EXAMINATION OF 4 I-123 LABELED PIPERIDINE-BASED SIGMA-RECEPTOR LIGANDS AS POTENTIAL MELANOMA IMAGING AGENTS - INITIAL STUDIES IN MOUSE-TUMOR MODELS

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 tu mor cell lines express sigma receptors, including malignant melanoma a nd tumors of the colon, lung, brain, breast and testes, To provide pot ential probes for the in vivo SPECT examination of sigma receptor dens ities, we have synthesized a series of halogenated 4-(phenoxymethyl)pi peridines and related compounds as high affinity sigma receptor ligand s. 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 ac tivities >74,000 MBq/mu mol were obtained. Radiochemical yields were 5 5-83% EOS and radiochemical purities were >98%. All four tracers were initially screened in vivo using distribution studies in nude mice wit h B16 melanoma tumors (8-12 mm diameter in the flank), In all four stu dies, 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 exhi bited for as long as 48 h post injection (PI). In the B16 melanoma mod el, the most promising results were obtained with 1-(2-hydroxyethyl)-4 -(iodophenoxymethyl)piperidine (I-123-3), for which tumor/tissue ratio s were significantly > 1.0 by 4 h PI for most organs and increased the reafter. Tumor/tissue ratios at 48 h were as follows: blood, 68.4; mus cle 31.7; brain, 7.4; lung, 6.3; liver, 1.3. In subsequent studies, I- 123-3 was evaluated in nude mice with A375 human malignant melanoma. A s in the B16 model, high uptake and prolonged retention of radioactivi ty in tumor tissues was noted. These results indicate that I-123-3 sho ws promise as a SPECT ligand for the detection of malignant melanoma. (C) 1997 Elsevier Science Inc.