigned to specific nuclei, but probably represents binding to nAChRs in the tegmental area, periaqueductal gray, red nucleus, and substantia nigra, all of which contain moderate to high densities of nAChRs according to postmortem studies. Unlike most other studied regions, the cerebellum and pons exhibited greater accumulation of radioactivity (normalized to administered dose per kg body weight) in human brain vs. that observed in the Rhesus monkey brain. These observations are consistent with findings from single photon emission computed tomography (SPECT) studies in humans with a radioiodinated analog of 2-[18F]FA, 5-[123I]iodo-3(2(S)-azetidinylmethoxy)pyridine (5-[123I]IA). Although little specific binding of either 5-[123I]IA or 2-[18F]FA uptake was observed in the cerebella of Rhesus monkeys, the receptor binding of both of these radioligands in the cerebella of baboons was more pronounced. These findings suggest that the differences in the nAChR distribution pattern are species-related.
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Results from PET studies in Rhesus monkey reported here demonstrate that administration of nicotine, unlabeled 2FA, or cytisine with 2-[18F]FA dramatically reduces the accumulation of radioactivity in brain regions that have moderate to high densities of nAChRs. The resulting brain images show a distribution of radioactivity that is nearly random (see Fig. 2 of online version). These findings, which are consistent with those from our previous in vitro and in vivo studies and those of others in rodents and nonhuman primates, demonstrate that 2FA specifically binds to cerebral nAChRs. The patterns of distribution of radioactivity in the human and nonhuman primate brain after 2-[18F]FA administration are similar and both correspond to the distribution of nAChRs. These results indicate that as in monkey brain, the cerebral accumulation of radioactivity in the human reflects its specific binding to nAChRs. Quantitative studies with 2-[18F]FA, including those in which its specific binding in the human brain is blocked by nicotine, are a subject for future research.
2. Dose limits for administration of 2-[18F]FA in humans
To estimate the radiation dose limits, PET scans of all internal organs in two participants and of organs between the diaphragm and upper thighs in three participants were performed and excreted radioactivity in the urine of six participants was measured. The results of these studies demonstrated that organs receiving the greatest radiation exposure were the urinary bladder wall, liver, and kidneys. These findings were consistent with our previous observations in mice and monkeys. After bolus administration of 2-[18F]FA to research participants, 89–93% of the administered dose was eliminated from the body in the urine. The biological half-life of the radioactivity calculated from the urine data was 4.0 ± 0.3 h (mean±SD). The clearance of radioactivity from the blood plasma was closely approximated by the sum of three exponential functions. The terminal half-life of the plasma radioactivity derived from the slowest exponential was 4.1 ± 0.3 h (mean±SD), in good agreement with the biological half-life calculated from the urine data.
The concentration of radioactivity in any organ, except urinary bladder and kidneys, never exceeded that in the liver at any time for up to 7 h after the injection. This suggests that all other organs in the human body received radiation doses from their own radioactivity smaller than that received by the liver from its radioactivity (Table 1
). To calculate estimates of radiation doses, we used the residence time for the urinary bladder contents (based on the accumulation of radioactivity in the urine) and residence times for seven organs that could be visualized or identified from their anatomical location (kidneys, liver, muscles, red marrow, trabecular and cortical bones, and brain).
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Due to the low concentration of radioactivity in most organs, especially at later time points, their identification on the PET images was difficult. To avoid an underestimation of the radiation dose estimates, especially in values for the whole body effective dose (ED) and effective dose equivalent (EDE), we chose the most conservative approach for our calculations. To calculate residence times for all organs that accumulated relatively small amounts of radioactivity (i.e., other than the urinary bladder, kidneys, liver, muscles, red marrow, trabecular and cortical bones, and brain), we assumed that at all time points their concentrations of radioactivity were equal to that in the liver. This approach resulted in some overestimation of radiation exposure to the body, as evidenced by the fact that the sum of residence times for all organs (3.3±0.3 h) calculated without voiding exceeded the theoretical residence time for 18F (2.6 h) by 25%.
As shown in Table 1
, even with this overestimation the radiation doses to the remaining organs, as well as to the whole body ED and whole body EDE, are reasonably low. The urinary bladder wall is the critical organ limiting the dose of 2-[18F]FA that can be administered to humans. The radiation dose estimates for any other organ are less than one-third that of the urinary bladder wall.
To calculate the radiation doses shown in Table 1
, we used a dynamic bladder model and a 2.4 h voiding interval. Use of a 1 h voiding period resulted in an absorbed dose equivalent for the urinary bladder wall (critical organ) of less than half that calculated for a 2.4 h voiding period (80±14 µSv/MBq and 180±30 µSv/MBq for 1 h and 2.4 h voiding intervals, respectively). Therefore, frequent voiding or/and stimulating voiding by encouraging water consumption or by intravenous hydration is recommended for decreasing the exposure to the bladder.
The results of the present study predict that multiple studies (up to 4 per year) using a bolus administration of 2.6 MBq/kg (0.071 mCi/kg) of 2-[18F]FA per study could be performed on a single subject without exceeding the limits imposed by FDA regulations for human use of a "radioactive research drug" (21 CFR 361.1). It is expected that this dose would be sufficient to calculate total volumes of distribution for most brain regions. Continued study will likely provide a more accurate estimation of the radiation dose to each organ and greater knowledge of the variability of the radiation dose to the urinary bladder wall among individuals. Results of these further studies may show that a higher dose of 2-[18F]FA could be used in humans without exceeding the radiation dose limit.
Administration of a higher dose of 2-[18F]FA will also increase the mass dose of the radioligand unless a more stringent limit in the minimal specific activity of the radioligand administered is adopted. In our study, the injected mass dose administered to the human research participants varied from 1.3 to 10 pmol/kg (5±2 pmol/kg, mean±SE) based on the dose of 1.6±0.1 MBq/kg (0.043±0.002 mCi/kg; mean±SE) of 2-[18F]FA and specific activities ranging from 210 to 1100 GBq/µmol (5.6–30.0 Ci/µmol) at the time of administration. Heart rate, blood pressure, respiratory rate, and ECG parameters were monitored on all six participants at predetermined intervals for the first 24 h after the 2-[18F]FA injection. The participants reported feeling no "drug" effect. We observed no significant changes from baseline values for any cardiovascular parameter (i.e., heart rate, respiratory rate, blood pressure, ECG) from the time of injection to 24 h postinjection. Results from our preclinical studies demonstrated that the minimal dose causing a pharmacological effect in mice, rats, or monkeys exceeded the maximal dose of 2-[18F]FA (10 pmol/kg) used in human by >2000-fold. Therefore, increasing the administered dose of 2-[18F]FA by a factor of 2 should be safe as well. Nonetheless, caution should be used with an increased mass dose until its safety in humans is established.
CONCLUSIONS
The results of the present study demonstrate that 2-[18F]FA is suitable for visualizing nAChRs in the human brain with PET at radioligand doses that produce radiation exposures within the guidelines set by the FDA for research studies in adults. Our data indicate that up to four 2-[18F]FA injections of 185 MBq/70 kg (5 mCi/70 kg) each could be given to a single research volunteer within FDA guidelines. Taken together, our findings suggest that 2-[18F]FA will have utility in quantitative imaging of thalamic nAChRs and might be useful for studying these receptors in other brain regions.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0492fje; doi: 10.1096/fj.02-0492fje 
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