Technetium-99m-MRP20, a potential brain perfusion agent: in vivo biodistribution and SPECT studies in non-primate animals.

MRP20 (N-(2(1H pyrolylmethyl]N'-(4-pentene-3-one-2] ethane-1,2-diamine) complexes with technetium-99m, yielding a neutral, lipophilic species. This compound has been characterized as [TcO(MRP20)]. Biologic investigation of [99mTc][TcO(MRP20)] in female rats showed 2.35% ID in the brain 30 min p.i. with no significant wash-out over 3 hr. A single-photon emission computed tomography (SPECT) study in a dog demonstrated rapid tracer uptake in the brain, reaching a maximum within 1 min, with 2.24% i.d. 15 min p.i., decreasing to 1.7% after 4 hr. The complex undergoes hydrolysis in vitro forming a cationic species. This is possibly the trapping mechanism in the brain in vivo. The main excretory route of [99mTc][TcO(MRP20)] is via the hepatobiliary tract. There is evidence of some "in vivo" cell labeling and soft-tissue uptake.

Synthesis, structure and biological properties of Z-17alpha-(2-iodovinyl)-11beta-chloromethyl estradiol-17beta (Z-CMIV), a high affinity ligand for the characterization of estrogen receptor-positive tumors.

Linkage of a 11beta-chloromethyl group to estradiol-17beta (E2) dramatically increases the binding affinity of the steroid for the estrogen receptor (ER) with the formation of a quasi-irreversible steroid-receptor complex. We have synthesized the two isomers of 11beta-chloromethyl-17alpha-iodovinyl-estradiol (E-CMIV and Z-CMIV) by a novel route. Both derivatives demonstrated high binding affinity and selectivity for ER (RBAs: ER = 820 and 1008; SHBG = 1.2 and 0.25, respectively; E2 = 100). On the basis of X-ray crystallographic data for Z-CMIV and its precursor, we have postulated that Z-CMIV might interact strongly with aromatic amino-acids within a hydrophobic groove of the ER hormone binding domain (HBD) that incorporates pockets corresponding to the 11beta and 17alpha steroid substituents. The binding properties of Z-CMIV labeled with 125I were investigated, especially its ability to detect and quantify altered ER forms with low binding affinity for E2. Sucrose density gradient analysis revealed that Z-CMIV has a higher activation potency than E2 as it converts a higher proportion of non-activated monomers in the cytosol into activated monomers with the potential to dimerize. In in vitro (MCF-7 cells) and in vivo (rat uterus) determinations of estrogenic activity, Z-CMIV was as potent as E2 in increasing progesterone receptor (PgR) concentrations and decreasing ER levels and in stimulating uterine growth. [125I]-Z-CMIV could open the way to new applications in the diagnosis and therapy of ER-positive breast cancers, especially those containing altered (variant) ERs.

Synthesis and biological studies of neutral technetium (V) complexes containing NNOS donor sets.

Complexation of ligands containing an N3S donor set has been affected with [99mTc]. These are part of a ligand series of analogous structures which exhibit similar chemistry and potentially interesting biology. The complexes which have been characterized with [99Tc] as [TcOL] are neutral and lipophilic and their biological behaviour has been assessed in rats. After HPLC purification of the no-carrier added preparation, brain uptake of the tracers was greater than 1% at 15 min p.i. Muscle activity was significant with slow blood clearance.