A Remarkable Difference in Pharmacokinetics of Fluorinated Versus Iodinated Photosensitizers Derived from Chlorophyll-a and a Direct Correlation between the Tumor Uptake and Anti-Cancer Activity.

To investigate and compare the pharmacokinetic profile and anti-cancer activity of fluorinated and iodinated photosensitizers (PSs), the 3-(1'-(o-fluorobenzyloxy)ethyl pyropheophorbide and the corresponding meta-(m-) and para (p-) fluorinated analogs (methyl esters and carboxylic acids) were synthesized. Replacing iodine with fluorine in PSs did not make any significant difference in fluorescence and singlet oxygen (a key cytotoxic agent) production. The nature of the delivery vehicle and tumor types showed a significant difference in uptake and long-term cure by photodynamic therapy (PDT), especially in the iodinated PS. An unexpected difference in the pharmacokinetic profiles of fluorinated vs. iodinated PSs was observed. At the same imaging parameters, the fluorinated PSs showed maximal tumor uptake at 2 h post injection of the PS, whereas the iodinated PS gave the highest uptake at 24 h post injection. Among all isomers, the m-fluoro PS showed the best in vivo anti-cancer activity in mice bearing U87 (brain) or bladder (UMUC3) tumors. A direct correlation between the tumor uptake and PDT efficacy was observed. The higher tumor uptake of m-fluoro PS at two hours post injection provides a solid rationale for developing the corresponding 18F-agent (half-life 110 min only) for positron imaging tomography (PET) of those cancers (e.g., bladder, prostate, kidney, pancreas, and brain) where 18F-FDG-PET shows limitations.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3 weeks on-treatment and 1 week off-treatment for a period of 13 weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

Alcohol binge drinking decreases brain glucose metabolism and functional connectivity in adolescent rats.

Alcohol misuse represents a serious health concern, especially during adolescence, with approximately 18% of high school students engaging in binge drinking. Despite widespread misuse of alcohol, its effects on how the brain functions is not fully understood. This study utilized a binge drinking model in adolescent rats to examine effects on brain function as measured by brain glucose metabolism (BGluM). Following an injection of [18 FDG] fluro-2-deoxy-D-glucose, rats had voluntary access to either water or various concentrations of ethanol to obtain the following targeted doses: water (no ethanol), low dose ethanol (0.29 ± 0.03 g/kg), moderate dose ethanol (0.98 ± 0.05), and high dose ethanol (2.19 ± 0.23 g/kg). Rats were subsequently scanned using positron emission tomography. All three doses of ethanol were found to decrease BGluM in the restrosplenial cortex, visual cortex, jaw region of the somatosensory cortex, and cerebellum. For both the LD and MD ethanol dose, decreased BGluM was seen in the superior colliculi. The MD ethanol dose also decreased BGluM in the subiculum, frontal association area, as well as the primary motor cortex. Lastly, the HD ethanol dose decreased BGluM in the hippocampus, thalamus, raphe nucleus, inferior colliculus, and the primary motor cortex. Similar decreases in the hippocampus were also seen in the LD group. Taken together, these results highlight the negative consequences of acute binge drinking on BGluM in many regions of the brain involved in sensory, motor, and cognitive processes. Future studies are needed to assess the long-term effects of alcohol binge drinking on brain function as well as its cessation.

Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a.

We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors.

Preclinical studies with JAA-F11 anti-Thomsen-Friedenreich monoclonal antibody for human breast cancer.

AIM: The Thomsen-Friedenreich antigen (TF-Ag) is a disaccharide hidden on normal cells, but selectively exposed on the surface of breast, colon, prostate and bladder cancer cells. JAA-F11, a highly specific monoclonal antibody to TF-Ag, reduces metastasis and prolongs survival in a mouse model. In addition,(124)I-JAA-F11 localizes 4T1 tumors in mice. These studies continue translation of JAA-F11 to human breast cancer. MATERIALS & METHODS & RESULTS: Of the 41 human breast cancer cell lines tested, 78% were positive for reactivity with JAA-F11 by whole-cell enzyme immunoassay and positivity occurred unrelated to estrogen, progesterone or HER2 receptor status. JAA-F11 inhibited the growth rate of the human cancer cell lines tested. At 1 h, approximately 80% of JAA-F11 internalized in the three cell lines tested. (124)I-JAA-F11 specifically imaged human triple-negative tumors in mice by microPET. CONCLUSION: The results highlight the potential that humanized JAA-F11 may have for immunotherapy and drug conjugate therapy in breast cancer patients.

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

Exercise Modifies the Brain Metabolic Response to Chronic Cocaine Exposure Inhibiting the Stria Terminalis.

It is well known that exercise promotes health and wellness, both mentally and physiologically. It has been shown to play a protective role in many diseases, including cardiovascular, neurological, and psychiatric diseases. The present study examined the effects of aerobic exercise on brain glucose metabolic activity in response to chronic cocaine exposure in female Lewis rats. Rats were divided into exercise and sedentary groups. Exercised rats underwent treadmill running for six weeks and were compared to the sedentary rats. Using positron emission tomography (PET) and [18F]-Fluorodeoxyglucose (FDG), metabolic changes in distinct brain regions were observed when comparing cocaine-exposed exercised rats to cocaine-exposed sedentary rats. This included activation of the secondary visual cortex and inhibition in the cerebellum, stria terminalis, thalamus, caudate putamen, and primary somatosensory cortex. The functional network of this brain circuit is involved in sensory processing, fear and stress responses, reward/addiction, and movement. These results show that chronic exercise can alter the brain metabolic response to cocaine treatment in regions associated with emotion, behavior, and the brain reward cascade. This supports previous findings of the potential for aerobic exercise to alter the brain's response to drugs of abuse, providing targets for future investigation. These results can provide insights into the fields of exercise neuroscience, psychiatry, and addiction research.

Unpredictable chronic mild stress differentially impacts resting brain glucose metabolism in fatty acid-binding protein 7 deficient mice.

Fatty acid-binding proteins (FABPs) are intracellular chaperone proteins involved in the trafficking of n-3 polyunsaturated fatty acids and endocannabinoids. Inhibiting two of the main FABP subtypes found in the brain (FABP5 and FABP7) hinders endocannabinoid uptake and hydrolysis. Prior data indicates that cannabinoid receptor stimulation can ameliorate the consequences associated with chronic stress. To this end, FABP expression may play a similar role in response to stressful conditions. Male C57BL/6 J (WT) and FABP7 knockout (KO) mice were assigned to either a non-stress cohort or an unpredictable chronic mild stress (UCMS) cohort for a period of 4 weeks. Immediately after 4 weeks, mice were injected with [18F]2-fluoro-2-deoxy-d-glucose (FDG) and scanned using micro positron emission tomography (mPET) to examine brain glucose metabolism (BGluM). WT mice exposed to UCMS showed reduced BGluM in striatal, cortical, and hypothalamic regions and showed increased BGluM in the hippocampus, thalamus, periaqueductal gray, superior colliculi, inferior colliculi, and cerebellum. In contrast, there were limited effects of UCMS on BGluM in FABP7 KO mice, with a reduction in the thalamus, periaqueductal gray, and superior colliculi. These findings provide novel insight into FABP7 expression and indicate this gene to play an important role in response to aversive stimuli.

Chronic treatment and abstinence from methylphenidate exposure dose-dependently changes glucose metabolism in the rat brain.

Methylphenidate (MP) is extensively prescribed for attention deficit hyperactivity disorder (ADHD). While MP is effective in ameliorating symptoms of ADHD, MP is also used illicitly among healthy subjects without ADHD for cognitive-enhancing purposes. The deleterious consequences associated with long-term MP use as well as its cessation on brain activity remains to be understood. To address this, we administered either water, low dose MP (LD MP), or high dose MP (HD MP) to healthy adolescent Sprague Dawley rats, with five days on the treatment and two days off for thirteen consecutive weeks. Rats were then abstinent from their respective treatments for four weeks. Using positron emission tomography (PET) and fluorodeoxyglucose [18F] (FDG), we scanned rats at three time points: after thirteen weeks of treatment, after one week of abstinence, and after four weeks of abstinence. After thirteen weeks of LD and HD MP treatment, increases in brain glucose metabolism (BGluM) were seen in several cortical and subcortical regions associated with sensory and motor functions as well as learning and memory. One-week abstinence from LD MP treatment promoted increased BGluM compared to both water treated and HP MP treated groups. After four weeks of abstinence, little group differences were seen. Longitudinally, we observed contrasting differences on BGluM depending on whether a LD or HD of MP was administered. Our results demonstrate that MP treatment during adolescence can significantly alter BGluM. Moreover, these changes in brain activity do not subside in many areas of the brain after both one and four-week drug abstinence.

11C-meta-hydroxyephedrine defects persist despite functional improvement in hibernating myocardium.

BACKGROUND: Regional cardiac sympathetic nerve dysfunction develops in hibernating myocardium and may play a role in its association with sudden cardiac death. Interventions to improve cardiac function (i.e., revascularization) improve survival, but the potential reversibility of sympathetic nerve dysfunction remains unclear. METHODS AND RESULTS: Pigs (n = 11) were chronically instrumented with a proximal left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium. Prior to therapeutic interventions, there was LAD occlusion with collateral-dependent myocardium, reduced regional function (echocardiographic LAD wall-thickening 23% +/- 4% vs 83% +/- 6% in Remote, P < .001), and large defects in (11)C-meta-hydroxyephedrine (HED) PET (48% +/- 4% of LV area, 26% +/- 2% integrated reduction). Successful PCI or pravastatin therapy improved regional (LAD wall-thickening 23% +/- 4% to 42% +/- 6%, P < .05) and global LV function (fractional shortening 24% +/- 2% to 31% +/- 2%, P < .01), but did not alter regional HED uptake, retention, defect size, or defect severity. CONCLUSIONS: Despite significant functional improvement of hibernating myocardium as a result of PCI or pravastatin therapy, there were no changes in HED defect size or severity. Thus, inhomogeneity in myocardial sympathetic innervation persisted, and the lack of plasticity suggests that even in the absence of significant infarction, structural rather than functional defects are responsible for reduced myocardial norepinephrine uptake in chronic ischemic heart disease.

Highlights on the imaging (nuclear/fluorescence) and phototherapeutic potential of a tri-functional chlorophyll-a analog with no significant toxicity in mice and rats.

Herein we report the positron emission tomography (PET) imaging potential of a 124I-labeled radiopharmaceutical (PET-ONCO). In tumored mice, it shows high uptake in a variety of tumors: brain (GL261, U87), Colon (Colon26), lung (Lewis lung), breast (4 T1), bladder (UMUC3), pancreas (PANC-1) implanted in mice. This agent also shows promise for imaging associated metastatic disease (breast to lung, to bone). Interestingly, the iodinated compound derived from chlorophyll-a, in combination with the corresponding 124I-analog, can serve as a dual imaging agent (PET/fluorescence, complimentary to each other), with an option of photodynamic therapy (PDT). In contrast to Fluorine-18 (half-life 110 min), the Iodine-124 radionuclide has a physical half-life of roughly 4 days. Thus, unlike 18F-FDG, PET-ONCO can be transported longer distances. While the time for optimal tumor-uptake was observed at 24 h, improved tumor contrasts of both primary and metastasis were obtained at 48 and 72 h post- injection (i. v.) of PET-ONCO. In both mice and rats at a single dose study, PET-ONCO did not show any organ toxicity.

Compared to purpurinimides, the pyropheophorbide containing an iodobenzyl group showed enhanced PDT efficacy and tumor imaging (124I-PET) ability.

Two positional isomers of purpurinimide, 3-[1'-(3-iodobenzyloxyethyl)] purpurin-18-N-hexylimide methyl ester 4, in which the iodobenzyl group is present at the top half of the molecule (position-3), and a 3-(1'-hexyloxyethy)purpurin-18-N-(3-iodo-benzylimide)] methyl ester 5, where the iodobenzyl group is introduced at the bottom half (N-substitued cyclicimide) of the molecule, were derived from chlorophyll-a. The tumor uptake and phototherapeutic abilities of these isomers were compared with the pyropheophorbide analogue 1 (lead compound). These compounds were then converted into the corresponding 124I-labeled PET imaging agents with specific activity >1 Ci/micromol. Among the positional isomers 4 and 5, purpurinimide 5 showed enhanced imaging and therapeutic potential. However, the lead compound 1 derived from pyropheophorbide-a exhibited the best PET imaging and PDT efficacy. For investigating the overall lipophilicity of the molecule, the 3-O-hexyl ether group present at position-3 of purpurinimide 5 was replaced with a methyl ether substituent, and the resulting product 10 showed improved tumor uptake, but due to its significantly higher uptake in the liver, spleen, and other organs, a poor tumor contrast in whole-body tumor imaging was observed.

Expression of HMP/AN2, a melanoma associated antigen, in murine cerebral gliomas: potential for radioimmunotargeting.

Human melanoma proteoglycan (HMP), a melanoma-associated antigen, is expressed in both human melanomas and gliomas. We used HMP-specific monoclonal antibody (mAb) VT68.2 to investigate whether murine GL261 cerebral gliomas express the HMP homologue AN2 and to determine whether AN2 could be targeted for selective delivery of radiation in vivo. HMP-specific mAb VT68.2 stained murine GL261 glioma cells grown in culture and intracerebrally in syngeneic C57BL/6 mice. Positron emission tomography with radiolabeled mAb VT68.2 showed high-contrast, positive images of gliomas against a negative background. At 96 h after injection, glioma uptake of radiolabeled mAb VT68.2 was 10x greater than that of the isotype control mAb and 20x greater than that detected in normal cerebral tissue. Our results show murine GL261 cerebral gliomas express AN2 and HMP-specific mAb VT68.2 accumulates selectively and specifically at high concentration and is retained within murine cerebral gliomas. Thus, HMP is a potential target for antibody-mediated selective delivery of radiation to cerebral gliomas in vivo.

A Pyropheophorbide Analogue Containing a Fused Methoxy Cyclohexenone Ring System Shows Promising Cancer-Imaging Ability.

Herein we report the synthesis, photophysical properties, positron emission tomography (PET) imaging and photodynamic therapy (PDT) efficacy of methyl 3-(1'-m-iodobenzyloxy)ethyl-3-devinyl-verdin 4 (with or without the 124 I isotope). The PET imaging ability and ex vivo biodistribution of [124 I]4 were compared with the well-studied methyl [3-(124 1'-m-iodobenzyloxy)ethyl]-3-devinyl-pyropheophorbide-a methyl ester (PET-ONCO or [124 I]2) and [18 F]fluorodeoxyglucose ([18 F]FDG) in BALB/c mice bearing colon-26 tumors. Whole-body PET images of [124 I]4 containing a fused methoxy cyclohexenone ring system showed excellent tumor contrast with time (72>48>24 h post-injection). Ex vivo biodistribution results indicate that relative to the current clinical standard [18 F]FDG and [124 I]2 in 2 % ethanol formulation, [124 I]4, at the same radioactive dose (25 µCi per mouse), showed higher tumor uptake at 24 h post-injection and longer tumor retention. In biological environments, compound 4 showed lower fluorescence and lower singlet oxygen yield than 2, which is possibly due to higher aggregation caused by the presence of a fused cyclohexenone ring system, resulting in limited in vitro/in vivo PDT efficacy. Therefore, the chlorophyll-a analogue [124 I]4 provides easy access to a novel PET imaging agent (with no skin phototoxicity) to image cancer types-brain, renal carcinomas, pancreas-in which [18 F]FDG shows limitations.

Epidermal Growth Factor Receptor-Targeted Multifunctional Photosensitizers for Bladder Cancer Imaging and Photodynamic Therapy.

The in vitro and in vivo anticancer activity of iodinated photosensitizers (PSs) with and without an erlotinib moiety was investigated in UMUC3 [epidermal growth factor (EGFR)-positive] and T24 (EGFR-low) cell lines and tumored mice. Both the erlotinib-conjugated PSs 3 and 5 showed EGFR target specificity, but the position-3 erlotinib-PS conjugate 3 demonstrated lower photodynamic therapy efficacy than the corresponding non-erlotinib analogue 1, whereas the conjugate 5 containing an erlotinib moiety at position-17 of the PS showed higher tumor uptake and long-term tumor cure (severe combined immunodeficient mice bearing UMUC3 tumors). PS-erlotinib conjugates in the absence of light were ineffective in vitro and in vivo, but robust apoptotic and necrotic cell death was observed in bladder cancer cells after exposing them to a laser light at 665 nm. In contrast to 18F-fluorodeoxyglucose, a positron emission tomography agent, the position-17 erlotinib conjugate (124I-analogue 6) showed enhanced UMUC3 tumor contrast even at a low imaging dose of 15 µCi/mouse.

Tumor immunolocalization using 124 I-iodine-labeled JAA-F11 antibody to Thomsen-Friedenreich alpha-linked antigen.

Clinical immunolocalization has been attempted by others with an anti-Thomsen-Friedenreich antigen (TF-Ag) mAb that bound both alpha- and beta-linked TF-Ag. In this report, 124 I-labeled mAb JAA-F11 specific for alpha-linked TF-Ag showed higher tumor specificity in in vivo micro-positron emission tomography (micro-PET) of the mouse mammary adenocarcinoma line, 4T1, showing no preferential uptake by the kidney. Labeled product remained localized in the tumor for at least 20 days. Glycan array analysis showed structural specificity of the antibody.

Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.

Optimization of 124I production via 124Te(p,n)124I reaction.

(124)I was produced, via (124)Te(p,n)(124)I reaction, in greater than 3.7GBq (100 mCi, EOB) amount by bombarding (124)TeO(2) targets at 24 microA current for about 8h. This was achieved by keeping the target at 37 degrees relative to the beam during irradiation, by sweeping the beam across the target and by keeping the incident energy of the proton at 14.1MeV. The time-averaged yield of our 8h run was 21.1 MBq/microAh (0.57 mCi/microAh), which was 90% of the theoretical yield calculated using thick target yield data obtained from the reported excitation function for the reaction. At the end of bombardment, the level of (125)I and (126)I impurities, co-produced with (124)I, were 0.03% and 0.007%, respectively.

Multimodality agents for tumor imaging (PET, fluorescence) and photodynamic therapy. A possible "see and treat" approach.

Methyl 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a derivative), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophilic aromatic iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addition to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analogue of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 micromol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (lambda(max) 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.

Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand (11)C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.