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

In Vivo Evaluation of α7 Nicotinic Acetylcholine Receptor Agonists [11C]A-582941 and [11C]A-844606 in Mice and Conscious Monkeys

BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers. METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain

Test-retest reproducibility of cerebral adenosine A(2A) receptor quantification using [C-11]preladenant

Objective To evaluate the reproducibility of cerebral adenosine A(2A) receptor (A(2A)R) quantification using [C-11]preladenant ([C-11]PLN) and PET in a test-retest study. Methods Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (V-T) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30 min). Plasma-free fraction (f(P)) of [C-11]PLN was measured and used for correction of V-T values. Distribution volume ratio (DVR) was calculated from V-T of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30 min). Absolute test-retest variability (aTRV), and intra-class correlation coefficient (ICC) of V-T and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A(2A)R blocker) was analyzed by Pearson's correlation analysis. Results Regional time-activity curves were well described by 2-TCM models. Estimation of V-T by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for V-T and 14% for V-T/f(P) (ICC, 0.72 for V-T and 0.87 for V-T/f(P)). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r(2) = 0.96). Coefficients of variation for V-T, V-T/f(P), DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [C-11]PLN binding to target regions were observed (p < 0.01). Conclusions In this study, moderate test-retest reproducibility and large inter-subject differences were observed with [C-11]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [C-11]PLN PET studies

U(12) A New Symmetry Possibly Realizing in Hadron Spectroscopy

Starting from the multi-local Klein-Gordon equations with Lorentz-scalar squared-mass operator we give a covariant quark representation of the general composite mesons and baryons with definite Lorentz transformation property. The phenomenologically observed hadron mass spectra is pointed out to satisfy possibly the approximate symmetry under the tilde U(4) transformation group concerning the spinor freedom of light constituent quarks, including the chiral transformation as a subgroup. This symmetry predicts the existence of new type of chiral mesons and baryons out of the conventional framework in non-relativistic quark model: For light q qbar systems, the scalar sigma- and axial-vector a1-nonets are predicted to exist as relativistic S-wave states besides the ordinary P-wave state mesons. Two "exotic" JPC=1-+ mesons are predicted to exist as relativistic P-wave states, which are possibly assigned as pi1(1400) and pi1(1600). For light quark baryons the extra 56 with positive parity and the extra 70 with negative parity of the static SU(6) are predicted to exist as the ground state chiral particles.Comment: 9 pages uses ptptex.st

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

Process validation and preclinical development of a new PET cerebral blood flow tracer [11C]MMP for initial clinical trials

Abstract Background 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [18F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [15O]H2O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[11C]methylamphetamine ([11C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [15O]H2O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [11C]MMP prior to clinical translation. Results The decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low. Conclusions [11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit

Parametric PET Image Reconstruction via Regional Spatial Bases and Pharmacokinetic Time Activity Model

It is known that the process of reconstruction of a Positron Emission Tomography (PET) image from sinogram data is very sensitive to measurement noises; it is still an important research topic to reconstruct PET images with high signal-to-noise ratios. In this paper, we propose a new reconstruction method for a temporal series of PET images from a temporal series of sinogram data. In the proposed method, PET images are reconstructed by minimizing the Kullback–Leibler divergence between the observed sinogram data and sinogram data derived from a parametric model of PET images. The contributions of the proposition include the following: (1) regions of targets in images are explicitly expressed using a set of spatial bases in order to ignore the noises in the background; (2) a parametric time activity model of PET images is explicitly introduced as a constraint; and (3) an algorithm for solving the optimization problem is clearly described. To demonstrate the advantages of the proposed method, quantitative evaluations are performed using both synthetic and clinical data of human brains