A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL)=17-19, with a high selectivity for lanthanides over Ca(2+), Cu(2+), and Zn(2+). The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex)(298)=7.7-9.3×10(6) s(-1)) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV(≠)=7.2-8.8 cm(3) mol(-1)). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively.

The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used 11 C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11 C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11 C-metoclopramide brain kinetics were compared using PET in rats (n 5 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11 C-metoclopramide brain distribution (V T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: 11 C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11 C-metoclopramide brain kinetics (V T 5 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm −3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11 C-metoclopramide V T (7.80 ± 1.43 mL⋅cm −3 ) with a 4.4-fold increase in K 1 (influx rate constant) and a 2.3-fold increase in binding potential (k 3 /k 4 ) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V T 5 6.28 ± 0.48 mL⋅cm −3 ) with a 2.0-fold increase in K 1 and a 2.2-fold decrease in k 2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11 C-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: 11 C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate 11 C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive 11 C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution (V T) and the influx (K 1) and efflux (k 2) rate constants between plasma and selected brain regions. Furthermore, 11 C-metoclopramide washout from the brain was estimated by determining the elimination slope (k E,brain) of the brain time-activity curves. Results: In baseline scans, 11 C-metoclopramide showed appreciable brain distribution (V T 5 2.11 ± 0.33 mL/cm 3). During CsA infusion, whole-brain gray matter V T and K 1 were increased by 29% ± 17% and 9% ± 12%, respectively. K 2 was decreased by 15% ± 5%, consistent with a decrease in k E,brain (−32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.

Longitudinal data in this small cohort of participants with early HD support [(18)F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.

PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. The regional brain kinetics of a tracer dose of C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without ( = 4) or with ( = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution ( ), as well as the influx ( ) and efflux ( ) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope ( ; min) from 30 to 60 min. Tariquidar significantly increased the brain distribution ofC-metoclopramide ( = 4.3 ± 0.5 mL/cm and 8.7 ± 0.5 mL/cm for baseline and ABCB1 inhibition conditions, respectively, < 0.001), with a 1.28-fold increase in ( < 0.05) and a 1.64-fold decrease in ( < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). correlated significantly ( < 0.0001) with AUC from 30 to 60 min ( = 0.95), with AUC from 0 to 30 min ( = 0.87), and with ( = 0.62). C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.

The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ ABCG2 inhibitors to enhance brain distribution of 11 C-erlotinib in nonhuman primates as a model of the human BBB. Methods: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11 C-erlotinib under baseline conditions (n 5 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n 5 4) or elacridar (12 mg/kg/h, n 5 3). Results: Under baseline conditions, 11 C-erlotinib distribution to the brain (total volume of distribution [V T ], 0.22 6 0.015 mL/cm 3 ) was markedly lower than its distribution to muscle tissue surrounding the skull (V T , 0.86 6 0.10 mL/cm 3 ). Elacridar infusion resulted in a 3.5 6 0.9-fold increase in 11 C-erlotinib distribution to the brain (V T , 0.81 6 0.21 mL/cm 3 , P , 0.01), reaching levels comparable to those in muscle tissue, without changing 11 Cerlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11 C-erlotinib brain distribution was also significantly (1.7 6 0.2-fold) increased (V T , 0.38 6 0.033 mL/cm 3 , P , 0.05), with a concomitant increase in 11 C-erlotinib plasma exposure. Conclusion: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11 C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.

Neuropathological studies showed early locus coeruleus (LC) neuronal loss associated with tauopathy in Alzheimer’s Disease (AD). We used the LC signal intensity (LC‐I) on 3T MRI to assess the LC integrity in AD (n = 37) and controls (n = 17). The LC‐I was decreased in AD regardless of typical (amnesic) and atypical presentation (logopenic aphasia/visuo‐spatial deficit), from the prodromal stage, and independently of the amyloid load measured by PiB‐PET. The LC‐I was correlated with memory performance of typical AD. This supports the pathophysiological model in which the LC plays a critical role in AD and may thus be a potential therapeutic target.