Structure-localization relationships of 11C-labeled phentermine derivatives: effect of aromatic substitution.

A series of phentermine analogs, including the unsubstituted, the para-F, -Cl, -Br and -I, and the meta-CF3 derivatives, were labeled by [11C]methylation and evaluated in rats to determine the structure-localization relationships for this class of regional cerebral blood flow imaging agents. All the phentermines were well-localized in the brain; however, only the para-substituted agents were well-retained. Localization in the nontarget tissue was affected by the lipophilicity of the substituent. Comparison with the radioiodinated analogs showed virtually identical results, which suggests that the compounds were not significantly metabolized. The agent with the best biodistribution characteristics was the N-[11C]methyl-p-iodophentermine, with the p-bromo analog almost equivalent.

Selective monomethylation of the primary amine function using [11C]CH3I and the N-trifluoroacetyl derivative: preparation of N-[11C-methyl]chlorphentermine.

A simple, rapid and efficient method for the preparation of a potential brain blood-flow agent, N-[11C-methyl]-chlorphentermine ([11C]NMCP), is described. Optimization of the radiochemical yield of [11C]NMCP was accomplished by a Gabriel-like reaction which permits the transformation of a primary amine to a secondary amine through a sequence of acylation, deprotonation, monomethylation and saponification. This method precludes the formation of polymethylated by-products which can reduce radiochemical yields, particularly with low specific activity 11CO2.

Beta-adrenoceptor antagonist activity of bivalent ligands. 1. Diamide analogues of practolol.

Two series of bivalent ligands (P-X-P) containing the (R,S)-3-[(4-aminoaryl)oxy]-1-(isopropylamino)propan-2-ol pharmacophore and a connecting alpha,omega-dicarbonylpoly(methylene) [X = -OC(CH2)nCO-] or alpha,omega-N,N'-bis(carbonylmethylene) polymethylenediamine [X = -OCCH2NH(CH2)nNHCH2CO-] spanner were synthesized and evaluated for beta-adrenoceptor antagonist activity in rat heart and lung membrane preparations. The target compounds were obtained as a mixture of stereoisomers in modest yields by using a three to four step sequence beginning with N-benzylpractolol. The results from the competitive binding studies indicated that binding affinity increased by a factor of up to 160 by increasing the length of the group spanning the pharmacophore moieties. Modest increases in cardioselectivity were also obtained. The data suggest that further increases in spanner length and lipophilicity and optical resolution may improve the potential of a labeled bivalent beta 1-adrenoceptor antagonist to function as a myocardial imaging agent.

N-[11C-Methyl]chlorphentermine and N,N-[11C-dimethyl]chlorphentermine as brain blood-flow agents for positron emission tomography.

N-[11C-methyl]chlorphentermine ([11C]NMCP) and N,N-[11C-dimethyl]chlorphentermine ([11C]NDMCP) were prepared from chlorphentermine and 11CH3I in DMF and evaluated in rats as brain blood-flow agents for positron emission tomography (PET). Tissue distribution of [11C]NMCP showed that brain uptake was 2.70 +/- 0.40% of injected dose per organ at 5 min with no change in radioactivity concentration up to 30 min after i.v. injection. Approximately 80% of the initial brain uptake remained at 60 min. On the other hand, initial brain uptake of [11C] NDMCP (3.66 +/- 0.31 and 3.63 +/- 0.88% injected dose per organ at 5 and 15 min, respectively) was greater than that of [11C]NMCP. The brain activity however, rapidly decreased to 2.38 +/- 0.17 and 1.82 +/- 0.32% at 30 and 60 min, respectively. Because of its longer retention in the brain compared with [11C]NDMCP, [11C]NMCP would be a potential brain blood-flow agent for quantitative PET studies.

Synthesis and biodistribution of 125I labeled bivalent analogs of practolol as potential myocardial imaging agents.

Iodinated bivalent ligands 3 and 4 and a monovalent ligand 5 were prepared from the cardioselective beta-antagonist, practolol. 125I-labeled 3, 4 and 5 were prepared by solid phase isotopic exchange reaction with carrier-free Na125I and examined in rats as potential receptor-site-directed myocardial imaging agents. Biodistribution of these agents in rats indicated that 125I-3 and 125I-4 were localized in the heart similarly to 125I-5 and the [125I]iodobenzoyl (6) that was previously reported. Localization of 125I-3 and 125I-4, was more persistent in the heart than that of 125I-monovalent ligands 5 and 6. Heart-to-blood ratios of 125I-3 and 125I-4 were significantly lower than those of 125I-5 and 125I-6, due mainly to slow blood clearance rates of 125I-3 and 125I-4.

Synthesis and evaluation of p-iodo-phentermine (IP) as a brain perfusion imaging agent.

p-(123I and 131I)iodo alpha,alpha-dimethylphenethylamine (p-iodophentermine, IP) as the alpha-methylated analogue of iodoamphetamine has been prepared. It is hoped that this methyl substitution will increase the lipophilicity of the agent, enhance resistance to metabolism by monoamine oxidase, and will result in increased initial uptake and slower washout from the brain as compared to N-isopropyl-p-(123I)iodoamphetamine. IP was prepared by diazotization of p-aminophentermine followed by decomposition of the diazonium salt with KI. Radioiodinated IP was prepared either by the solid-phase isotopic exchange reaction or by decomposition of the piperidinotriazene derivative with a radiochemical yield of 40-60%. Biodistribution of 131I-IP in rats showed brain uptake in the range of 1.7% dose g-1 at 5, 30 and 60 min. Imaging studies with 123I-IP in dogs showed high brain extraction and slow washout of activity.

Preparation and evaluation of 3-[125I]iodo-4-aminophentermine as a brain perfusion imaging agent. Comparison with labeled phentermine derivatives.

A radioiodinated derivative of the anorexinergic drug phentermine was synthesized and evaluated as a potential brain imaging agent. Stoichiometric iodination of the intermediate 4-aminophentermine (AmP) gave a mixture of mono and diiodo products, while the radioiodination at the no-carrier-added (NCA) level gave 73% isolated yield of the 3-[125I]iodo-4-aminophentermine with less than 2% of the diiodo derivative. The tissue distribution of the radiochemical in rats showed that it was readily extracted by the brain followed by relatively slow clearance from that organ. However, a comparison with other labeled phentermine derivatives indicated that the total brain uptake, retention and selectivity of the new agent were poorer, probably as a result of the presence of the 4-amino substituent.