Alvina Ng

Increased Stress-Induced Dopamine Release in Psychosis

BACKGROUND A pathologic response to common life stressors, in which a hyperresponsive dopaminergic system is thought to play a key role, is a potential etiologic factor in the triggering and relapse of psychosis. However, there is no direct evidence that brain dopaminergic response to stress is exaggerated in psychosis. METHODS Using the ability of endogenous dopamine (DA) to compete with [(11)C]-(+)-PHNO binding, as measured with positron emission tomography, we examined stress-induced DA release in response to a validated psychosocial stress task. We studied 12 clinical high-risk (CHR), 10 antipsychotic-naive subjects with schizophrenia (SCZ), and 12 matched healthy volunteers (HV). Stress-induced DA release was estimated as the percent change in binding potential between conditions (stress and control scan) in the striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). RESULTS We found a significant difference between groups in the AST (F = 8.13, df = 2,31, p = .001), and at the SMST (F = 3,64, df = 2,31, p = .03) but not in the LST (F = .43, df = 2,31, p = .40) with CHR and SCZ having larger [(11)C]-(+)-PHNO displacement in response to the stress. Bonferroni-corrected comparisons confirmed that HV displacement (-2.86%) in the AST was significantly different in CHR (6.97%) and SCZ (11.44%) (with no significant difference between CHR and SCZ). CONCLUSIONS This study reveals a sensitized dopaminergic response to stress in a psychiatric condition and may have important theoretical and clinical implications regarding efforts to abort or delay relapse and/or conversion to psychosis.

Side Effects Profile in Humans of 11C-(+)-PHNO, a Dopamine D2/3 Agonist Ligand for PET

cation, and standard operating procedure protocols. Consequently, the solutions have to be prepared from highpurity batches, have to be kept in closed vials, and have to be refrigerated or stored at 220 C for a limited time only. If not, the sterility of the Millipore water and the saline solutions is not guaranteed, the composition of the acetone/HCl mixtures will change because of the low boiling points of the compounds, and the acetone in acidic media will undergo an aldol addition reaction forming 4-methyl-3-penten-2-on. We appreciate the effort of Petrik et al. to ‘‘finally’’ identify this well-known product, confirming the standard education of chemistry students (6). If it was the intention of the present letter to the editor to reflect the relevancy of creating and following standard operating procedures for the synthesis of radiopharmaceuticals, we completely agree. Regarding the nontoxic compound 4-methyl-3penten-2-on, Petrik et al. correctly state that its formation is negligible if acetone/HCl mixtures are stored with protection from light at 220 C or if freshly prepared mixtures are used.

Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB-benzodiazepine receptors.

Two quinolines identified as positive allosteric modulators of γ-aminobutyric acid (GABA)(A) receptors containing the α(2) subunit, 9-amino-2-cyclobutyl-5-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (4) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (5), were radiolabelled at the methoxy position with carbon-11 (half-life=20.4 min). These quinolines represent a new class of potential radiotracers for imaging the benzodiazepine site of GABA(A) receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [(11)C]CH(3)I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [(11)C]CO(2)) with high specific activities (>70 GBq μ mol(-1); >2 Ci μ mol(-1)) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [(11)C]2-methoxypyridine moieties. Although both radiotracers demonstrated promising imaging characteristics based on preliminary ex vivo biodistribution studies in conscious rodents, higher brain uptake was observed with [(11)C]5 and therefore this radiotracer was further evaluated. Carbon-11 labelled 5 readily penetrated the brain (>1 standard uptake value in cortical regions at 15 min post-injection of the radiotracer), had an appropriate regional brain distribution for GABA(A) receptors that appeared to be reversible, and did not show any appreciable radiometabolites in rat brain homogenates up to 15 min post-injection. Preadministration of flumazenil (1, 10 mg kg(-1)) or 5 (5 mg kg(-1)) effectively blocked >50% of [(11)C]5 binding to the GABA(A) receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABA(A) receptors. Additionally (R,S)-N-(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3-diphenylpropan-1-amine, 6, an allosteric modulator of GABA(B) receptors, was efficiently labelled in one step using [(11)C]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABA(B). In conclusion, [(11)C]5 is worthy of further evaluation in higher species for imaging GABA(A) receptors in the central nervous system.

Whole-Body Distribution and Radiation Dosimetry of 11C-(+)-PHNO, a D2/3 Agonist Ligand

Using PET, we measured the whole-body distribution of 11C-(+)-PHNO (11C-(+)-4-propyl-9-hydroxynaphthoxazine), a D2/3 agonist, as a function of time in adult subjects in order to determine the internal radiation dose. Methods: PET whole-body data were acquired after the injection of 11C-(+)-PHNO (∼360 MBq) in 6 healthy subjects (3 male and 3 female). The PET acquisition duration was a maximum of 112.5 min, and 9 discrete time frames were obtained. After reconstruction of the emission data, 6 organs were identified in the images as exhibiting uptake above background levels. Regions of interest were delineated on these organs, and time–activity curves were generated. The time–activity curve data were corrected for the injected activity, specific organ density, and volume, from which normalized accumulated activities (previously known as residence times) were calculated. The normalized accumulated activities were then used with the software code OLINDA/EXM 1.1 to calculate the internal doses for the standard adult male and female models. Results: The mean effective dose was estimated to be 4.5 ± 0.3 μSv/MBq when all subjects were included and the male model was applied for the dosimetry calculation, and the mean effective dose was estimated to be 5.2 ± 0.2 μSv/MBq when the females were considered separately and the female model was applied for the calculation. The organ receiving the highest dose was the liver (17.9 ± 3.9 μSv/MBq), followed by the kidneys (14.3 ± 3.6 μSv/MBq) and the urinary bladder wall (13.5 ± 3.7 μSv/MBq). Conclusion: The estimated radiation doses for 11C-(+)-PHNO are similar to those reported for other radiotracers labeled with 11C. 11C-(+)-PHNO may be used for multiple PET scans in the same subject and remain within regulatory guidelines.