Synthesis and biological evaluation of novel (123)I-labeled 4-(4-iodophenyl)butanoyl-L-prolyl-(2S)-pyrrolidines for imaging prolyl oligopeptidase in vivo.

Prolyl oligopeptidase (POP) may be associated with neuromodulation and development of neurodegenerative diseases and it was recently shown to participate in the inflammatory cascade along with matrix metalloproteinases. Radiotracers, which can be used for non-invasive imaging, are needed for investigating the role of POP in normal physiology and in pathophysiological conditions in vivo. We synthesized two novel POP-specific (123)I-radiolabeled 4-phenylbutanoyl-L-prolyl-pyrrolidines of which 4-(4-[(123)I]iodophenyl)butanoyl-L-prolyl-2(S)-cyanopyrrolidine ([(123)I]2f, Ki = 4.2 nM) was selected. The selected compound has an electrophilic cyano group that is known to increase the dissociation time of POP inhibitors. [(123)I]2f was synthesized in high radiochemical yield and purity (87 ± 4%, >99%, respectively) and with a specific activity of 456 ± 98 GBq/µmol. [(123)I]2f was evaluated in healthy mice (C57Bl/6JRccHsd) by ex vivo biodistribution studies and SPECT imaging. Pretreatment with the known inhibitor 4-phenylbutanoyl-L-prolyl-(2S)-cyanopyrrolidine (KYP-2047, 2d, Ki = 0.023 nM) showed that binding of [(123)I]2f was POP specific. In addition, [(123)I]2f was evaluated in models of neuroinflammation and acute localized inflammation. A minor increase in binding of [(123)I]2f was observed in the inflamed region in the acute localized inflammation model. Similar increase in binding was not observed in the neuroinflammation model.

Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. METHODOLOGY/PRINCIPAL FINDINGS: We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. CONCLUSIONS/SIGNIFICANCE: Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.

Synthesis and biological evaluation of 6/7-exo-methyl-3beta-(4-iodo)phenyltropane-2beta-carboxylic acid methyl esters.

6beta/7beta-Methyl-2-methoxycarbonyltropinones (3a, 3b) were synthesized and used as starting materials in the synthesis of 6beta/7beta-methyl-2beta-methoxycarbonyl-3beta-phenyltropanes (6a, 6b), 6beta/7beta-methyl-2beta-methoxycarbonyl-3beta-(4-iodo)phenyltropanes (7a, 7b) and 6beta-methyl-2beta-methoxycarbonyl-3beta-(4-iodo)phenylnortropane (8). The effect of 6/7-groups was evaluated by in vitro receptor binding to dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters. Introduction of a methyl group at the 6- or 7-position diminished the overall affinity for the transporters, though mostly to NET. In vivo locomotor tests were performed in mice for compounds 7a and 8. Compound 8 had no apparent effect on locomotor activity. Compound 7a increased locomotion in a wide dose range, but was much less potent than a reference compound, 2beta-carbomethoxy-3beta-(4-iodo)phenyl-tropane (beta-CIT).

Treatment improves serotonin transporter binding and reduces binge eating.

RATIONALE: Serotonin (5-HT) is involved in the control of eating behaviour by inhibiting food intake. Obese women with binge-eating disorder (OB-BED) were recently found to have reduced 5-HT transporter binding. OBJECTIVES: The aim of this study was to investigate the effect of a successful treatment on 5-HT transporters in OB-BED. METHODS: The 5-HT transporter binding of seven OB-BED was measured by single-photon emission computed tomography (SPECT), by using iodine-123-labelled nor-beta-CIT as a tracer, before treatment and after successful treatment, when the OB-BED were asymptomatic. Treatment consisted of group psychotherapy and fluoxetine medication. The control subjects, six obese women without eating disorders, were also studied twice by using SPECT. RESULTS: The 5-HT transporter binding of the symptomatically recovered OB-BED increased significantly (24+/-22%) after treatment, whereas in the control group, binding remained unchanged. CONCLUSIONS: The results tentatively suggest that 5-HT transporter binding in OB-BED is an adaptive mechanism, which can be affected by treatment. Furthermore, there seems to be a link between improved 5-HT transporter binding and reduced binge eating.

Biodistribution and radiation dosimetry of [123I]ADAM in healthy human subjects: preliminary results.

[(123)I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)] has recently been shown to be a very promising imaging ligand for the detection of serotonin transporters (SERT) in human brain, because of its high specificity for SERT. [(123)I]ADAM has previously been used only for animal studies. In this work, we investigated the radiation dosimetry and biodistribution of [(123)I]ADAM based on whole-body scans in healthy human volunteers. Following the administration of 196+/-20 MBq (range 157-220 MBq) [(123)I]ADAM, serial whole-body images were performed up to 24 h. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve source organs were considered in estimating absorbed radiation doses for organs of the body. The highest absorbed organ doses were found to the lower large intestine wall (8.3.10(-2) mGy/MBq), kidneys (5.2.10(-2) mGy/MBq), urinary bladder wall (4.9.10(-2) mGy/MBq) and thyroid (4.3.10(-2) mGy/MBq). The effective dose was estimated to be 2.2.10(-2) mSv/MBq. The results suggest that [(123)I]ADAM is of potential value as a tracer for single-photon emission tomography imaging of serotonin receptors in humans, with acceptable dosimetry and high brain uptake.