Radiolabeling and Preliminary In Vivo Evaluation of the Candidate CCR2 Targeting PET Radioligand [11C]AZD2423

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 18; no. 2; p. 135
• Main Authors: Dahl, Kenneth, Johnström, Peter, Tóth, Miklós, Bolin, Martin, Varnäs, Katarina, Nakao, Ryuji, Takano, Akihiro, Khani Meynaq, Yasir, Bayrakdarian, Malken, Cselényi, Zsolt, Halldin, Christer, Farde, Lars, Schou, Magnus
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.01.2025; MDPI
• Subjects: Automation; Blood-brain barrier; Brain research; Carbon; carbonylation; Chemokine Receptor 2; Ligands; Permeability; PET imaging; radiochemistry; radiopharmaceutical; Visualization; Chemokine Receptor 2; PET imaging; carbonylation; radiochemistry; radiopharmaceutical
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph18020135

Background: AZD2423 is a high-affinity and selective negative allosteric modulator of the chemokine receptor type 2 (CCR2). This receptor plays important roles in the extravasation and transmigration of monocytes under inflammatory conditions. The aims of the current positron emission tomography (PET) study were as follows: (i) to develop an efficient synthetic method for labeling AZD2423 with carbon-11 (11C, t1/2 = 20.4 min) and (ii) to evaluate its potential to visualize CCR2 binding in the non-human primate (NHP) brain. Methods: [11C]AZD2423 was synthesized using a novel two-step, two-pot [11C]carbon monoxide carbonylation procedure. PET imaging studies in NHPs (n = 2) were conducted to assess its brain penetration and in vivo distribution. Results: Radiolabeling of [11C]AZD2423 was accomplished with good yield (7.4 ± 0.6%, n = 4) and high radiochemical purity (>99%) using [11C]carbon monoxide. Preliminary PET imaging in NHPs revealed low [11C]AZD2423 brain exposure under both baseline and pretreatment conditions (SUVpeak = 0.4, n = 2). However, high concentrations of radioactivity were observed in organs outside the brain at baseline, e.g., the thyroid gland (SUVpeak = 3.3, n = 2), parotid gland (SUVpeak = 3.4, n = 2), and submandibular gland (SUVpeak = 4.4, n = 2). This radioactivity was markedly reduced following pretreatment with AZD2423 (3.0 mg/kg), indicating specific binding of [11C]AZD2423 to CCR2 in vivo. The presence of specific CCR2 binding was further validated using two-tissue compartment modeling, which demonstrated a 59–63% reduction in the total volume of distribution values in the analyzed peripheral tissues. Conclusions: Altogether, [11C]AZD2423 shows potential as a PET radioligand for the in vivo visualization of CCR2 expression in tissues outside the brain and may also serve as a lead compound for the further development of a CCR2 PET radioligand suitable for brain imaging.