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4-([(18)F]fluoro)benzoyl-neurotensin(8-13) ((18)FB-Arg(8)-Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 1) and two analogs stabilized in one and two positions ((18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 2, (18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)-Tle(12)-Leu(13)-OH, 3) were synthesized in a radiochemical yield of 25-36% and a specific activity of 5-15 GBq/mmol. The peptides were evaluated in vitro and in vivo for their potential to image tumors overexpressing neurotensin receptor 1 (NTR1) by positron emission tomography (PET). All analogs exhibited in vitro binding affinity in the low nanomolar range to NTR1-expressing human tumors, measured by quantitative receptor autoradiography, HT-29 and WiDr cells, and to sections of tumors derived from these cell lines in mice. The radiotracers were internalized in the cells in vitro, and the fluorinated peptides were able to mobilize intracellular Ca(2+) of WiDr cells. In in vivo studies in rats and in mice bearing HT-29 cell tumors, only a moderate uptake of the radioligands into the studied tumors was observed, presumed to be due to degradation in vivo and fast elimination by the kidneys. In comparison with the other analogs, the specific tumor uptake expressed as tumor-to-muscle relation was highest for the radioligand 3. The blood clearance of 3 was reduced by co-injection of peptidase inhibitors. The catabolic pathways of the radiofluorinated peptides were elucidated. The results suggest that the high binding affinity to NTR1 and the stabilization against proteolytic degradation are not yet sufficient for tumor imaging by PET.

Parameters studies revealed that successful labeling of DTPA-Neurotensin(8-13) analogues depend on several physico-chemical parameters. The pH of the reaction mixture seemed to be the most critical parameter for obtaining high labeling yields; quantitative radiolabelling was only guaranteed at a pH between 4.2 and 5.5. At a pH of 4.5, metal ion contaminants originating from peptide synthesis and purification procedures were shown not to effect radiolabelling. Nevertheless, proper reducing agents were included in a proposed Kit labeling procedure in order to avoid potential competition from trivalent metal ion contamination, and thus guarantee successful 111In-complexation. The complexing capacity of DTPA for radioactive In(3+) strongly depends upon the pH. As a consequence, labeling yields must be expressed as [[K(ass) x alpha(4) x [DTPA-NT](0)/(1+ K(ass) x alpha(4) x [DTPA-NT](0))], to where K(ass) is the association constant and alpha(4) is a pH dependent correction factor of the association constant.

5-HT2A receptors have been implicated in the pathophysiology of mood disorders and in the therapeutic effect of the so-called atypical antipsychotics. Recently, a new radioiodinated ligand with high affinity and selectivity for serotonin 5-HT2A receptors, 123iodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl] 5-iodo-2-methoxybenzamide (123I-5-I-R91150), has been developed and has been shown to be suitable for single-photon emission tomography (SPET) imaging. In this study the influence of age and gender on the ligand binding was investigated in normal volunteers. One hundred and fifty MBq of 123I-5-I-R91150 was administered to 26 normal volunteers (13 females and 13 males) with an age range of 23-60 years. SPET imaging was performed with a triple-headed gamma camera. For semi-quantitative analysis, ratios of ligand binding in different regions of interest to the binding in the cerebellum were calculated. Mean ratios of 1.7 were obtained. No gender difference was demonstrated. 5-HT2A binding was shown to decline with age. Over an age range of 40 years a reduction in ligand binding of 42% +/- 7% was found. These results are in agreement w in vitro and positron emission tomography findings of a decline in 5-HT2A receptor binding with age. The findings confirm the suitability of 123I-5-I-R91150 for SPET imaging of 5-HT2A receptors, and highlight the necessity for age-matched controls in clinical studies.

The uptake of iodine-123 alpha-methyl-l-tyrosine (IMT) in the primary tumours and metastatic lymph nodes of squamous cell carcinoma of the head and neck was examined with single-photon emission tomography (SPET). Eleven patients with biopsy-proven carcinomas were studied prior to any therapeutic action. The evaluation of cervical lymph node involvement was based on the findings of physical examination, computed tomography and magnetic resonance imaging, and in six patients on the histological data relating to tissue samples obtained by fine-needle lymph node aspiration or surgical intervention. SPET imaging was performed 10 min after the injection of 130-170 MBq IMT using a triple-head gamma camera equipped with medium-energy collimators. High-quality IMT SPET depicted the primary tumour in 10 of 11 patients (sensitivity: 91%). Tumours located in the larynx were visualized more clearly than those located in the mouth or oropharynx. The mean tumour-to-background ratio was 2.35 (range: 1.6-3.1) for laryngeal tumours and 1.67 (range: 1.2-2.2) for mouth and oropharyngeal tumours. Metastatic cervical lymph nodes were involved to various degrees in 8 of the 11 patients. Among these eight patients there were 16 sites, nine of which were detected by IMT SPET (sensitivity: 56%). If the IMT SPET findings were recorded per side of the neck, the sensitivity was 64%. Five of the seven missed metastatic lymph nodes were smaller than 15 mm. The mean tumour-to-background ratio of the scintigraphically visualized lymph nodes was 1.81+/-0.51 (range: 1.39-2.77). Asymmetric physiological submandibular salivary gland IMT uptake led to false-positive lymph node assessment in three patients. This study indicates the potential use of IMT SPET as a metabolic imaging modality in patients with head and neck squamous cell carcinoma.