- Email: [email protected]
Biodistribution and radiation dosimetry of [N-methyl-11C]mirtazapine, an antidepressant affecting adrenoceptors
ARTICLE IN PRESS
Applied Radiation and Isotopes 59 (2003) 175–179
Biodistribution and radiation dosimetry of [N-methyl-11C]mirtazapine, an antidepressant affecting adrenoceptors Katalin Marthia,b, S^ren B. Hansena, Steen Jakobsena, Dirk Bendera, Stefan Bo Smithc, Donald F. Smithc,* a
PET Center, Aarhus University Hospital, N^rrebrogade 44, Aarhus C 8000, Denmark Research Group for Technical Analytical Chemistry, Hungarian Academy of Sciences, University of Technology and Economics, Budapest 1111, Hungary c Institute for Basic Research in Psychiatry, Department of Biological Psychiatry, Aarhus University Psychiatric Hospital, Skovagerej 2, Risskov 8240, Denmark b
Received 15 March 2003; accepted 23 May 2003
Abstract Central adrenoceptors cannot currently be studied by PET neuroimaging due to a lack of appropriate radioligands. The fast-acting antidepressant drug mirtazapine, radiolabelled for PET, may be of value for assessing central adrenoceptors, provided that the radiation dosimetry of the radioligand is acceptable. To obtain that information, serial whole-body images were made for up to 70 min following intravenous injection of 326 and 185 MBq [N-methyl-11C]mirtazapine (specific activities E.O.S. of 119 and 39 GBq/mmol, respectively) in a healthy volunteer. Ten source organs plus remaining body were considered in estimating absorbed radiation doses calculated using MIRD 3.1. The highest absorbed organ doses were found to the lungs (3.4 10 2 mGy/MBq), adrenals (1.2 10 2 mGy/ MBq), spleen (1.2 10 2 mGy/MBq), and gallbladder wall (1.1 10 2 mGy/MBq). The effective dose was estimated to be 6.8 10 3 mSv/MBq, which is similar to that produced by several radioligands used routinely for neuroimaging. r 2003 Elsevier Ltd. All rights reserved. Keywords: [N-methyl-11C]Mirtazapine; Biodistribution; Dosimetry; Antidepressant; Noradrenergic neurotransmission; PET
1. Introduction Molecular neuroimaging is becoming increasingly popular for studying neuropsychiatric disorders. At present, however, some major neurotransmitter systems cannot be investigated in humans due to the lack of appropriate radioligands; one such system involves central adrenoceptors (Talbot and Laruelle, 2002). Recently, we found in the living porcine brain that the *Corresponding author. Tel.: +45-89493332; fax: +45-89493020. E-mail address: [email protected] (D.F. Smith).
antidepressant drug mirtazapine, radiolabelled with C-11 (Fig. 1), has favorable properties for PET neuroimaging (Marthi et al., 2002). Since the therapeutic effects of mirtazapine are attributed primarily to the actions of the drug at central adrenoceptors, plus secondary actions on serotonin (de Boer, 1996; Anttila and Leinonen, 2001; Kent, 2000), we believe that [Nmethyl-11C]mirtazapine could be used to study noradrenergic processes. Here, we report the whole-body distribution and effective dose produced by [Nmethyl-11C]mirtazapine in a healthy volunteer, in accordance with requirements of radiation control agencies for introducing a new radiopharmaceutical for human use.
0969-8043/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0969-8043(03)00156-8
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
176
that we intend to use in subsequent studies for PET neuroimaging. The time interval for scanning of regions in the three consecutive whole-body scans was 2, 3 and 4 min, respectively.
2.4. Dosimetry calculations
11
Fig. 1. Structure of [N-methyl- C]mirtazapine.
2. Materials and methods 2.1. Ethics The study was approved by the Ethical Committee for Aarhus Municipality, the Danish Medicines Agency, and the Unit for Good Clinical Practice of Aarhus University Hospital, and it was carried out in accordance with the World Medical Association Declaration of Helsinki. The volunteer gave written, informed consent for participating in the study. 2.2. Radiochemistry [N-methyl-11C]Mirtazapine was prepared as described in detail elsewhere (Marthi et al., 2002). Briefly, a fully automated procedure was used for radiolabelling Ndesmethyl mirtazapine (Z)-2-butenedioate by methylation with [11C]methyl iodide and for purifying the product by HPLC chromatography.
Time–activity curves were obtained from the repeated whole-body scans. Organs with an increased accumulation of tracer relative to their surroundings were identified and were included as individual source organs. For the larger organs, the tracer content was determined by extraction of the concentration (Bq/ml) from a large ROI defined in a transaxial plane through the organ. These concentrations were converted to total content by multiplying by the relevant organ mass for the 70 kg standard man (Cristy and Eckerman, 1987) and dividing by the organ density. Also, the data were multiplied by 68/70 in order to correct for the difference in body weight between our volunteer and the standard Caucasian man. For the small organs with high contrast to background (spleen, gallbladder, pancreas, and adrenals), it was found to be more reliable to extract the tracer content directly based on multiple ROIs defined to surround the organ. The cumulative activities were obtained by numerical integration of the time–activity curves, assuming that the activity remaining in an organ after the last measurement decreases only by physical decay. Finally, the doses for 25 target organs and the effective dose were estimated using the MIRD 3.1 software (Stabin, 1996).
2.5. Metabolite analysis 2.3. Biological procedures We used a healthy, 43 year-old female volunteer weighing 68 kg. She reclined in the PET scanner (ECAT Exact HR47, Siemens/CTI, Knoxville, TN) and was partially immobilized by a customized head holder and by straps across her body. We carried out a set of wholebody transmission scans followed by six whole-body emission scans. Each whole-body scan consisted of seven regions 15 cm in length, starting at the top of the head and ending above the knees of the subject. The first three whole-body scans occurred after intravenous injection of 326 MBq [N-methyl-11C]mirtazapine (specific activity of 119 GBq/mmol at the end of synthesis, 15 min before injection). The next three whole-body scans took place after intravenous injection of 185 MBq [N-methyl-11C]mirtazapine (specific activity of 39 GBq/mmol at the end of synthesis, 19 min before injection). An interval of 94 min elapsed between the two injections. The doses and specific activities were selected as being in the range
Venous blood samples were drawn for metabolite analysis at four times after each injection of [Nmethyl-11C]mirtazapine. Metabolite analysis was carried out by mixing blood plasma (0.5 ml) with an equal volume of acetonitrile, centrifuging the mixture, passing the supernatant through a 0.45 mm syringe filter, loading the extract into a 1 ml volume Rheodyne injection valve, and fractionating it by a Luna 5 m CN column (250 4.6 mm; Phenomenex 5 mm). The mobile phase was 10 mM sodium acetate (pH adjusted to 4.2 with acetic acid) and acetonitrile (80/20 v/v). The eluent was delivered at 2 ml/min, and the extracts were eluted to a GABI radioactivity detector with Winnie Software from Raytest (Biotech-IgG, Copenhagen). The fraction of unchanged [N-methyl-11C]mirtazapine in plasma was determined with radiodetection by integration of the peak corresponding to [N-methyl-11C]mirtazapine, and it was expressed as a percentage of the total of all radioanalytes detected.
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
3. Results 3.1. Biodistribution The metabolism of [N-methyl-11C]mirtazapine was such that approximately 50% of the radiopharmaceutical remained unmetabolized in the bloodstream at the end of each whole-body scan (Fig. 2). The timecourse and whole-body distribution of [N-methyl-11C]mirtazapine-derived radioactivity were similar after intravenous injection of either 185 or 326 MBq, with highest initial levels in spleen, gallbladder, liver
Fig. 2. Time-course of metabolism of [N-methyl-11C]mirtazapine in bloodstream of a healthy subject after intravenous injection of 326 or 185 MBq of the radiopharmaceutical (diamonds and circles, respectively).
177
and lung, intermediate levels in brain and heart, and relatively low levels in kidney and small intestine (Figs. 3–5).
3.2. Radiation absorbed dose estimates Table 1 shows the mean absorbed organ doses for various target organs after intravenous injection of [Nmethyl-11C]mirtazapine. The organs receiving the highest doses were the lungs, liver, adrenals, spleen, and gallbladder wall. The effective dose was estimated to be 6.5 10 3 mSv/MBq for the higher specific activity injection, and 7.1 10 3 mSv/MBq for the lower specific activity injection. No single organ received a dose more than five times the effective dose.
Fig. 4. Time-course of decay-corrected percent injected dose of [N-methyl-11C]mirtazapine in selected body organs after intravenous injection of 326 MBq.
Fig. 3. Geometric mean whole-body images demonstrating the biodistribution of 326 MBq [N-methyl-11C]mirtazapine in a healthy subject 0–15 min (left), 17–39 min (middle), and 41–69 min (right) postinjection.
ARTICLE IN PRESS 178
K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
4. Discussion Molecular neuroimaging is popular for studying neuropsychiatric disorders, although some aspects of neurotransmission cannot yet be studied in humans due to a lack of appropriate radioligands (Talbot and Laruelle, 2002). We reasoned that the pharmacological
Fig. 5. Time-course of standard uptake values of [Nmethyl-11C]mirtazapine in selected body organs after intravenous injection of 326 MBq.
effects of mirtazapine on central adrenoceptors combined with the favorable properties of [N-methyl-11C]mirtazapine for PET neuroimaging could make this radiopharmaceutical a useful tool for studying the role of noradrenergic mechanisms in affective disorders, provided that radiation safety requirements are met. In the present study, relatively high amounts of radioactivity occurred in lung, adrenals, liver, spleen, gallbladder, and brain. We speculate that the observed distribution of radioactivity reflects at least three processes. Firstly, we account for the relatively high amounts of radioactivity in lung, adrenals and brain by the relatively high density of adrenoceptors in those organs (Hentrich et al., 1986; Gibbs and Summers, 2002; Eskandari and Sternberg, 2002). Secondly, we assume that the relatively high levels of radioactivity noted in the spleen reflect the propensity of mirtazapine for erythrocytes (Timmer et al., 2000). Thirdly, the relatively large amounts of radioactivity noted in liver and gallbladder probably relate to demethylation of the radiopharmaceutical and elimination of methyl-11C (Timmer et al., 2000).
Table 1 Radiation dose estimates to different human target organs for intravenously injected [N-methyl-11C]mirtazapine Absorbed dose (mGy/MBq) A Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Bone surfaces Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
B 2
1.06 10 7.87 10 3 2.26 10 3 9.02 10 3 1.85 10 3 2.14 10 3 2.54 10 3 2.27 10 3 8.05 10 3 4.99 10 3 1.46 10 2 2.98 10 2 2.02 10 3 1.95 10 3 4.78 10 3 2.29 10 3 2.23 10 3 1.56 10 3 1.17 10 2 1.54 10 3 2.66 10 3 2.00 10 3 2.48 10 3 1.96 10 3 2.89 10 3 6.5 10 3
Mean 2
1.22 10 7.97 10 3 2.20 10 3 1.11 10 2 1.56 10 3 1.93 10 3 2.40 10 3 2.11 10 3 8.21 10 3 5.27 10 3 1.85 10 2 3.42 10 2 1.86 10 3 1.68 10 3 5.30 10 3 2.14 10 3 2.03 10 3 1.39 10 3 1.03 10 2 1.28 10 3 2.57 10 3 1.78 10 3 2.58 10 3 1.70 10 3 2.90 10 3 7.1 10 3
1.14 10 7.92 10 2.23 10 1.01 10 1.71 10 2.04 10 2.47 10 2.19 10 8.13 10 5.13 10 1.66 10 3.20 10 1.94 10 1.82 10 5.04 10 2.22 10 2.13 10 1.48 10 1.10 10 1.41 10 2.62 10 1.89 10 2.53 10 1.83 10 2.90 10 6.80 10
2 3 3 2 3 3 3 3 3 3 2 2 3 3 3 3 3 3 2 3 3 3 3 3 3 3
A—after injection of 326 MBq (sp. Act. 119 GBq/mmol) and B—185 MBq (sp. Act. 39 GBq/mmol) into the same volunteer. Abbreviations: LLI: lower large intestine; ULI: upper large intestine.
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
The estimated effective doses for the two sets of whole-body scans were similar, namely 6.5 10 3 mSv/ MBq for the higher specific activity and 7.1 10 3 mSv/ MBq for the lower specific activity. Similarly, the variation of individual organ doses between the scans was relatively small. Consequently, we specify the average effective dose to be 6.8 10 3 mSv/MBq. Thus, for a typical administered bolus of 300 MBq [Nmethyl-11C]mirtazapine, the effective dose would amount to 2 mSv, which corresponds to less than a 1year dose of additional background radiation exposure. This effective dose is similar to that of several PET radioligands currently used widely for human brain imaging (e.g. [18F]FDG, [18F]DOPA, O-(2-[18F]fluoroethyl)-L-tyrosine, [11C]spiperone) (Mejia et al., 1991; Tang et al., 2003; International Commission on Radiological Protection, 1997). Studies are now required for determining whether [N-methyl-11C]mirtazapine can provide insight concerning the role of central adrenoceptors in neuropsychiatric disorders.
Acknowledgements We thank NV Organon for providing mirtazapine and N-desmethyl mirtazapine (Z)-2-butenedioate and for permitting us to publish our findings. We thank also the bioanalysts and technical staff of the PET Center for their skillful assistance and Y. Stork for diligent secretarial work. This project was supported by the following agencies: Fonden til Psykiatriens Fremme, the Danish Medical Research Council, and Pulje til Styrkelse af Psykiatrisk Forskning.
References Anttila, S.A., Leinonen, E.V., 2001. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 7, 249–264.
179
Cristy, M., Eckerman, K., 1987. Specific absorbed fractions of energy at various ages from internal photon sources, I–VII. ORNL/TM-8381 V1–V7, Oak Ridge National Laboratory. de Boer, T., 1996. The pharmacologic profile of mirtazapine. J. Clin. Psychiatr. 57 (Suppl 4), 19–25. Eskandari, F., Sternberg, E.M., 2002. Neural-immune interactions in health and disease. Ann. NY. Acad. Sci. 966, 20–27. Gibbs, M.E., Summers, R.J., 2002. Role of adrenoceptor subtypes in memory consolidation. Prog. Neurobiol. 67, 345–391. Hentrich, F., Gothert, M., Greschuchna, D., 1986. Noradrenaline release in the human pulmonary artery is modulated by presynaptic alpha 2-adrenoceptors. J. Cardiovasc. Pharmacol. 8, 539–544. International Commission on Radiological Protection, 1997. ICRP Publication 80. Radiation dose to patients from radiopharmaceuticals, Addendum 2 to ICRP Publication 53, Annals of ICRP, Pergamon. Kent, J.M., 2000. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355, 911–918. Marthi, K., Bender, D., Gjedde, A., Smith, D., 2002. [11C]Mirtazapine for PET neuroimaging: radiosynthesis and initial evaluation in the living porcine brain. Eur. Neuropsychopharmacol. 12, 427–432. Mejia, A.A., Nakamura, T., Masatoshi, I., Hatazawa, J., Masaki, M., Watanuki, S., 1991. Estimation of absorbed doses in humans due to intravenous administration of fluorine-18-fluorodeoxyglucose in PET studies. J. Nucl. Med. 32, 699–706. Stabin, M.G., 1996. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J. Nucl. Med. 37, 538–546. Talbot, P.S., Laruelle, M., 2002. The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development. Eur. Neuropsychopharmacol. 12, 503–511. Tang, G., Wang, M., Tang, X., Luo, L., Gan, M., 2003. Pharmacokinetics and radiation dosimetry estimation of O(2-[18F]fluoroethyl)-L-tyrosine as oncologic PET tracer. Appl. Radiat. Isot. 58, 219–225. Timmer, C.J., Sitsen, J.M., Delbressine, L.P., 2000. Clinical pharmacokinetics of mirtazapine. Clin. Pharmacokinet. 38, 461–474.
Applied Radiation and Isotopes 59 (2003) 175–179
Biodistribution and radiation dosimetry of [N-methyl-11C]mirtazapine, an antidepressant affecting adrenoceptors Katalin Marthia,b, S^ren B. Hansena, Steen Jakobsena, Dirk Bendera, Stefan Bo Smithc, Donald F. Smithc,* a
PET Center, Aarhus University Hospital, N^rrebrogade 44, Aarhus C 8000, Denmark Research Group for Technical Analytical Chemistry, Hungarian Academy of Sciences, University of Technology and Economics, Budapest 1111, Hungary c Institute for Basic Research in Psychiatry, Department of Biological Psychiatry, Aarhus University Psychiatric Hospital, Skovagerej 2, Risskov 8240, Denmark b
Received 15 March 2003; accepted 23 May 2003
Abstract Central adrenoceptors cannot currently be studied by PET neuroimaging due to a lack of appropriate radioligands. The fast-acting antidepressant drug mirtazapine, radiolabelled for PET, may be of value for assessing central adrenoceptors, provided that the radiation dosimetry of the radioligand is acceptable. To obtain that information, serial whole-body images were made for up to 70 min following intravenous injection of 326 and 185 MBq [N-methyl-11C]mirtazapine (specific activities E.O.S. of 119 and 39 GBq/mmol, respectively) in a healthy volunteer. Ten source organs plus remaining body were considered in estimating absorbed radiation doses calculated using MIRD 3.1. The highest absorbed organ doses were found to the lungs (3.4 10 2 mGy/MBq), adrenals (1.2 10 2 mGy/ MBq), spleen (1.2 10 2 mGy/MBq), and gallbladder wall (1.1 10 2 mGy/MBq). The effective dose was estimated to be 6.8 10 3 mSv/MBq, which is similar to that produced by several radioligands used routinely for neuroimaging. r 2003 Elsevier Ltd. All rights reserved. Keywords: [N-methyl-11C]Mirtazapine; Biodistribution; Dosimetry; Antidepressant; Noradrenergic neurotransmission; PET
1. Introduction Molecular neuroimaging is becoming increasingly popular for studying neuropsychiatric disorders. At present, however, some major neurotransmitter systems cannot be investigated in humans due to the lack of appropriate radioligands; one such system involves central adrenoceptors (Talbot and Laruelle, 2002). Recently, we found in the living porcine brain that the *Corresponding author. Tel.: +45-89493332; fax: +45-89493020. E-mail address: [email protected] (D.F. Smith).
antidepressant drug mirtazapine, radiolabelled with C-11 (Fig. 1), has favorable properties for PET neuroimaging (Marthi et al., 2002). Since the therapeutic effects of mirtazapine are attributed primarily to the actions of the drug at central adrenoceptors, plus secondary actions on serotonin (de Boer, 1996; Anttila and Leinonen, 2001; Kent, 2000), we believe that [Nmethyl-11C]mirtazapine could be used to study noradrenergic processes. Here, we report the whole-body distribution and effective dose produced by [Nmethyl-11C]mirtazapine in a healthy volunteer, in accordance with requirements of radiation control agencies for introducing a new radiopharmaceutical for human use.
0969-8043/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0969-8043(03)00156-8
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
176
that we intend to use in subsequent studies for PET neuroimaging. The time interval for scanning of regions in the three consecutive whole-body scans was 2, 3 and 4 min, respectively.
2.4. Dosimetry calculations
11
Fig. 1. Structure of [N-methyl- C]mirtazapine.
2. Materials and methods 2.1. Ethics The study was approved by the Ethical Committee for Aarhus Municipality, the Danish Medicines Agency, and the Unit for Good Clinical Practice of Aarhus University Hospital, and it was carried out in accordance with the World Medical Association Declaration of Helsinki. The volunteer gave written, informed consent for participating in the study. 2.2. Radiochemistry [N-methyl-11C]Mirtazapine was prepared as described in detail elsewhere (Marthi et al., 2002). Briefly, a fully automated procedure was used for radiolabelling Ndesmethyl mirtazapine (Z)-2-butenedioate by methylation with [11C]methyl iodide and for purifying the product by HPLC chromatography.
Time–activity curves were obtained from the repeated whole-body scans. Organs with an increased accumulation of tracer relative to their surroundings were identified and were included as individual source organs. For the larger organs, the tracer content was determined by extraction of the concentration (Bq/ml) from a large ROI defined in a transaxial plane through the organ. These concentrations were converted to total content by multiplying by the relevant organ mass for the 70 kg standard man (Cristy and Eckerman, 1987) and dividing by the organ density. Also, the data were multiplied by 68/70 in order to correct for the difference in body weight between our volunteer and the standard Caucasian man. For the small organs with high contrast to background (spleen, gallbladder, pancreas, and adrenals), it was found to be more reliable to extract the tracer content directly based on multiple ROIs defined to surround the organ. The cumulative activities were obtained by numerical integration of the time–activity curves, assuming that the activity remaining in an organ after the last measurement decreases only by physical decay. Finally, the doses for 25 target organs and the effective dose were estimated using the MIRD 3.1 software (Stabin, 1996).
2.5. Metabolite analysis 2.3. Biological procedures We used a healthy, 43 year-old female volunteer weighing 68 kg. She reclined in the PET scanner (ECAT Exact HR47, Siemens/CTI, Knoxville, TN) and was partially immobilized by a customized head holder and by straps across her body. We carried out a set of wholebody transmission scans followed by six whole-body emission scans. Each whole-body scan consisted of seven regions 15 cm in length, starting at the top of the head and ending above the knees of the subject. The first three whole-body scans occurred after intravenous injection of 326 MBq [N-methyl-11C]mirtazapine (specific activity of 119 GBq/mmol at the end of synthesis, 15 min before injection). The next three whole-body scans took place after intravenous injection of 185 MBq [N-methyl-11C]mirtazapine (specific activity of 39 GBq/mmol at the end of synthesis, 19 min before injection). An interval of 94 min elapsed between the two injections. The doses and specific activities were selected as being in the range
Venous blood samples were drawn for metabolite analysis at four times after each injection of [Nmethyl-11C]mirtazapine. Metabolite analysis was carried out by mixing blood plasma (0.5 ml) with an equal volume of acetonitrile, centrifuging the mixture, passing the supernatant through a 0.45 mm syringe filter, loading the extract into a 1 ml volume Rheodyne injection valve, and fractionating it by a Luna 5 m CN column (250 4.6 mm; Phenomenex 5 mm). The mobile phase was 10 mM sodium acetate (pH adjusted to 4.2 with acetic acid) and acetonitrile (80/20 v/v). The eluent was delivered at 2 ml/min, and the extracts were eluted to a GABI radioactivity detector with Winnie Software from Raytest (Biotech-IgG, Copenhagen). The fraction of unchanged [N-methyl-11C]mirtazapine in plasma was determined with radiodetection by integration of the peak corresponding to [N-methyl-11C]mirtazapine, and it was expressed as a percentage of the total of all radioanalytes detected.
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
3. Results 3.1. Biodistribution The metabolism of [N-methyl-11C]mirtazapine was such that approximately 50% of the radiopharmaceutical remained unmetabolized in the bloodstream at the end of each whole-body scan (Fig. 2). The timecourse and whole-body distribution of [N-methyl-11C]mirtazapine-derived radioactivity were similar after intravenous injection of either 185 or 326 MBq, with highest initial levels in spleen, gallbladder, liver
Fig. 2. Time-course of metabolism of [N-methyl-11C]mirtazapine in bloodstream of a healthy subject after intravenous injection of 326 or 185 MBq of the radiopharmaceutical (diamonds and circles, respectively).
177
and lung, intermediate levels in brain and heart, and relatively low levels in kidney and small intestine (Figs. 3–5).
3.2. Radiation absorbed dose estimates Table 1 shows the mean absorbed organ doses for various target organs after intravenous injection of [Nmethyl-11C]mirtazapine. The organs receiving the highest doses were the lungs, liver, adrenals, spleen, and gallbladder wall. The effective dose was estimated to be 6.5 10 3 mSv/MBq for the higher specific activity injection, and 7.1 10 3 mSv/MBq for the lower specific activity injection. No single organ received a dose more than five times the effective dose.
Fig. 4. Time-course of decay-corrected percent injected dose of [N-methyl-11C]mirtazapine in selected body organs after intravenous injection of 326 MBq.
Fig. 3. Geometric mean whole-body images demonstrating the biodistribution of 326 MBq [N-methyl-11C]mirtazapine in a healthy subject 0–15 min (left), 17–39 min (middle), and 41–69 min (right) postinjection.
ARTICLE IN PRESS 178
K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
4. Discussion Molecular neuroimaging is popular for studying neuropsychiatric disorders, although some aspects of neurotransmission cannot yet be studied in humans due to a lack of appropriate radioligands (Talbot and Laruelle, 2002). We reasoned that the pharmacological
Fig. 5. Time-course of standard uptake values of [Nmethyl-11C]mirtazapine in selected body organs after intravenous injection of 326 MBq.
effects of mirtazapine on central adrenoceptors combined with the favorable properties of [N-methyl-11C]mirtazapine for PET neuroimaging could make this radiopharmaceutical a useful tool for studying the role of noradrenergic mechanisms in affective disorders, provided that radiation safety requirements are met. In the present study, relatively high amounts of radioactivity occurred in lung, adrenals, liver, spleen, gallbladder, and brain. We speculate that the observed distribution of radioactivity reflects at least three processes. Firstly, we account for the relatively high amounts of radioactivity in lung, adrenals and brain by the relatively high density of adrenoceptors in those organs (Hentrich et al., 1986; Gibbs and Summers, 2002; Eskandari and Sternberg, 2002). Secondly, we assume that the relatively high levels of radioactivity noted in the spleen reflect the propensity of mirtazapine for erythrocytes (Timmer et al., 2000). Thirdly, the relatively large amounts of radioactivity noted in liver and gallbladder probably relate to demethylation of the radiopharmaceutical and elimination of methyl-11C (Timmer et al., 2000).
Table 1 Radiation dose estimates to different human target organs for intravenously injected [N-methyl-11C]mirtazapine Absorbed dose (mGy/MBq) A Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Bone surfaces Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
B 2
1.06 10 7.87 10 3 2.26 10 3 9.02 10 3 1.85 10 3 2.14 10 3 2.54 10 3 2.27 10 3 8.05 10 3 4.99 10 3 1.46 10 2 2.98 10 2 2.02 10 3 1.95 10 3 4.78 10 3 2.29 10 3 2.23 10 3 1.56 10 3 1.17 10 2 1.54 10 3 2.66 10 3 2.00 10 3 2.48 10 3 1.96 10 3 2.89 10 3 6.5 10 3
Mean 2
1.22 10 7.97 10 3 2.20 10 3 1.11 10 2 1.56 10 3 1.93 10 3 2.40 10 3 2.11 10 3 8.21 10 3 5.27 10 3 1.85 10 2 3.42 10 2 1.86 10 3 1.68 10 3 5.30 10 3 2.14 10 3 2.03 10 3 1.39 10 3 1.03 10 2 1.28 10 3 2.57 10 3 1.78 10 3 2.58 10 3 1.70 10 3 2.90 10 3 7.1 10 3
1.14 10 7.92 10 2.23 10 1.01 10 1.71 10 2.04 10 2.47 10 2.19 10 8.13 10 5.13 10 1.66 10 3.20 10 1.94 10 1.82 10 5.04 10 2.22 10 2.13 10 1.48 10 1.10 10 1.41 10 2.62 10 1.89 10 2.53 10 1.83 10 2.90 10 6.80 10
2 3 3 2 3 3 3 3 3 3 2 2 3 3 3 3 3 3 2 3 3 3 3 3 3 3
A—after injection of 326 MBq (sp. Act. 119 GBq/mmol) and B—185 MBq (sp. Act. 39 GBq/mmol) into the same volunteer. Abbreviations: LLI: lower large intestine; ULI: upper large intestine.
ARTICLE IN PRESS K. Marthi et al. / Applied Radiation and Isotopes 59 (2003) 175–179
The estimated effective doses for the two sets of whole-body scans were similar, namely 6.5 10 3 mSv/ MBq for the higher specific activity and 7.1 10 3 mSv/ MBq for the lower specific activity. Similarly, the variation of individual organ doses between the scans was relatively small. Consequently, we specify the average effective dose to be 6.8 10 3 mSv/MBq. Thus, for a typical administered bolus of 300 MBq [Nmethyl-11C]mirtazapine, the effective dose would amount to 2 mSv, which corresponds to less than a 1year dose of additional background radiation exposure. This effective dose is similar to that of several PET radioligands currently used widely for human brain imaging (e.g. [18F]FDG, [18F]DOPA, O-(2-[18F]fluoroethyl)-L-tyrosine, [11C]spiperone) (Mejia et al., 1991; Tang et al., 2003; International Commission on Radiological Protection, 1997). Studies are now required for determining whether [N-methyl-11C]mirtazapine can provide insight concerning the role of central adrenoceptors in neuropsychiatric disorders.
Acknowledgements We thank NV Organon for providing mirtazapine and N-desmethyl mirtazapine (Z)-2-butenedioate and for permitting us to publish our findings. We thank also the bioanalysts and technical staff of the PET Center for their skillful assistance and Y. Stork for diligent secretarial work. This project was supported by the following agencies: Fonden til Psykiatriens Fremme, the Danish Medical Research Council, and Pulje til Styrkelse af Psykiatrisk Forskning.
References Anttila, S.A., Leinonen, E.V., 2001. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 7, 249–264.
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