Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Body Mass Index and Age Effects on Brain 11ß-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study.

CONTEXT: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11ß-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE: We analyzed positron emission tomography (PET) scans with an 11ß-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 µg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 µg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. RESULTS: Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. CONCLUSIONS: In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11ß-HSD1 in the brain and correlation of increased 11ß-HSD1 levels in the brain with advancing age.

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans.

PURPOSE: The α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans. METHODS: PET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (V T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed. RESULTS: In the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM V T. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm3 in cerebellum to 25.9 ± 2.9 mL/cm3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%. CONCLUSIONS: These results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.

Synthesis and Evaluation of Gd(III) -Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate-Specific Membrane Antigen.

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate-specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR-based molecular imaging. We have synthesized three new high-affinity, low-molecular-weight Gd(III) -based PSMA-targeted contrast agents containing one to three Gd(III)  chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA-based MR molecular imaging.