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Human and Non-human Primate PET Imaging of the Brain Serotonin Transporter

Author: Nashwa Jarkas, PhD

The serotonergic system is involved in the pathophysiology and/or pharmacotherapy of many diseases and disorders including major depression, suicide, eating disorders, impulsivity/personality disorders, sleep disorders, and anxiety disorders. Serotonin transporter (SERT) also plays a key role in the central nervous system (CNS) synaptic serotonin transmission.

Pre and Post Synaptic Neurons

Pre- and Post-synaptic Neurons.

Imaging the human brain SERT will help in understanding the mechanisms of these disorders and therefore find better treatments for neuropsychiatric patients. Imaging the SERT has been significantly improved by using diphenylsulfide compounds also known as biphenylthiols. In our laboratory, a series of biphenylthiol derivatives have been developed including HOMADAM.

[11C]HOMADAM showed superior in vitro and in vivo biological properties as a SERT radiotracer when compared to the others. [11C]HOMADAM has been prepared from the corresponding precursor with an average decay-corrected radiochemical yield of 25%. MicroPET brain imaging studies in monkeys demonstrated that [11C]HOMADAM uptake was selectively high in the SERT-rich tissues such as the midbrain, thalamus (Thal), pons, caudate (Caud), putamen (Put), and medulla (Figure 3). It has been translated to image the human brain where it also exhibits favorable kinetics and high SERT-rich tissue-to-cerebellum ratios.

Results in Rhesus Monkeys

Figure 2

Figure 3

Comparison of [11C]HOMADAM MicroPET Time Activity Curves (TAC) of a Rhesus Monkey Brain at Baseline and after Displacement with Antidepressant Citalopram (0.5 mg/Kg) Administered 40 min Post Injection.

Baseline:

Figure 4

[11C]HOMADAM MicroPET Plane Through Midbrain Summed Images 0-60 min in a Rhesus Monkey (Baseline).

Post Lexapro Administration:

Figure 5

[11C]HOMADAM MicroPET Plane Through Midbrain Summed Images 60-120 min Following i.v. 0.02 mg/Kg Lexapro (antidepressant) in the same Rhesus Monkey.

Results in Humans

Figure 6

[11C]HOMADAM HRRT Images Show High Uptake in Human Diencephalon and Midbrain (Baseline).

Figure 7

Figure 8

*Cer: Cerebellum
[11C]HOMADAM  HRRT TAC in a Human Brain Shows High SERT Rich Tissue-to-Cerebellum Ratios and Favorable Kinetics.

Conclusion

We have developed [11C]HOMADAM as a highly promising radioligand with high ratios of specific to nonspecific binding in the human brain known SERT-rich structures, such as the raphe nuclei. Imaging the brain SERT in vivo with PET radiotracers such as [11C]HOMADAM would better help us in understanding the mechanisms of action of the SERT in patients suffering from neuropsychiatric disorders. Therefore, better drugs could be explored. As a result, we are also developing fluorinated derivatives of HOMADAM. When radiolabeled with fluorine-18 that possesses longer half-life than carbon-11, the best fluorinated candidate would help imaging the high (such as hypothalamus) and low (such as cortical regions) SERT density brain regions and allow for longer studies. This research project is supported by an NIMH K01 Award Grant.

Project Team

Nashwa Jarkas, PhD, Ronald Voll, PhD, Mell Camp, CNMT, Larry Williams, BS, Mark Goodman, PhD

Publications

Nachwa Jarkas, Jonathan McConathy, John R. Votaw, Ronald J. Voll, Eugene Malveaux, Vernon M. Camp, Larry Williams, Robin R. Goodman, Clinton D. Kilts, Mark M. Goodman. 2005, "Synthesis and characterization of EADAM: a selective radioligand for mapping the brain serotonin transporters by positron emission tomography". Nuclear Medicine and Biology, 32, 75-86.

Nachwa Jarkas, John R. Votaw, Ronald J. Voll, Larry Williams, Vernon M. Camp, Michael J. Owens, David C. Purselle, J. Douglas Bremner, Clinton D. Kilts, Charles B. Nemeroff, Mark M. Goodman. 2005, "Carbon-11 HOMADAM: a novel PET radiotracer for imaging serotonin transporters". Nuclear Medicine and Biology, 32, 211-224.

Nachwa Jarkas, Jonathan McConathy, Ronald J. Voll, Mark M. Goodman. 2005, "Synthesis, in vitro characterization and radiolabeling of N,N-dimethyl-2-(2’-amino-4’-substituted-phenylthio)benzylamines, potential candidates as selective serotonin transporter radioligands". Journal of Medicinal Chemistry, 48, 4254-4265.

Nachwa Jarkas, Ronald J. Voll, Larry Williams, John R. Votaw, Mike Owens, and Mark M. Goodman. 2008, "Synthesis and in vivo evaluation of halogenated N,N-dimethyl-2-(2’-amino-4’-hydroxymethylphenylthio)benzylamine derivatives as PET serotonin transporter radioligands ".  Journal of Medicinal Chemistry, 51, 271-281.

Jonathan A. Nye, John R. Votaw, Nachwa Jarkas, David Purselle, Vernon Camp, James D. Bremner, Clinton D. Kilts, Charles B. Nemeroff, and Mark M. Goodman. 2008,  “Compartmental modeling of 11C-HOMADAM binding to the serotonin transporter in the healthy human brain”. Journal of Nuclear Medicine, 49, 2018-2025.

Nachwa Jarkas, Ronald J. Voll, Larry Williams, and Mark M. Goodman. 2010, "Validation of two fluoro-analogues of N,N-dimethyl-2-(2’-amino-4’-hydroxymethyl-phenylthio)benzylamine as serotonin transporter imaging agents using microPET". Nuclear Medicine and Biology, 37, 593-603.

N. Jarkas, J. McConathy, L. Martarello, T. Ely, C. D. Kilts, J. R. Votaw and M. M. Goodman. 2001, "Synthesis, characterization and radiolabeling of new derivatives of ADAM, potential radiotracers for mapping serotonin transporters (SERT) by PET". Journal of Nuclear Medicine, 42, 149P.

N. Jarkas, J. McConathy, E. Malveaux, J. R. Votaw and M. M. Goodman. 2002, "Radiolabeling and in vivo characterization of 11C-EADAM: an attractive PET radioligand for serotonin transporters (SERT)". Journal of Nuclear Medicine, 43, 164P.

N. Jarkas, J. McConathy, E. J. Malveaux, L. A. Williams, J. R. Votaw, C. D. Kilts and M. M. Goodman. 2003, "Synthesis, characterization and microPET imaging of serotonin transporters (SERT) with [11C]-HOMADAM: a new diarylsulfide SERT PET imaging agent". Journal of Nuclear Medicine, 44, 48P.

N. Jarkas, J. McConathy, C. Plisson, R. Voll, L. A. Williams, J. R. Votaw and M. M. Goodman. 2003, "Carbon-11 labeled 4'-substituted ADAM analogues for mapping the serotonin transporter (SERT) by PET". Journal of Labelled Compounds and  Radiopharmaceuticals, 46, S169.           

N. Jarkas, C. Plisson, R. J. Voll, L. A. Williams, J. R. Votaw and M. M. Goodman. 2004, "Preparation and pharmacological characterization of a new serotonin transporter (SERT) PET imaging agent: [11C]FMADAM". Journal of Nuclear Medicine, 45, 439P.

N. Jarkas, R. J. Voll, L. A. Williams, J. R. Votaw, M. M. Goodman. 2005, "The PET imaging agent [11C]BFHOMADAM as a new ligand for the serotonin transporters (SERT)". Journal of Nuclear Medicine, 46, 137P.

N. Jarkas, R. J. Voll, L. A. Williams, J. R. Votaw, M. M. Goodman. 2005, "Synthesis, radiosynthesis and in vivo imaging studies comparing three C-11 labeled PET ligands for mapping the serotonin transporter (SERT)". Journal of Labelled Compounds and  Radiopharmaceuticals, 48, S136.

N. Jarkas, R. J. Voll, L. A. Williams, J. R. Votaw, M. M. Goodman. 2007, "Synthesis and evaluation of a serotonin transporter ligand (SERT) PET imaging agent: [11C]BrHOMADAM". Journal of Labelled Compounds and  Radiopharmaceuticals, 50, S295.