Catecholaminergic neurotransmission in heart and brain : development of tracers for positron emission tomography

The catecholamines norepinephrine and its biosynthetic precursor dopamine are two principal neurotransmitters in the human central nervous system (CNS). Moreover, norepinephrine is a major transmitter substance in the peripheral, autonomic nervous system. Positron emission tomography (PET) is a non-invasive imaging technique that uses positron-labeled molecules to image and measure the function of biological processes in vivo. Neuronal catecholaminergic pathways, both in CNS and periphery, are involved in various disease conditions and form important targets for therapeutic agents. Different elements of synaptic neurotransmission can be targeted for molecular imaging with PET. This doctoral thesis exemplifies two strategies in the development of a catecholaminergic PET tracer.

First, radiolabeled analogues of the false adrenergic neurotransmitter metaraminol (MR) were synthesized as potential PET tracers to assess presynaptic adrenergic nerve function in the heart. Due to the considerable vasopressor activity of the parent molecule the achievement of high specific radioactivity (SR) was of central interest. MR was labeled in 4- and 6-position of the aromatic ring with no-carrier-added 76Br or 18F. Whereas the first approach afforded tracers without neuronal affinity, the 18F-labeled compounds localized avidly and specifically within adrenergic neurons. Due to higher radiochemical yields for 4-substitution, 4-[18F]fluorometaraminol appeared to be the preferred tracer for cardiac neuronal imaging,

Second, new radioligands to map dopamine D2-like receptors in the brain were prepared and characterized. These include the high-affinity benzamide [11C]epidepride, which is suitable for the delineation of lowdensity extrastriatal dopamine D2 receptors. In addition, the novel D4 ligand PB-12 was labeled with 11C, but failed to visualize the dopamine D4 receptor in monkey brain. Moreover, available procedures for radiolabeling of the benzamide ligands [11C]raclopride and [11C]FLB 457 were optimized. For the synthesis of [11C]raclopride the recently developed methylating agent [11C]methyl triflate was employed as a more reactive alternative to [11C]methyl iodide. For [11C]FLB 457 the SR was improved by more than 50% compared to the standard approach by using a new gas-phase method for the preparation of [11C]methyl iodide. High SR is of particular importance for ligands like [11C]FLB 457 that are used to map low-density receptor populations.

List of scientific papers

I. Langer O, Dollé F, Loc'h C, Halldin C, Vaufrey F, Coulon C, Crouzel C, Någren K, Mazière B (1997). Preparation of 4- and 6-[76Br]bromometaraminol, two potential radiotracers for the study of the myocardial norepinephrine neuronal reuptake system with PET. J Labelled Cpd Radiopharm. 39:803-816.
https://doi.org/10.1002/(SICI)1099-1344(199710)39:10<803::AID-JLCR27>3.0.CO;2-R

II. Langer O, Dollé F, Halldin C, Vaufrey F, Coulon C, Ottaviani M, Bottlaender M, Crouzel C, Någren K, Mazière B (2000). Synthesis of high-specific-radioactivity 4- and 6-[18F]fluorometaraminol - PET tracers for the adrenergic nervous system of the heart. [Submitted]

III. Langer O, Valette H, Dollé F, Halldin C, Loc´h C, Fuseau C, Coulon C, Ottaviani M, Bottlaender M, Mazière B, Crouzel C (2000). High specific radioactivity (1R,2S)-4-[(18)F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart. Nucl Med Biol. 27(3):233-238.
https://pubmed.ncbi.nlm.nih.gov/10832079

IV. Langer O, Någren K, Dollé F, Lundkvist C, Sandell J, Swahn CG, Vaufrey F, Crouzel C, Mazière B, Halldin C (1999). Precursor synthesis and radiolabelling of the dopamine D2 receptor ligand [11C]raclopride from [11C]methyl triflate. J Labelled Cpd Radiopharm. 42:1183-1193.
https://doi.org/10.1002/(SICI)1099-1344(199912)42:12<1183::AID-JLCR274>3.0.CO;2-Z

V. Sandell J, Langer O, Larsen P, Dollé F, Vaufrey F, Demphel S, Crouzel C, Halldin C (2000). Improved specific radioactivity of the PET radioligand [11C]FLB 457 by use of the GE Medical Systems PETtrace MeI MicroLab. J Labelled Cpd Radiopharm. 43:331-338.
https://doi.org/10.1002/(SICI)1099-1344(20000330)43:4<331::AID-JLCR320>3.0.CO;2-H

VI. Langer O, Halldin C, Dollé F, Swahn CG, Olsson H, Karlsson P, Hall H, Sandell J, Lundkvist C, Vaufrey F, Loc'h C, Crouzel C, Mazière B, Farde L (1999). Carbon-11 epidepride: a suitable radioligand for PET investigation of striatal and extrastriatal dopamine D2 receptors. Nucl Med Biol. 26(5):509-518.
https://pubmed.ncbi.nlm.nih.gov/10473189

VII. Langer O, Halldin C, Chou YH, Swahn CG, Någren K, Perrone R, Berardi F, Leopoldo M, Farde L (2000). Carbon-11 PB-12, an attempt to visualize the dopamine D4 receptor in the primate brain with positron emission tomography. Nucl Med Biol. 27(8):707-14.
https://pubmed.ncbi.nlm.nih.gov/11150701