Synthesis of [2‐{(4‐chlorophenyl) (4‐[ 125 I]iodophenyl)} methoxyethyl]‐1‐piperidine‐3‐carboxylic acid, [ 125 I]CIPCA: A potential radiotracer for GABA uptake sites

The synthesis of racemic [2‐{(4‐Chlorophenyl) (4‐iodophenyl)} methoxyethyl]‐1‐piperidine‐3‐carboxylic acid, (CIPCA) and its radioiodinated analog [ 125ß I]CIPCA is described. CIPCA was synthesized from 4‐iodobenzoyl chloride in five steps in 16% overall yield. Ammonium sulfate catalyzed solid‐state isotopic exchange of CIPCA with Na 125 I provided [ 125 I]CIPCA in 34% isolated radiochemical yield at a specific activity of 118 Ci/mmol. [ 125 ICIPCA] demonstrated moderate brain extraction and good in vivo radiostability in preliminary biodistribution studies conducted in CD‐1 mice. [ 125 I]CIPCA is a potentially useful radiotracer for study of the GABA uptake system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90161/1/2580361008_ftp.pd

Potential tumor- or organ-imaging agents. 28. Radioiodinated esters of cholesterol and pregnenolone

Previous studies had shown radioiodinated esters of cholesterol and pregnenolone to accumulate in steroid-secreting tissues of the rat. This was particularly true for radioiodinated iopanoate esters. The present study was undertaken to examine the effect of the iopanoyl amino group on the tissue distribution of these esters. While the tissue distribution profiles for cholesteryl iopanoate and the desamino analog (III) were somewhat comparable, such was not the case for the corresponding esters of pregnenolone. Moreover, this subtle structural change of removing the amino group was observed to affect the stability of the esters to hydrolysis. This conclusion is in accordance with the observation that the tissue distribution profiles for the free acids I and II are not significantly different from each other. These studies serve to demonstrate that relatively minor modifications of the acyl moiety have a profound effect on both the uptake and distribution of these sterol esters in various tissues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26697/1/0000245.pd

Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers

Meta-hydroxyephedrine (HED) comprises four stereoisomers consisting of two enantiomeric pairs related to ephedrine and pseudoephedrine. HED is transported into adrenergic neurons and radiolabeled HED has been employed in positron emission tomography (PET) to image adrenergic neurons in vivo. To extend structure-activity analyses of binding sites within monoamine transporters and to determine which stereoisomer displayed the best selectivity for PET imaging applications, we tested the HED compounds for their abilities to inhibit [ 3 H]neurotransmitter uptake into platelets, transfected cells, and chromaffin vesicles. We hypothesized that the HED compounds would be most potent at the norepinephrine transporter (NET) compared to the serotonin or dopamine transporters and that the 1R diastereomers would be more effective than 1S diastereomers. Supporting the hypotheses, all stereoisomers were most potent at the NET and the 1R,2S stereoisomer was the most potent inhibitor overall. However, the 1S,2R isomer may be preferred for PET applications because of better selectivity among the transporters and reduced neuronal recycling.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42456/1/702-109-10-1229_21091229.pd

Iodine-125 and fluorine-18 labeled aryl-1,4-dialkylpiperazines: Potential radiopharmaceuticals for in vivo study of the dopamine uptake system

A series of fluorine-18 and iodine-125 labeled aryl-1,4-dialkylpiperazine analogs, derivatives of GBR 12935, were synthesized as radiotracers for positron emission tomography or single photon emission computerized tomography imaging of the brain based on their affinity for the presynaptic dopamine reuptake system. High specific activity fluorine-18 tracers were prepared by nucleophilic aromatic substitution reactions; iodine-125 tracers were prepared by isotopic exchange reactions. In vitro competitive binding studies demonstrated that iodine substitution is tolerated in the 4-position of the phenyl ring of the phenalkylpiperazine group. In vivo regional brain biodistribution studies in mice indicated no selectivity of the radioiodinated ligands for the dopamine reuptake site, with striatum/cerebellum concentration ratios of 1. Similar negative results with the new fluorine-18 derivatives demonstrated that in vivo selectivity for the dopamine reuptake site appears to be critically dependent on the carbon chain length between the piperazine ring and the solitary aromatic ring. These studies suggest that development of new radiopharmaceuticals based on the GBR 12935 structure cannot be based solely on considerations of in vitro binding affinities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30090/1/0000461.pd

NMDA receptor channels: Labeling of MK-801 with iodine-125 and fluorine-18

Methods for labeling the glutamate channel blocking agent MK-801 with iodine-125 (125I) and fluorine-18 (18F) are described. Radioiodine was incorporated in the 1- or 3-positions of the aromatic ring of (+/-)MK-801 by solid-state halogen exchange techniques. Attachment of the [18F]fluoromethyl group to the bridgehead methyl position was achieved by reaction of [18F]fluoride with the triflamide alcohol 8 or the novel cyclic sulfamate 9 recently reported by Merck chemists. Radiochemical yields of (+/-)13-[18F]- fluoromethyl-MK-801 were >72%, EOB; radiochemical purity >99%. In competitive binding studies using rat brain homogenates, (+/-)3-bromo-MK-801 showed greater affinity than (+/-)MK-801 for the glutamate-linked channel. The experimental log P (2.1 +/- 0.1) of MK-801 is optimal for transit of the blood-brain barrier. These preliminary findings support further testing of 3-[123I]iodo-MK-801 and (+/-)13-[18F]fluoromethyl-MK-801 as possible agents for in vivo mapping of the glutamate receptor complex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27605/1/0000649.pd

Radioiodination via isotope exchange in pivalic acid

A variety of benzoic and aryl aliphatic mono and polyiodinated acids and esters (sterol, triglyceride) were radioiodinated in 55-99% radiochemical yield by isotope exchange with Na 125I in a melt of pivalic acid. In general, the reaction was complete in 1 h at 155[deg]C with little or no substrate decompostion. High specific activity studies afforded 125I-labeled iopanoic acid with a specific activity of over 700 Ci/mmol.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26445/1/0000533.pd

Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand

A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3-[125I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [125I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C5 maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells. Additionally, F3Cys conjugated with NIR fluorochrome AlexaFluor 647 C2 maleimide demonstrated high tumor specific uptake in melanoma cancer MDA-MB-435 and lung cancer A549 xenografts in nude mice whereas a similarly labeled control peptide did not show any tumor uptake. These results were also confirmed by ex vivo tissue analysis. No-carrier-added [125I]IBMF3 was synthesized by a radioiododestannylation approach in 73% overall radiochemical yield. In vitro cell uptake studies conducted with [125I]IBMF3 displayed a 5-fold increase in its cell uptake at 4 h when compared to controls. SPECT imaging studies with [125I]IBMF3 in tumor bearing nude mice showed clear visualization of MDA-MB-435 xenografts on systemic administration. These studies demonstrate a potential utility of F3 peptide-based radioligands for tumor imaging with PET or SPECT techniques

Synthesis and carbon-11 labeling of the stereoisomers of meta -hydroxyephedrine (HED) and meta -hydroxypseudoephedrine (HPED)

The synthesis of the four stereoisomers of carbon-11 labeled meta -hydroxyephedrine (HED) and meta -hydroxypseudoephedrine (HPED) was undertaken for evaluation of their in vivo kinetic behavior. The stereoisomers of HED and HPED were synthesized by conversion of their respective enantiomerically-pure, normethyl precursors ( meta -hydroxyphenylpropanolamine stereoisomers) to the carbamate derivatives and subsequent reduction with lithium aluminum hydride. Direct N -[ 11 C]methylation of the appropriate normethyl precursor with [ 11 C]methyl triflate and HPLC purification provided the radiotracers in 27–42% (average = 36%; n = 12) decay-corrected radiochemical yields in a 40 min synthesis time from end-of-bombardment. The specific activity of the radiotracers was 1260–1625 Ci/mmol (average = 1368 Ci/mmol; n = 8) at end-of-synthesis and the radiochemical purity >98%. Copyright © 2000 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34875/1/345_ftp.pd