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A series of iodinated thiadiazolyltetrahydro-1-methyl-pyridine (TZTP) compounds was synthesized and evaluated in vitro and in vivo as potential radioligands for imaging of the muscarinic M2 receptor subtype with SPET. One of these compounds, 5-(E)-iodopentenylthio-TZTP, has high in vitro affinity (Ki = 4.9 nM) and moderate selectivity for the muscarinic M2 receptor subtype. Although the uptake pattern in the biodistribution studies in rats is consistent with muscarinic M2 receptor disribution, specific in vivo binding to these receptors could not be demonstrated. The usefulness of this tracer in human SPET imaging may therefore be limited.

We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).

A new (radio)iodinated, beta-adrenoceptor ligand, (S)-(-)-4-[3-[(1,1-dimethyl-3-iodo-(2E)-propenyl)-amino]-2- hydroxypropoxy]carbazole (CYBL8E, 1), was prepared. 1 is an iodinated analogue of the high-affinity beta-adrenoceptor antagonist carazolol (2). The asymmetric synthesis was achieved in four steps starting from 4-hydroxycarbazole. The iodine-123-labeled form was obtained by an iododestannylation reaction with [123I]NaI in the presence of H2O2. Using classical in vitro displacement experiments with membrane fractions of cardiac left ventricular muscle, 1 proved to have a high affinity for the receptor (Ki = 0.31 +/- 0.03). Biodistribution studies performed in New Zealand white rabbits demonstrated the specificity of the binding in vivo to the receptor. Uptake of [123I]1 was reduced significantly in both atrial muscle, left ventricular muscle, frontal cortex, cerebellum, and striatum, by the pretreatment of the animals with different beta-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective beta-adrenoceptor antagonist, which binds specifically to the beta-adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of beta-adrenoceptors using single photon emission computerized tomography.

A series of 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazines (CYD1, 2, 3, 5) with a 4-substituent incorporating a 1-hydroxy-3-iodo-2-propenyl moiety, except CYD2 which lacks the hydroxy, was synthesized as potential in vivo imaging ligands for the dopamine transporter. For two of the piperazine derivatives (CYD3 and 5), possible stereoselectivity was considered as well (both E- and Z-form). Their in vitro potency for inhibition of [3H]dopamine uptake in rat striatal synaptosomes was 10-fold lower than that of GBR 12,909 used as a reference. The highest Ki values were 137 and 101 nM for CYD1E and CYD3E, respectively. Inhibition potency was higher for the E- than for the Z-isomers. In vivo distribution of radioactivity in rats injected with the 123I-labeled CYDs showed preferred striatal uptake for CYD1E and CYD3E as compared to the cerebellum and occipital cortex. Although the E-isomer of CYD3 showed the best in vitro and in vivo binding characteristics, its striatal uptake ratios (maximal value: 2.7 for striatum-to-cerebellum at 4 h p.i.) are too low to consider application in human Single Photon Emission Computed Tomography studies.