Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Objectives: Sigma-1 receptor (S1R) is resident to mitochondrial-associated endoplasmic reticulum and plasma membranes with implications in a variety of diseases including Alzheimer's disease, ALS, and cancer. Previous PET S1R radiotracers are characterized by slow kinetics that impedes their use for human brain imaging. Recently a series of spirocyclic piperidine-based ligands showed great promise as S1R PET imaging probes, based on their high selectivity towards S1R and good binding characteristics in rodents or porcine. [1-3] Here, we report the first monkey PET imaging studies of four ligands (1-4) in this series to assess their pharmacokinetic and in vivo binding properties, and to select the most suitable tracer for advancing to humans.
Methods:
Each tracer was injected as a bolus (~5 mCi) to the same rhesus monkey.
Baseline scans were obtained on a Siemens FOCUS 220 scanner over 4 h. Two hour blocking scans were performed with administration of SA4503 (0.5 mg/kg) [4] before tracer injection. Arterial blood was drawn during each scan for metaboite analysis by HPLC and construction of the plasma input functions. Regional brain time-activity curves (TACs) were analyzed by one-tissue (1T), two-tissue (2T), and multilinear analysis-1 (MA1) models to obtain regional volumes of distribution (V_T). The free fraction (f_p) in plasma was meassured via ultrafiltration method. Log D of each tracer was also determined.
Results:
Fast metabolism of the tracers was observed in rhesus monkeys, with ~ 35%, 18%, and 19% parent fraction, respectively, for 1 (2), 3 and 4 at 60 min post-injection. Plasma f_P values were 2%, 8%, and 17%, for 1 (2), 3 and 4, consistent with their respective measured Log D values of 2.80, 2.55, and 2.50. In the brain, all four tracers showed high and fast uptake. Tissue activity washout was rapid for 2 and 4, and much slower for 1 and 3, in line with their respective in vitro S1R binding affinities. Both the 1T and MA1 kinetic models provided good fits of regional TACs, and reliable V_T estimates with low errors. Across all regions, 1T V_T values were greatest for 3, follwed by 1, 4, and 2. The highest V_T values were in the cingulate gyrus for all tracers. Ligand 4 showed the greatest differential uptake across different brain regions. SA4503 at the dose of 0.5 mg/kg blocked ~85% (2) and ~95% (4) of radiotracer binding, respectively.