Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase

Abstract

BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.

Thioesters for the in vitro evaluation of agents to image brain cholinesterases

“…Synthesized according to a previously described procedure 24 and the analytical data was consistent and purity greater than 98%. Analytical data: MP: 128-130°C (Lit MP = 130°C …”

“…Specific BuChE visualization was also attempted with 4-(N-[ 11 C]methyl) piperidinyl n-butyrate ( 11 C-MP4B) 22 but was unsuccessful 23 . Alternate types of BuChE imaging ligands, derived from N-methylpiperidinol and N-methyl pyrrolidinol, were subsequently synthesized and tested in a normal rat model system 24 . Using autoradiographic analysis these para- 123 iodobenzoate esters were found to have entered the brain and their distribution recapitulated, for the most part, the known distribution of BuChE therein.…”

Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology

“…3) involved protection of PIP (1) with a triisopropylsilyl group and replacement of iodine by a tributyltin by reaction with hexabutylditin in the presence of palladium catalyst. In contrast to a comparable ester-tributyltin intermediate synthesis (35), attempts at conversion of PIP (1) of the iodophenyl moiety of PIP (1). The silyl carbamate protecting group was readily removed during the workup.…”

“…Conversion of IMPY to the tributyltin intermediate was achieved using a procedure similar to that used for PIP (1) and previous ester molecules (35). However, subsequent attempts to incorporate 123 I into IMPY using N-chlorosuccinimide as a free radical initiator were unsuccessful.…”

“…In addition, cholinesterases are found in high concentrations in the plasma, thus, potentially presenting a challenge for the intravenous administration of such cholinesterase imaging agents to reach the brain for in vivo assessment. However, in this respect, studies of BChE imaging agents to date (27,35) suggest that cholinesterase radiopharmaceuticals can be delivered to the brain in sufficient quantity for imaging enzyme activity. SPECT imaging of transgenic AD mice may further elucidate the in vivo characteristics of this cholinesterase imaging agent.…”