Synthesis of a nonpeptide carbon-11 labeled substance P antagonist for PET studies

Abstract

CP 96,345 is a nonpeptide high affinity antagonist of the substance P (NK1) receptor. The radiosynthesis of [11C]CP 96,345 suitable for Positron Emission Tomography (PET) applications is described. [11C]CP 96,345 was prepared by O-methylation of a desmethyl precursor via in situ generation of its phenolate salt. The in vivo tissue distribution of [11C]CP 96,345 in guinea pigs (n = 2) at 5 and 30 min was determined. Uptake was low in brain (approximately 0.04% dose/g) and highest (approximately 1-2% dose/g) in the spleen and lungs. The present findings indicate that the use of [11C]CP 96,345 in PET might be more applicable to the study of substance P receptors in peripheral tissues involved with inflammatory disease and arthritis.

The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy

“…First generation radiotracers were selected from many lead structures, based upon autoradiographic studies of NK1Rs. These compounds were initially investigated in vivo for their ability to be taken up by the brain and other organs in animal models [146,147,148,149] (Figure 4). Early evaluation of [ 11 C]CP-96,345 [146] concluded that despite radioligand high lipophilicity, the cationic form excluded radiotracer passage through the blood–brain barrier and allowed for peripheral tissue imaging only.…”

“…These compounds were initially investigated in vivo for their ability to be taken up by the brain and other organs in animal models [146,147,148,149] (Figure 4). Early evaluation of [ 11 C]CP-96,345 [146] concluded that despite radioligand high lipophilicity, the cationic form excluded radiotracer passage through the blood–brain barrier and allowed for peripheral tissue imaging only. PET detection of central and peripheral NK1R occupancy was performed later on hamsters using [ 11 C]CP-99,994 [147] and pigs using [ 11 C]CP-643,051 [148].…”

Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

“…However, the compounds cannot be used for detecting changes in substance P levels due to slow dissociation from the receptor. Most attempts to develop in vivo NK 1 -receptor radioligands have been unsuccessful or indifferent, except for the two ligands mention above [23-26]. …”

Synthesis and Biological Evaluation of Halogenated Naphthyridone Carboxamides as Potential Ligands for in Vivo Imaging Studies of Substance P Receptors

“…A few radioligands have been synthesized for PET or SPECT studies of NK1 receptors (Figure 1). The first ones had quinuclidine {[ 11 C]CP-96,345 (17,18) and [ 125 I]L 703606 (19)} or piperidine structures {[ 11 C]CP-99,-994 (20), [ 18 F]FTP (21), [ 11 C]GR 203040 (22), [ 11 C]GR 205171 (22), [ 18 F]L 829,165 (23), and [ 11 C]CP-643,051 (24)}. More recently, a tryptophan derivative {[ 11 C]LY 303870 (25)} and a substituted piperazine {[ 11 C]R 116301 (26)} were also described.…”

“…The search for highly selective radioligands as well as the development of a unique tracer for PET and SPECT is still needed. This challenge requires the presence, in the same structure, of atoms (C, F, I, Br) that can be substituted for their positron ( 11 C, 18 F, 77 Br) or gamma ( 123/125 I) isotope. In 1995, Takeda company described a series of 6-pyrido [3,4-b]pyridinecarboxamide derivatives as a novel class of highly potent, selective, and orally active NK1 receptor antagonists (Figure 2) (27)(28)(29)(30).…”