Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials.

An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59-0.87; P=<0.0001]) using a 5-point scale to assess [18F] labeled fluorodeoxyglucose metabolic activity in lymphomatous lesions. These results suggest an operationally practical 5-point scale workflow paradigm for potential use in larger clinical trials evaluating lymphoma therapeutics.

Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials.

In the era of personalized medicine, diagnostic approaches are helping pharmaceutical and biotechnology sponsors streamline the clinical trial process. Molecular assays and diagnostic imaging are routinely being used to stratify patients for treatment, monitor disease, and provide reliable early clinical phase assessments. The importance of diagnostic approaches in drug development is highlighted by the rapidly expanding global cancer diagnostics market and the emergent attention of regulatory agencies worldwide, who are beginning to offer more structured platforms and guidance for this area. In this paper, we highlight the key benefits of using companion diagnostics and diagnostic imaging with a focus on oncology clinical trials. Nuclear imaging using widely available radiopharmaceuticals in conjunction with molecular imaging of oncology targets has opened the door to more accurate disease assessment and the modernization of standard criteria for the evaluation, staging, and treatment responses of cancer patients. Furthermore, the introduction and validation of quantitative molecular imaging continues to drive and optimize the field of oncology diagnostics. Given their pivotal role in disease assessment and treatment, the validation and commercialization of diagnostic tools will continue to advance oncology clinical trials, support new oncology drugs, and promote better patient outcomes.

(99m)Tc hexamethyl-propylene-aminoxime single-photon emission computed tomography prediction of conversion from mild cognitive impairment to Alzheimer disease.

OBJECTIVE: To examine the utility of single-photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). DESIGN: Longitudinal, prospective study. SETTING: University-based memory disorders clinic. PARTICIPANTS: One hundred twenty seven patients with MCI and 59 healthy comparison subjects followed up for 1-9 years. MEASUREMENTS: Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, magnetic resonance imaging, and brain Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done. RESULTS: Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fisher's exact test p = 0.013). Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% confidence interval: 1.16-7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% confidence interval: 1.14-8.56, p = 0.027). In the 3-year follow-up sample, low parietal (p <0.05) and medial temporal (p <0.01) flow predicted conversion to AD, with or without controlling for age, Mini-Mental State Examination, and apolipoprotein E ε4 genotype. These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal, and entorhinal cortex volumes. CONCLUSIONS: SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.

F-18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis.

PURPOSE: The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers. METHOD: We compared the fluorine-18 fluorodeoxyglucose (F-18 FDG) PET brain scans of boxers (group) (N=19) with those of controls (group) (N=7) using both statistical parametric mapping and region of interest analysis. RESULTS: Boxers showed decreased F-18 FDG uptake by 8-15% in the following brain areas: posterior cingulate cortex, parieto-occipito, frontal lobes (Broca's area) bilaterally, and the cerebellum (P<0.005) as compared with controls. CONCLUSION: Our results suggest that F-18 FDG PET scans of boxers suspected of chronic traumatic brain injury show unique patterns of hypometabolism, and that these patterns may reflect the mechanisms of repeated traumatic brain injury unique to boxers.

Epilepsy duration impacts on brain glucose metabolism in temporal lobe epilepsy: results of voxel-based mapping.

OBJECTIVE: [(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE). METHODS: [(18)F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis. RESULTS: Forty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 +/- 12.3 years (3-46 years), <5 years in 10 patients and >or=10 years in 30 patients. Visual analysis of [(18)F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [(18)F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (>or=10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P < 0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P < 0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P < 0.05). CONCLUSION: Voxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE.

Interventional nuclear brain imaging.

Interventional nuclear brain imaging incorporates a variety of radiopharmaceutical techniques to enhance the functional assessment of the central nervous system. Many interventional nuclear brain imaging techniques initially were used in research protocols. In recent years, however, these same challenge paradigms are being increasingly applied with clinical imaging studies. At present, clinical interventional brain imaging techniques include pharmaceutical manipulations with drug administration or withdrawal, physical provocation, electrical stimulation, cognitive activation, and targeting of neurocircuitries with specific molecular receptor-ligand interactions. This review highlights how these approaches have resulted in more accurate measurement of regional cerebral metabolism, delineation of neurocircuitries, presurgical patient selection, and treatment management.

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

AIM: Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [11C]R121920 and [11C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1. METHODS: PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET. RESULTS: Both [11C]R121920 and [11C]DMP696 distributed rapidly and uniformly throughout the brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [(125)I]Tyr(0)-sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (Bmax) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded Bmax of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants (K(D)) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore, Bmax and K(D) were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. CONCLUSION: Neither [11C]R121920 nor [11C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography.

CONTEXT: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant. OBJECTIVES: To assess in vivo brain serotonin transporter binding potential (BP(1), proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: A sample of 18 medication-free patients with bipolar depression and 41 controls. MAIN OUTCOME MEASURES: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([(11)C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms. RESULTS: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP(1) in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP(1). CONCLUSIONS: Lower serotonin transporter BP(1) in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions.

Brain glucose supply and the syndrome of infantile neuroglycopenia.

OBJECTIVE: To describe neuroglycopenia as a specific syndrome caused by insufficient glucose availability during brain development. DESIGN: Neurologic examinations, neuropsychologic tests, biochemical methods, and functional imaging. PARTICIPANTS: Patients afflicted by genetic mutation of the cerebral glucose transporter type 1 and a patient afflicted by persistent infantile hypoglycemia (hyperinsulinism) matched to her healthy twin. RESULTS: The hallmark of the phenotype is the combination of infantile epilepsy and cerebellar and pyramidal tract dysfunction, together with permanent neuropsychologic abnormalities and reduced thalamocortical glucose uptake despite subsequent supply of energetic substrate. CONCLUSIONS: When neuroglycopenia-the lack of adequate glucose supply to the nervous system-occurs in the developing brain, thalamic and cortical metabolism mature aberrantly, causing epilepsy associated with other characteristic neurologic and behavioral disturbances, a pattern also reflected in functional images, as if there were a temporal window during which glucose were crucial for brain development. When maturation is complete, glucose merely serves as a fuel, and then, when deficient, it only causes unrelated disturbances.

Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates.

PURPOSE: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. METHODS: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. RESULTS: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT. CONCLUSION: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

In vivo assessment of [11C]MRB as a prospective PET ligand for imaging the norepinephrine transporter.

PURPOSE: Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter's role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates. METHODS: Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test-retest and blocking conditions using 1 mg/kg nisoxetine. RESULTS: MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine. CONCLUSION: Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.

In vitro and in vivo evaluation of [11C]MPEPy as a potential PET ligand for mGlu5 receptors.

Excessive activation via the metabotropic glutamate receptor subtype 5 (mGluR(5)) has been implicated in depression, neuropathic pain and other psychiatric, neurological and neurodegenerative diseases. A mGluR(5) radioligand for in vivo quantification by positron emission tomography (PET) would facilitate studies of the role of this receptor in disease and treatment. 3-Methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity antagonist at the mGluR(5) receptor was selected as a candidate ligand; a recent publication by Yu et al. [Nucl Med Biol 32 (2005) 631-640] presented initial micro-PET results for [(11)C]MPEPy with enthusiasm. Building on their efforts, we report as unique contributions (1) an improved chemical synthesis method, (2) the first data using human tissue, (3) phosphor images for rat brain preparations, (4) a novel comparison of anesthetic agents and (5) in vivo data in baboon. In vitro phosphor imaging studies of this ligand using human and rat brain tissue demonstrated high specific binding in the hippocampus, striatum and cortex with minimal specific binding in the cerebellum. In contrast, in vivo micro-PET studies in rats using urethane anesthesia, PET studies in baboons using isoflurane anesthesia and ex vivo micro-PET studies in unanesthetized rats each showed little specific binding in the brain. Despite the promising in vitro results, the low signal-to-noise ratio found in vivo does not justify the use of [(11)C]MPEPy as a PET radiotracer in humans.

Synthesis and in vivo evaluation of [O-methyl-11C](2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine as a 5-HT2A receptor PET ligand.

The serotonin2A (5-HT2A) receptor is implicated in the pathophysiology of schizophrenia and mood disorders, and in vivo studies of this receptor would be of value in studying the pathophysiology of these disorders and in measuring the relationship of clinical response to receptor occupancy for 5-HT2A antagonists such as atypical antipsychotics. Therefore, (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)-phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine (MPM) (13), a selective and high-affinity (K(i)=0.79 nM) 5HT2A antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-hydroxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine (12) with [11C]methyltriflate in order to determine the suitability of [11C]MPM to quantify 5-HT2A in living brain using PET. Desmethyl-MPM 12 and standard MPM were prepared, starting from 3-hydroxymethylphenol (2), in excellent yield. The yield obtained for radiolabeling was 40+/-5% (EOB), and the total synthesis time was 30 min at EOS. PET studies with [11C]MPM in baboon showed a distribution in the brain consistent with the known distribution of 5-HT2A receptors. The time-activity curves for the high-binding regions peaked at approximately 45 min after injection. Blocking studies with M100907 demonstrated not only 38-57% blocking of tracer binding in brain regions known to have 5-HT2A receptors but also 38% blocking in cerebellum, which has a low 5-HT2A receptor concentration. Although [11C]MPM exhibits appropriate kinetics in baboon for imaging 5-HT2A receptors, its specific binding in cerebellum and higher proportion of nonspecific binding limit its usefulness for the in vivo quantification of 5-HT2A receptors with PET.

Synthesis and in vivo evaluation of [11C]SN003 as a PET ligand for CRF1 receptors.

Synthesis and evaluation of [O-methyl-11C](4-methoxy-2-methylphenyl)[1-(1-methoxymethylpropyl)-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl]amine or [11C]SN003 ([11C]6), as a PET imaging agent for CRF1 receptors, in baboons is described. 4-[1-(1-Methoxymethylpropyl)-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4-ylamino]-3-methylphenol (5), the precursor molecule for the radiolabeling, was synthesized from 2,4-dichloro-6-methyl-3-nitropyridine in seven steps with 20% overall yield. The total time required for the synthesis of [11C]SN003 is 30 min from EOB using [11C]methyl triflate in the presence of NaOH in acetone. The yield of the synthesis is 22% (EOS) with >99% chemical and radiochemical purities and a specific activity of >2000 Ci/mmol. PET studies in baboon show that [11C]6 penetrates the BBB and accumulates in brain. No detectable specific binding was observed, likely due to the rapid metabolism or low density of CRF1 receptors in primate brain.

Synthesis, in vitro and in vivo evaluation of [O-methyl-11C] 2-{4-[4-(3-methoxyphenyl)piperazin-1-yl]-butyl}-4-methyl-2H-[1,2,4]-triazine-3,5-dione: a novel agonist 5-HT1A receptor PET ligand.

Synthesis and in vivo evaluation of 2-{4-[4-(3-methoxyphenyl)piperazin-1-yl]-butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (5 or MMT), a high affinity and selective serotonin 5-HT1AR agonist PET tracer, are described. GTPgammaS assay shows that MMT is an agonist with an EC50 comparable to 5-HT. Radiolabeling of 5 was achieved in 30% yield (EOS) from desmethyl-MMT (4) with >99% chemical and radiochemical purities and a specific activity >1000 Ci/mmol. PET studies in baboon show that [11C]5 penetrates the blood-brain barrier but, because of low specific binding and fast clearance of radioactivity it is not a suitable PET tracer for the in vivo quantification of 5-HT1AR.

Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin- 1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand.

Antagonist 5-HT(1A) PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-(11)C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (10), a potential high affinity (K(i) = 1.36 nM) 5-HT(1A) agonist PET tracer is described. Piperazine 10 is a 5-HT(1A) agonist with an EC(50) comparable to serotonin, based on cAMP formation and GTP(gamma)S binding assays. Radiosynthesis of [(11)C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [(11)C]CH(3)OTf in 25 +/- 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [(11)C]10 were >99% with a specific activity 1500 +/- 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [(11)C]10 specific binding in brain regions rich in 5-HT(1A) receptors. Binding of [(11)C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V(T)) of [(11)C]10 in baboon correlate with [(11)C]WAY100635 V(T) in baboons. These data provide evidence that [(11)C]10 is the first promising agonist PET tracer for the 5-HT(1A) receptors.

Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain.

OBJECTIVE: The authors examined effects of a triallelic functional polymorphism of the human serotonin-transporter-linked promoter region (5-HTTLPR) on in vivo expression of serotonin transporter in the brain in healthy volunteers and subjects with major depressive disorder. METHOD: Twenty-five medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and 42 healthy volunteers were clinically evaluated and genotyped. Serotonin transporter binding potential (f(1)B(max)/K(d)) was determined by using positron emission tomography with the radiotracer [(11)C]McN 5652 and metabolite-corrected arterial input functions. RESULTS: There was no difference in serotonin transporter binding potential by genotype in healthy volunteers or in subjects with major depressive disorder. Allelic frequencies did not differ between subjects with major depressive disorder and healthy volunteers. CONCLUSIONS: Associations of the 5-HTTLPR polymorphism to clinical phenotypes appear to be due to developmental effects of 5-HTTLPR on expression and not due to its direct effect on serotonin transporter binding in adulthood.

Lower serotonin transporter binding potential in the human brain during major depressive episodes.

OBJECTIVE: CSF analysis, neuroendocrine challenges, serotonin depletion studies, and treatment studies implicate the serotonergic system in the pathophysiology of major depressive disorder. On the basis of postmortem and imaging studies, the authors hypothesized that subjects with major depressive disorder in a major depressive episode have fewer serotonin transporter sites, compared with healthy subjects. METHOD: Serotonin transporter binding potential (f(1)B(max)/K(d)) was determined using positron emission tomography with [(11)C]McN 5652 in six brain regions in 25 medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and in 43 healthy volunteer comparison subjects. All subjects had arterial lines placed to determine metabolite-corrected arterial input functions. RESULTS: Serotonin transporter binding potential differed significantly by brain region and group. Post hoc analysis revealed lower binding potential in subjects with major depressive disorder, relative to the comparison subjects, in the amygdala and midbrain. The lower binding potential was more pronounced in the depressed subjects who had never received antidepressants. No correlation was found between binding potential in the midbrain and severity of depression or number of days without medication. Binding potential did not differ between suicide attempters and nonattempters. CONCLUSIONS: Subjects in a major depressive episode have lower serotonin transporter binding potential in the amygdala and midbrain, compared to healthy subjects.

Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study.

BACKGROUND: Serotonin 1A receptors (5-HT(1A)) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT(1A) and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT(1A) G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT(1A) than healthy volunteers (controls). We measure 5-HT(1A) in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. METHODS: Genotyped and determined 5-HT(1A) binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. RESULTS: No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. CONCLUSIONS: AN have higher 5-HT(1A) than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT(1A) receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT(1A).