I-123 MSP AND F[C-11]MSP - NEW SELECTIVE 5-HT2A RECEPTOR RADIOPHARMACEUTICALS FOR IN-VIVO STUDIES OF NEURONAL 5-HT2 SEROTONIN RECEPTORS - SYNTHESIS, IN-VITRO BINDING STUDY WITH UNLABELED ANALOGS AND PRELIMINARY IN-VIVO EVALUATION IN MICE

In vitro binding study on bovine brain membranes using [H-3]SCH23390, [H-3]spiperone, [H-3]prazosin and [H-3]RP62203 as radioligands (for D- 1, D-2, alpha(1) and 5-HT2A receptors respectively) indicate that the new butyrophenones 8-[3-(4-fluorobenzoyl)propyl]-1-methyl- 1,3,8-triaz aspiro[4,5]decan-4-one (FMSP) and 8-[3-(4-iodobenzoyl)propyl]- 1-methy l-1,3,8-triazaspiro[4,5]decan-4-one (IMSP) exhibit significantly highe r selectivity for the 5-HT2A over D-1, D-2 and al receptors. Consequen tly, the radiolabelled analogues F[C-11]MSP and I-123-MSP were prepare d in attempt to obtain potential radiopharmaceuticals for in vivo imag ing of neuronal 5-HT2A receptors with positron emission tomography (PE T) and single photon emission tomography (SPET). F[C-11]MSP was synthe sized by reaction of [C-11]CH3I with obenzoyl)propyl]-1,3,8-triazaspir o[4,5]decan-4-one (DMSP) in 12 +/- 3 % radiochemical yield, whereas I- 123-MSp was obtained in 82 +/- 8 % radiochemical yield by a no-carrier -added Cu(I)-assisted [I-123]iododebromination of propyl]-1-methyl-1,3 ,8-triazaspiro[4,5]decan-4-one (BrMSP). In vivo pharmacokinetic and br ain binding characterization of I-123-MSp assessed in mice following i ntravenous injection, showed a fast clearance of I-123-MSP from blood and relatively high initial uptakes in the liver, kidneys and in the l ung. Significant uptake and long retention were observed in the brain (up to 1.64 % i.d., 60 min p.i.), with a regional accumulation of radi oactivity consistent with the reported 5-HT2A receptors distribution i n the brain. Frontal cortex to cerebellum ratio of 3.5 was calculated at 60 min p.i. Furthermore, the initial brain uptake was significantly reduced after pretreatment of the animals with ritanserin, a selectiv e 5-HT2 antagonist, and by preinjection of the non-radiolabelled analo g IMSP, thus indicating the specificity of the brain uptake. These dat a suggest that I-123-MSp may be a promising compound for studying the serotoninergic 5-HT2 receptors with SPET. Due to the low specific acti vity of F[C-11]MSP currently obtained by the [C-11]methylation reactio n, systematic in vivo investigation of F[C-11]MSP are as yet not feasa ble.