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The application of in vivo magnetic resonance (MR) in drug development has several requirements that differ significantly from most applications primarily because the biopharmaceutical industry must develop new safe and effective drugs more quickly and at lower cost in a highly regulated environment. In vivo MR is recognized as a useful method to provide biomarkers for target engagement, treatment response, safety and mechanism of action that can be translated between animal and clinical studies. Thus, it has the potential to help identify drugs that are more likely to be safe and effective earlier in the process of drug development, which may help reduce the time and money required to get new drugs to patients with an unmet medical need. A brief introduction of how novel drugs are discovered and developed, what drives the biopharmaceutical industry’s interest in using biomarkers and what it takes to use MR as a biomarker to support drug development, including regulatory concerns, provides context for understanding what makes the application of in vivo MR in drug development different from most others. Exploration of three programs (trebananib, ZD6126 and axitinib) using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in the development of antivascular agents provides insight into how in vivo MR biomarkers impact drug discovery and development and the limitations of biomarkers.

Cerebral blood volume (CBV) fMRI with ultrasmall superparamagnetic iron oxide particles (USPIO) as a contrast agent was used to investigate olfactory processing in rats. fMRI data were acquired in sixteen 0.75-mm coronal slices covering the olfactory bulb (OB) and higher olfactory regions (HOR), including the anterior olfactory nucleus and piriform cortex. For each animal, multiple consecutive fMRI measurements were made during a 3-h experiment session, with each measurement consisting of a baseline period, an odorant stimulation period, and a recovery period. Two different stimulation paradigms with a stimulation period of 40s or 80s, respectively, were used to study olfactory processing. Odorant-induced CBV increases were robustly observed in the OB and HOR of each individual animal. Olfactory adaptation, which is characterized by an attenuation of responses to continuous exposure or repeated stimulations, has different characteristics in the OB and HOR. For adaptation to repeated stimuli, while it was observed in both the OB and HOR, CBV responses in the HOR were attenuated more significantly than responses in the OB. In contrast, within each continuous 40-s or 80-s odor exposure, CBV responses in the OB were stable and did not show adaptation, but the CBV responses in the HOR were state dependent, with no adaptation during initial exposures, but significant adaptation during following exposures. These results support previous reports that HOR plays a more significant role than OB in olfactory habituation. The technical approach presented in this study should enable more extensive fMRI studies of olfactory processing in rats.

Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [11C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.

Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18 months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs.

Substance P (SP) and neurokinin-1 receptors (NK-1R) are localized within central and peripheral sensory pain pathways. The roles of SP and NK-1R in pain processing, the anatomical distribution of NK-1R and efficacy observed in preclinical pain studies involving pain and sensory sensitization models, suggested that NK-1R antagonists (NK-1RAs) would relieve pain in patient populations. Despite positive data available in preclinical tests for a role of NK-1RAs in pain, clinical studies across several pain conditions have been negative. In this review, we discuss how functional imaging-derived information on activity in pain-processing brain regions could have predicted that NK-1RAs would have a low probability of success in this therapeutic domain.

This study aims to identify fMRI signatures of nociceptive processing in whole brain of anesthetized rats during noxious electrical stimulation (NES) and noxious mechanical stimulation (NMS) of paw. Activation patterns for NES were mapped with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) fMRI, respectively, to investigate the spatially-dependent hemodynamic responses during nociception processing. A systematic evaluation of fMRI responses to varying frequencies of electrical stimulus was carried out to optimize the NES protocol. Both BOLD and CBV fMRI showed widespread activations, but with different spatial characteristics. While BOLD and CBV showed well-localized activations in ipsilateral dorsal column nucleus, contralateral primary somatosensory cortex (S1), and bilateral caudate putamen (CPu), CBV fMRI showed additional bilateral activations in the regions of pons, midbrain and thalamus compared to BOLD fMRI. CBV fMRI that offers higher sensitivity compared to BOLD was then used to compare the nociception processing during NES and NMS in the same animal. The activations in most regions were similar. In the medulla, however, NES induced a robust activation in the ipsilateral dorsal column nucleus while NMS showed no activation. This study demonstrates that (1) the hemodynamic response to nociception is spatial-dependent; (2) the widespread activations during nociception in CBV fMRI are similar to what have been observed in (14)C-2-deoxyglucose (2DG) autoradiography and PET; (3) the bilateral activations in the brain originate from the divergence of neural responses at supraspinal level; and (4) the similarity of activation patterns suggests that nociceptive processing in rats is similar during NES and NMS.

Flavone acetic acid (FAA) is a new anticancer agent in Phase II trials in Europe. In preclinical testing FAA showed broad activity against murine solid tumors and minimal activity against murine leukemias. Our interest in studying the combination of FAA and radiation was based on two of its biological effects which might modify radiation damage. First, FAA depletes ATP and inhibits macromolecular synthesis which are needed to repair radiation-induced DNA strand breaks; and second, inhibition of tumor blood flow by FAA could lead to radiobiological hypoxia. Various schedules of FAA (170 mg/kg I.V.) (n = 9, SF = 0.44) and radiation (10 Gy) (n = 9, SF = 0.37) were investigated against s.c. implanted Glasgow osteogenic sarcoma. In the same model we studied both the kinetics of ATP depletion by 31P-Nuclear Magnetic Resonance Spectroscopy and the repair of radiation induced single and double strand breaks by alkaline elution. The combined response was not significantly different from log-additive when radiation was given 24, 5 or 1 hr before FAA. When FAA was given immediately before radiation an increase in tumor response, significantly different from log-additive (p = 0.03) was observed. This enhancement disappeared when radiation was delayed for between 1 and 48 hr after FAA. While decreased ATP levels and increased response to radiation occurred within minutes after FAA administration, no effect of FAA at either 180 or 200 mg/kg was observed on the repair of radiation induced single or double strand breaks (10 and 50 Gy, respectively; 5 hr after FAA) in spite of significant ATP depletion in the tumors.

Spin-lattice relaxation measurements with surface coils used in the single coil mode on stationary samples will produce accurate T 1 values if a three-parameter exponential fit is employed. A further sufficient requirement is that the T 1 measurement method (pulse sequence) conform to the following three criteria at all points in the sensitive volume of the surface coil. (i) The Z magnetization is consistently prepared to a nonequilibrium value at time zero. This initial condition must be the same at the start of every evolution period. (ii) After preparation, the magnetization is allowed to return toward thermal equilibrium during variable evolution periods τ. (iii) A constant fraction of the Z magnetization must then be sampled (observed) at the end of the evolution period. The inversion recovery, modified fast inversion recovery, and pulse-burst saturation recovery methods meet criteria (i)-(iii) and produce accurate T 1 values with a surface coil. A brief survey of surface coil T 1 measurements suggests that the greatest dynamic range is provided by using the inversion recovery or modified fast inversion recovery method, the pulse-burst saturation recovery method provides accurate T 1 measurements in a minimum amount of time, and the use of composite pulses does not significantly improve the accuracy of the measurement.

Sensitivity optimization in surface coil NMR is complicated by the inhomogeneity (or shape) of the B 1 field produced by the surface coil antenna. The sensitivity and the size and location of the observed volume are dependent upon experimental conditions. Therefore, we have derived three-dimensional signal intensity maps for a single-turn, flat, circular coil operating on resonance in the single-coil mode to determine the effect of experimental conditions on the sensitivity and spatial characteristics of the observed volume. The results indicate that rapid repetition rates ( T ⪡ T 1 ) provide optimum sensitivity and contribute significant signal intensity from regions not immediately adjacent to the coil. Intermediate repetition rates ( T ∼ T 1 ) provide a significant sensitivity increase over slow repetition rates ( T ⩾ 5 T 1 ) while localizing the volume observed primarily to regions adjacent to the coil. For homogeneous samples further separated from the coil (0.2–0.4 radii), longer pulse widths provide signal from a large region of the sample with a minimum loss in sensitivity. This analysis is verified by agreement of calculated and experimental total intensities as a function of flip angle (pulse width), relaxation time ( T 1 ), and repetition rate. Furthermore, the results from 2 H (30 MHz) and 19 F (188 MHz) NMR experiments with ionic and nonionic solutions indicate that rf attenuation problems associated with conductive samples are not likely to be significant in surface coil NMR experiments that utilize small diameter coils at high fields.

The signal intensity and inherent spatial localization in a single-pulse steady-state experiment using a circular surface receiver coil in the presence of a homogeneous rf excitation magnetic field (B1) is examined theoretically by computer simulation assuming zero interaction between the transmission-coil and the surface-coil radiofrequency circuits. The theoretical analysis is verified by NMR experiments employing appropriate “phantom” samples with the surface coil orthogonal to the transmitter coil to minimize interaction between the two. Under slow pulse repetition conditions the signal intensity of the homogeneous B1 transmission-surface-coil reception experiment is essentially the same as that obtained in the single-coil configuration surface-coil experiment and is independent of the orientation of the homogeneous B1 with respect to the surface coil. A significant consequence of this result is that the optimum performance of multiple-pulse sequences which require specific flip angles over the whole sample should be attained while retaining the spatially restrictive sensitivity profile of the surface coil. The homogeneous B1 transmission-surface-coil reception sensitive volume penetrates deeper into the sample than the surface-coil single-coil configuration sensitive volume, and therefore may be a more appropriate shape for in vivo NMR spectroscopy. The homogeneous B1 transmission actually induces more xy magnetization than surface-coil transmission does, but differences in signal phase from different regions of the sample result in an incoherent addition when the signal from all parts of the sample are summed together. In imaging experiments, each volume element of the sample is uniquely characterized by its Larmor frequency and phase, thus, signal reduction due to phase differences is absent.