Adriana Tavares

Amyloid Imaging With Carbon 11–Labeled Pittsburgh Compound B for Traumatic Brain Injury

OBJECTIVES To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue. DESIGN, SETTING, AND PARTICIPANTS In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24-60] years) and in 15 patients (median [range] age, 33 [21-50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21-70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29-71] years) who died of other causes. MAIN OUTCOMES AND MEASURES We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue. RESULTS Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels. CONCLUSIONS AND RELEVANCE [11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study (18F-MNI-654 test–retest, 2 men; 18F-MNI-659 test–retest, 4 men and 1 woman; 18F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18F-MNI-654 and over 3.5 h for 18F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time–activity data demonstrated that 18F-MNI-654 kinetics were much slower than 18F-MNI-659 kinetics. For 18F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test–retest variability less than 10% and intraclass correlation greater than 0.9. The 18F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18F tracers is being reported. Noninvasive quantification of 18F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18F-MNI-659 kinetics are fast enough for a good estimate of BPND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.

99mTc Auger electrons for targeted tumour therapy: A review

Purpose: Targeted radiotherapy using Auger electrons presents multiple advantages and challenges. The advantageous characteristics of this type of radiotherapy can explain the growing interest in these specific electrons for cancer therapy. During the last decade, Technetium-99m (99mTc) has been used as an imaging agent and only recently has it been analysed as a potential therapeutic agent. This paper aims to be a review on the potential use of 99mTc as a therapeutic agent. Conclusions: The physical properties of 99mTc along with its large availability through a generator in situ may represent a new and important pathway in targeted radiotherapy. Experimental data obtained so far has encouraged multiple researchers to investigate 99mTc further as a therapeutic agent for multiple common oncologic situations. In spite of these initial attempts to use 99mTc as a therapeutic agent beyond that of imaging, future studies are required to better define its dosimetric implications and radiobiological efficacy.

Radiotracer properties determined by high performance liquid chromatography: a potential tool for brain radiotracer discovery

INTRODUCTION Previously, development of novel brain radiotracers has largely relied on simple screening tools. Improved selection methods at the early stages of radiotracer discovery and an increased understanding of the relationships between in vitro physicochemical and in vivo radiotracer properties are needed. We investigated if high performance liquid chromatography (HPLC) methodologies could provide criteria for lead candidate selection by comparing HPLC measurements with radiotracer properties in humans. METHODS Ten molecules, previously used as radiotracers in humans, were analysed to obtain the following measures: partition coefficient (Log P); permeability (P(m)); percentage of plasma protein binding (%PPB); and membrane partition coefficient (K(m)). Relationships between brain entry measurements (Log P, P(m) and %PPB) and in vivo brain percentage injected dose (%ID); and K(m) and specific binding in vivo (BP(ND)) were investigated. Log P values obtained using in silico packages and flask methods were compared with Log P values obtained using HPLC. RESULTS The modelled associations with %ID were stronger for %PPB (r(2)=0.65) and P(m) (r(2)=0.77) than for Log P (r(2)=0.47) while 86% of BP(ND) variance was explained by K(m). Log P values were variable dependant on the methodology used. CONCLUSIONS Log P should not be relied upon as a predictor of blood-brain barrier penetration during brain radiotracer discovery. HPLC measurements of permeability, %PPB and membrane interactions may be potentially useful in predicting in vivo performance and hence allow evaluation and ranking of compound libraries for the selection of lead radiotracer candidates at early stages of radiotracer discovery.

Characterization in Humans of 18F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors

PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of 18F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. Methods: Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test–retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. Results: After intravenous bolus injection, 18F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A2A-rich regions, with an average test–retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. Conclusion: 18F-MNI-444 is a useful PET radiotracer for imaging A2A in the human brain. The superior in vivo brain kinetic properties of 18F-MNI-444, compared with previously developed A2A radiotracers, provide the opportunity to foster global use of in vivo A2A PET imaging in neuroscience research.

Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699

Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [(18)F]MNI-698 and [(18)F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [(18)F]MNI-698 and [(18)F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use.

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

PURPOSE Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. METHODS Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ((32)P), strontium-89 ((89)Sr), yttrium-90 ((90)Y ), tin-117 ((117m)Sn), samarium-153 ((153)Sm), holmium-166 ((166)Ho), thulium-170 ((170)Tm), lutetium-177 ((177)Lu), rhenium-186 ((186)Re), rhenium-188 ((188)Re), and radium-223 ((223)Ra). RESULTS (223)Ra alpha particles, (177)Lu beta minus particles, and (170)Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by (89)Sr and (153)Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than (177)Lu beta minus particles and (223)Ra alpha particles. CONCLUSIONS (223)Ra and (177)Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of (89)Sr and (153)Sm, and perhaps strengthen the use of (223)Ra and (177)Lu in the palliative treatment of bone metastases.

Evaluating 99mTc Auger electrons for targeted tumor radiotherapy by computational methods

Purpose Technetium-99m (T99mc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of T99mc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following T99mc Auger electron irradiation in comparison to iodine-131 (I131) beta minus particles and astatine-211 (A211t) alpha particle irradiation. Methods Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles. Results The results obtained with the algorithms used suggested that T99mc CKMMX (all M-shell Coster–Kroning—CK—and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer A211t alpha particles and higher than I131 beta minus particles. All the other T99mc electrons had a therapeutic potential similar to I131 beta minus particles. Conclusions T99mc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than I131 beta minus particles and a probability similar to A211t alpha particles. Based on the results here, T99mc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy.PURPOSE Technetium-99m (99mTc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of 99mTc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following 99mTc Auger electron irradiation in comparison to iodine-131 (131I) beta minus particles and astatine-211 (211At) alpha particle irradiation. METHODS Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles. RESULTS The results obtained with the algorithms used suggested that 99mTc CKMMX (all M-shell Coster-Kroning--CK--and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer 211At alpha particles and higher than 131I beta minus particles. All the other 99mTc electrons had a therapeutic potential similar to 131I beta minus particles. CONCLUSIONS 99mTc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy.

New iodinated quinoline-2-carboxamides for SPECT imaging of the translocator protein

With the aim of developing new SPECT imaging agents for the translocator protein (TSPO), a small library of iodinated quinoline-2-carboxamides have been prepared and tested for binding affinity with TSPO. N,N-Diethyl-3-iodomethyl-4-phenylquinoline-2-carboxamide was found to have excellent affinity (K(i) 12.0 nM), comparable to that of the widely used TSPO imaging agent PK11195.

Adenosine 2A Receptor Occupancy by Tozadenant and Preladenant in Rhesus Monkeys

Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A2A) receptors facilitates dopamine D2 receptor function. In phase 2 clinical trials, A2A antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A2A PET radiotracer, 18F-MNI-444, and used it to investigate the relationship between plasma levels and A2A occupancy by preladenant and tozadenant in nonhuman primates (NHP). Methods: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region–based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A2A occupancy in humans, based on median effective concentration (EC50) values estimated from the NHP PET measurements. Results: 18F-MNI-444 regional uptake was consistent with A2A receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A2A PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A2A receptor occupancy in humans. Conclusion: 18F-MNI-444 appears to be a better PET radiotracer for A2A imaging than currently available radiotracers. Assuming that EC50 in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A2A receptor occupancy than preladenant in humans at clinically tested doses.