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Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer's disease.

ABSTRACT: In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer's disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of β amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.

SUBMITTER: Badachhape AA

PROVIDER: S-EPMC7527957 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer's disease.

Badachhape Andrew A AA Working Peter K PK Srivastava Mayank M Bhandari Prajwal P Stupin Igor V IV Devkota Laxman L Tanifum Eric A EA Annapragada Ananth V AV Ghaghada Ketan B KB

Scientific reports 20200930 1

In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of ...[more]

PMID: 32999398

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Project description:ObjectiveThe aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males.Materials and methodsThis was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months.ResultsNo clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days.ConclusionSingle intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents.

Dataset Information

Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer's disease.

Publications

Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer's disease.

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