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Quantitative μ-Opioid Receptor PET with [18F]FCFN in Nonhuman Primates: Naloxone Blockade and Within-Scan Displacement

Year: 2026

Type: article

Abstract: Background/Objectives: Quantitative PET imaging of μ-opioid receptor (MOR) availability and pharmacologic engagement can advance in vivo studies of opioid receptor biology. We previously evaluated a series of 18F-labeled carfentanil analogs and prioritized the regioisomer [18F]fluorocarfentanil ([18F]FCFN) based on favorable brain kinetics, regional distribution, and naloxone-sensitive binding. Here, we provide proof-of-concept evaluation of [18F]FCFN in rhesus macaques to assess its potential for quantitative, pharmacologically responsive MOR PET. Methods: [18F]FCFN was produced by automated radiosynthesis. Dynamic [18F]FCFN PET scans were performed in two rhesus macaques under baseline conditions, after low- (0.005 mg/kg) and high-dose (0.2 mg/kg) naloxone pretreatment, and during within-scan intravenous or intranasal naloxone challenge. For arterial input scans, two-tissue compartment modeling with metabolite-corrected arterial input functions was used to estimate total distribution volume (VT). Nondisplaceable binding potential (BPND) was estimated using multilinear reference tissue model 2 with the cerebellum as the candidate reference region. Results: Automated radiosynthesis produced [18F]FCFN in high radiochemical yield and molar activity, enabling low-mass PET injections (0.09–0.32 μg). [18F]FCFN showed rapid brain uptake and MOR-consistent regional distribution, with lowest uptake in the cerebellum. Regional BPND correlated positively with VT at baseline (R2 = 0.983, p < 0.0001) and after high-dose blockade (R2 = 0.522, p < 0.004). Naloxone pretreatment reduced regional BPND in a dose-dependent manner. Within-scan intravenous and intranasal naloxone challenges also produced marked reductions in BPND. Conclusions: [18F]FCFN enables quantitative, pharmacologically sensitive MOR PET imaging in nonhuman primates at low injected masses. Concordant plasma-input and reference-tissue measures, dose-dependent blockade, and proof-of-concept within-scan displacement support its use for measuring MOR availability and dynamic antagonist engagement across administration routes.

Source: Pharmaceutics

DOI: 10.3390/pharmaceutics18091141