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A Serotonin Transporter Imaging Agent

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A Serotonin Transporter Imaging Agent Biodistribution and Imaging with 123I-ADAM: A Serotonin Transporter Imaging Agent Andrew B. Newberg, MD1; Karl Plo¨ssl, PhD1; P. David Mozley, MD2; James B. Stubbs, PhD3; Nancy Wintering, MSW1; Michelle Udeshi, MD1; Abass Alavi, MD1; Tomi Kauppinen, PhD4; and Hank F. Kung, PhD1 1University of Pennsylvania, Philadelphia, Pennsylvania; 2Eli Lilly and Company, Indianapolis, Indiana; 3Alpharetta, Georgia; and 4Division of Nuclear Medicine, Helsinki University Central Hospital, Helsinki, Finland were 1.95 Ϯ 0.13 for the midbrain, 1.27 Ϯ 0.10 for the medial Ϯ 2-((2-((Dimethylamino)methyl)phenyl)thio)-5-123I-iodophenyl- temporal regions, and 1.11 0.07 for the striatum. Conclusion: 123 amine (123I-ADAM) is a new radiopharmaceutical that selectively I-ADAM may be a safe and effective radiotracer for imaging binds the central nervous system serotonin transporters. The serotonin transporters in the brain and the body. purpose of this study was to measure its whole-body biokinet- Key Words: 123I-ADAM; radiopharmaceuticals; serotonin trans- ics and estimate its radiation dosimetry in healthy human vol- porter; brain; SPECT; dosimetry; radiobiology unteers. The study was conducted within a regulatory frame- J Nucl Med 2004; 45:834–841 work that required its pharmacologic safety to be assessed simultaneously. Methods: The sample included 7 subjects ranging in age from 22 to 54 y old. An average of 12.7 whole- body scans were acquired sequentially on a dual-head camera for up to 50 h after the intravenous administration of 185 MBq In the brain, serotonin participates in the mediation of (5 mCi) 123I-ADAM. The fraction of the administered dose in 13 emotion and cognition. The removal of free serotonin from regions of interest (ROIs) was quantified from the attenuation- the synaptic cleft is one of the primary mechanisms for corrected geometric mean counts in conjugate views. Multi- regulating serotonergic tone. Serotonin transporters exponential functions were iteratively fit to each time–activity (5-HTT) are macromolecular complexes that are de- curve using a nonlinear, least-squares regression algorithm. These curves were numerically integrated to yield source organ signed to remove serotonin from the synaptic cleft and residence times. Gender-specific radiation doses were then move it intact back into the neuronal cytoplasm, where it estimated with the MIRD technique. SPECT brain scans ob- can be repackaged for reuse or metabolized. Most drugs tained 3 h after injection were evaluated using an ROI analysis and diseases induce compensatory changes in transporter to determine the range of values for the region to cerebellum. function before affecting the concentration of the Results: There were no pharmacologic effects of the radiotracer postsynaptic serotonin receptors. Selective serotonin re- on any of the subjects, including no change in heart rate, blood uptake receptor inhibitor (SSRI) drugs such as fluoxitine pressure, or laboratory results. Early planar images showed and citalopram have been shown to have significant an- differentially increased activity in the lungs. SPECT images demonstrated that the radiopharmaceutical localized in the tidepressant effects (1). Hence, the study of this trans- midbrain in a distribution that is consistent with selective porter should have significant implications for the study transporter binding. The dose-limiting organ in both men and of mood disorders, other psychiatric and neurologic con- women was the distal colon, which received an average of ditions, and the effects of various pharmaceuticals on the 0.12 mGy/MBq (0.43 rad/mCi) (range, 0.098–0.15 mGy/MBq). serotonergic system. 123 The effective dose equivalent and effective dose for I-ADAM A few radiopharmaceuticals have been successfully de- Ϯ Ϯ were 0.037 0.003 mSv/MBq and 0.036 0.003 mSv/MBq, veloped for imaging the central nervous system 5-HTT in respectively. The mean adult male value of effective dose for ␤ ␤ 123 123I-ADAM is similar in magnitude to that of 111In-diethylenetri- vivo with 2 -carbomethoxy-3 -(4- I-iodophenyl)tropane 123 ␤ aminepentaacetic acid (0.035 mGy/MBq), half that of 111In-pen- ( I- -CIT), the most commonly used ligand currently (2– tetreotide (0.81 mGy/MBq), and approximately twice that of 5). These radiopharmaceuticals have been labeled with 123I-inosine 5Ј-monophosphate (0.018 mGy/MBq). The differ- positron-emitting isotopes (6,7)or123I-labeled single-pho- ences in results between this study and a previous publication ton emitters as in the case of ␤-CIT. These agents have been are most likely due to several factors, the most prominent being remarkably effective in demonstrating normal (8–10) and this dataset used attenuation correction of the scintigraphic abnormal neurologic (11,12) and psychiatric conditions data. Region-to-cerebellum ratios for the brain SPECT scans (13–15). Their success has led to efforts to produce more selective (e.g., ␤-CIT binds to both serotonin and dopamine Received Oct. 15, 2003; revision accepted Dec. 15, 2003. transporters) and easier-to-use imaging agents for use in For correspondence or reprints contact: Andrew B. Newberg, MD, 110 conventional medical settings (16,17). There has been a Donner Building, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. considerable interest in the development of selective tracers E-mail: [email protected]. for imaging 5HTT with PET or SPECT. PET compounds 834 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 45 • No. 5 • May 2004 such as 11C-(ϩ)-McN5652 and 11C-3-amino-4-(2-dimethyl- dioactivity remaining in the body at later time points, which aminomethylphenylsulfanyl)benzonitrile have been used could significantly affect the dosimetry. Furthermore, hav- quantitatively for PET imaging of 5HTT in human brain ing as many time points as possible should improve the (18–21). In parallel, an equivalent and useful iodinated statistical accuracy of the biologic model and, hence, the SPECT imaging agent for 5HTT has not been found, despite dose estimates. Also, the earlier report did not factor in several attractive radioiodinated candidates having been re- attenuation correction, which may significantly affect esti- ported in the literature (22–24). For these reasons, there is a mates of the radioactivity in various organs, especially those strong impetus to search for a better candidate for imaging in areas that are more likely to be affected. 5HTT with SPECT. The purpose of this article is to present a more detailed 2-((2-((Dimethylamino)methyl)phenyl)thio)-5-123I- analysis of the biodistribution, dosimetry, and safety data of iodophenylamine (123I-ADAM; Fig. 1) selectively binds the the use of 123I-ADAM in human subjects. We also were able 5-HTT. Biodistribution of 125I-ADAM in rat brain after to reanalyze the data from the 2 subjects in the Helsinki intravenous injection showed a high specific binding in the study to include factors such as attenuation to determine regions of hypothalamus, cortex, striatum, and hippocam- how their values compare with ours. With these data ob- pus, where 5-HTT are concentrated and the specific binding tained, future studies can be expanded into the clinical peaked at 120–240 min after injection (25). Preclinical setting in the evaluation of patients with a wide variety of studies in nonhuman primates with SPECT have produced neuropsychiatric disorders. midbrain-to-cerebellar ratios of ϳ2.25:1 (26). Overall, the 123 findings have suggested that I-ADAM may have several MATERIALS AND METHODS highly advantageous imaging characteristics for visualizing 5-HTT. Accrual and Assessment of Subjects The design was similar to the design of several others that our Like any other radiopharmaceutical, the use of 123I- laboratory has previously reported (29–32). The protocol was ADAM in humans requires estimating its radiation dosim- approved by the local Committee on Research Involving Humans etry—that is, the amount of radiation energy deposited in and the U.S. Food and Drug Administration (Investigational New each organ per unit dose of administered radioactivity (27). Drug no. 65,542). Healthy volunteers were recruited through ad- Image resolution generally improves with higher doses of vertisements in local papers and by word of mouth from other radioactivity. Enhanced clinical efficacy usually follows as volunteers. Medical histories were taken and physical examina- a direct result. Restraint is required, however, because tions were performed before inclusion. None of the volunteers had higher doses may incur greater risks of radiation-induced a known history of a health problem that could have significantly biologic harm. Striking a balance between efficacy and affected the biodistribution or elimination of the radioligand at the safety requires estimating the radiation doses delivered to time of study. None of the subjects reported taking any medica- each organ in the body. The process of estimating the tions at the time of the study other than oral contraceptive pills. All urine drug screens and serum laboratory tests were performed to radiation-absorbed doses requires quantifying the radioac- confirm that individuals were healthy. The final sample included 3 tivity distribution within the whole body at multiple time men and 4 women. The average education was 16.4 Ϯ 4.2 y points after administration and developing mathematic (range, 10–21 y). models that describe the uptake, retention, and clearance of the radioactivity from each organ of the body (e.g., a bio- Clinical Assessment Procedures logic model). The baseline clinical laboratory tests included a complete blood An earlier report of the dosimetry of 123I-ADAM in cell count with differential, serum electrolytes, and liver enzymes. human subjects was published by investigators at the Divi- Levels of creatinine, blood urea nitrogen, glucose, cholesterol, sion of Nuclear Medicine, Helsinki University Central Hos- triglycerides, albumin, and total protein were also assayed. Preg- nancy was ruled out in the women with a urine or serum pregnancy pital, in Finland (28). However, only 2 subjects were im- test within 48 h.
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