Preclinical evaluation of [18F]FB-A20FMDV2 as a selective marker for measuring αVß6 integrin occupancy using positron emission tomography in rodent lung.

PURPOSE: Integrin αvß6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvß6 in rodent lung to support human translational studies. METHODS: The synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvß6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software. RESULTS: [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/µmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 µSv/MBq. CONCLUSION: [18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvß6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.

Clinical quantification of the integrin αvß6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study).

PURPOSE: The RGD-integrin, αvß6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFß). This study sought to quantify expression of αvß6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvß6-selective [18F]FB-A20FMDV2 PET ligand. METHODS: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvß6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvß6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. RESULTS: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. CONCLUSIONS: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvß6, was markedly increased in subjects with PF compared with healthy subjects.

Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.