title: Examination of four 123I-labeled piperidine-based sigma receptor ligands as potential melanoma imaging agents: initial studies in mouse tumor models.
abstract: The development of sigma (sigma) receptor radioligands has become the focus of research over the past few years due to their potential uses in nuclear medicine. It has been shown that a wide variety of human tumor cell lines express sigma receptors, including malignant melanoma and tumors of the colon, lung, brain, breast and testes. To provide potential probes for the in vivo SPECT examination of sigma receptor densities, we have synthesized a series of halogenated 4-(phenoxymethyl)piperidines and related compounds as high affinity sigma receptor ligands. Four of these have been labeled with I-123 and evaluated in vivo in mouse tumor models. All four radioligands were synthesized no-carrier-added using oxidative radioiododestannylation methods and specific activities > 74,000 MBq/mumol were obtained. Radiochemical yields were 55-83% EOS and radiochemical purities were > 98%. All four tracers were initially screened in vivo using distribution studies in nude mice with B16 melanoma tumors (8-12 mm diameter in the flank). In all four studies, high uptake (up to 0.90 +/- 0.42 %ID, 12.99 +/- 4.28 %ID/g at 48 h) and excellent retention of radioactivity in tumor tissues was exhibited for as long as 48 h post-injection (PI). In the B16 melanoma model, the most promising results were obtained with [123I]-1-(2-hydroxyethyl)-4-(iodophenoxymethyl)piperidine (123I-3), for which tumor/tissue ratios were significantly > 1.0 by 4 h PI for most organs and increased thereafter. Tumor/tissue ratios at 48 h were as follows: blood, 68.4; muscle 31.7; brain, 7.4; lung, 6.3; liver, 1.3. In subsequent studies, 123I-3 was evaluated in nude mice with A375 human malignant melanoma. As in the B16 model, high uptake and prolonged retention of radioactivity in tumor tissues was noted. These results indicate that 123I-3 shows promise as a SPECT ligand for the detection of malignant melanoma.
authors.affiliation: Radiopharmaceuticals Division, Australian Nuclear Science and Technology Organisation, N.S.W, Australia.
authors.forename: R N
authors.initials: RN
authors.lastname: Waterhouse
authors.forename: J
authors.initials: J
authors.lastname: Chapman
authors.forename: B
authors.initials: B
authors.lastname: Izard
authors.forename: A
authors.initials: A
authors.lastname: Donald
authors.forename: K
authors.initials: K
authors.lastname: Belbin
authors.forename: J C
authors.initials: JC
authors.lastname: O'Brien
authors.forename: T L
authors.initials: TL
authors.lastname: Collier
mesh_terms: D000818:Animals; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging*; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000032:analysis*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D007457:Iodine Radioisotopes; D010880:Piperidines; D017480:Receptors, sigma