Automated synthesis, preclinical toxicity, and radiation dosimetry of [F-18]MC225 for clinical use:a tracer for measuring P-glycoprotein function at the blood-brain barrier

Introduction: [18F]MC225 is a selective substrate for P-glycoprotein (P-gp) that has good metabolic stability and shows higher baseline uptake compared with other P-gp substrates such as (R)-[11C]Verapamil. Prior to clinical translation, it is necessary to perform process validation of the radiosynthesis, assessment of preclinical toxicity, and radiation dosimetry. Methods: The production of [18F]MC225 was automated on a CFN-MPS200 multipurpose synthesizer. The acute toxicity of MC225 was evaluated at a dose of 2.5 mg/kg bodyweight, which is more than 10,000-fold the postulated maximum clinical dose of [18F]MC225. The acute toxicity of [18F]MC225 injection at a 200-fold dose, to administer a postulated dose of 185 MBq of [18F]MC225, was also evaluated after the decay-out of 18F. The mutagenicity of MC225 was studied by a reverse mutation test using Salmonella typhimurium and Escherichia coli (Ames test). In vivo biodistribution and dosimetry studies of [18F]MC225 were carried out in normal mice. Human dosimetry was estimated using OLINDA software. Results: The mean decay-corrected yields of [18F]MC225 at end of synthesis were 13%, with > 99% radiochemical purity, > 1000 GBq/!mol molar activity, and ! 1.5 !g/185 MBq of total chemical contents. All process validation batches complied with the product specifications and the process was confirmed to be appropriate for the production of [18F]MC225. No acute toxicity of MC225 or [18F]MC225 injection was found. No mutagenic activity was observed for MC225. The biodistribution study demonstrated both hepatobiliary and renal excretion of radioactivity. The most critical organ was the pancreas, with (63.8 !Gy/MBq) or without urination (63.9 !Gy/MBq) at 360 min after injection. The estimated effective dose (!Sv/MBq) with and without urination at 360 min after injection was calculated as 15.7 and 16.9, respectively. Conclusion: [18F]MC225 shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [18F]MC225 PET imaging is well within acceptable dose limits

EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals:impact on safety and imaging quality

Abstract This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed

Cross-coupling of [11C]methyllithium for 11C-labelled PET tracer synthesis

The cross-coupling of aryl bromides with [11C]CH3Li for the labelling of a variety of tracers for positron emission tomography (PET) is presented. The radiolabelled products were obtained in excellent yields, at rt and after short reaction times (3-5 min) compatible with the half-life of 11C (20.4 min). The automation of the protocol on a synthesis module is investigated, representing an important step towards a fast method for the synthesis of 11C-labelled compounds for PET imaging

First clinical assessment of [ 18 F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood-brain barrier

Objective: 5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([18F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood-brain barrier (BBB) of [18F]MC225 in healthy subjects. Methods: [18F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [18F]MC225 injection. Dynamic [18F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [18F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). VT was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time-activity curves [TACs] and negative slope of calculated TACs) were compared with the VT values. Results: No serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was 0.9). AUCs of TACs were positively correlated with VT (2-TCM) values (r2: AUC0-60 min = 0.61, AUC0-30 min = 0.62, AUC30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with VT (2-TCM) values (r2 = 0.53, p < 0.0001). Conclusions: This initial evaluation indicated that [18F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB. Keywords: Blood–Brain barrier; Dosimetry; First-in-human; P-glycoprotein; Positron emission tomography

New molecular targets for PET and SPECT imaging in neurodegenerative diseases

The pathophysiology of neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD) has not yet been completely elucidated. However, in the past few years, there have been great knowledge advances about intra-and extracellular proteins that may display impaired function or expression in AD, PD and other ND, such as amyloid beta (AB), alpha-synuclein, tau protein and neuroinfiammatory markers. Recent developments in the imaging techniques of positron emission tomography (PET) and single photon emission computed tomography (SPECT) now allow the non-invasive tracking of such molecular targets of known relevance to ND in vivo. This article summarizes recent findings of PET and SPECT studies using these novel methods, and discusses their potential role in the field of drug development for ND as well as future clinical applications in regard to differential diagnosis of ND and monitoring of disease progression.Brazilian Agency: CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) Brazilian agenc

Focused ultrasound for opening blood-brain barrier and drug delivery monitored with positron emission tomography

Focused ultrasound (FUS) is a minimally-invasive technology used for treatment of many diseases, including diseases related to the colon, uterus, prostate, and brain. Although it has been mainly used for ablative procedures, the ability of FUS to open the blood-brain barrier (BBB) presents a promising new application. However, the mechanism of BBB opening by FUS remains unclear. This review focuses on the use of FUS to open the BBB for enhancing drug delivery and investigating how Positron Emission Tomography (PET) provides insight into the underlying mechanism

Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [ 18 F]MC225 and PET

The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [18F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [18F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar. Twenty-three rats were intravenously injected with different doses of tariquidar ranging from 0.75 to 12 mg/kg, 30-min before the dynamic [18F]MC225-PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain influx constant K1 and distribution volume VT, which allow the estimation of P-gp function. ANOVA and post-hoc analyses of K1 values showed significant differences between controls and groups with tariquidar doses >3 mg/kg; while applying VT the analyses showed significant differences between controls and groups with tariquidar doses >6 mg/kg. Dose-response curves were fitted using different models. The four-parameter logistic sigmoidal curve provided the best fit for K1 and VT data. Half-maximal inhibitory doses (ID50) were 2.23 mg/kg (95%CI: 1.669-2.783) and 2.93 mg/kg (95%CI: 1.135-3.651), calculated with K1 or VT values respectively. According to the dose-response fit, differences in [18F]MC225-K1 values could be detected at tariquidar doses ranging from 1.37 to 3.25 mg/kg. Our findings showed that small changes in the P-gp function, caused by low doses of tariquidar, could be detected by [18F]MC225-K1 values, which confirms the high sensitivity of the radiotracer. The results suggest that [18F]MC225 may allow the quantification of moderate P-gp impairments, which may allow the detection of P-gp dysfunctions at the early stages of a disease and potential transporter-mediated drug-drug interactions