Development of the radiosynthesis of high-specific-activity 123I-NKJ64

Tavares, Adriana; Jobson, Nicola K.; Dewar, Deborah; Sutherland, Andrew; Pimlott, Sally L.

doi:10.1016/j.nucmedbio.2010.11.011

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…Since our procedure for radiolabeling involved the use of a small amount of hydrochloric acid to neutralize sodium hydroxide contained in the delivered Na 125 I, it was theoretically possible for the tin labeling precursors to undergo protodestannylation, a commonly known issue for iodination using a tin precursor. 26 Although this phenomenon is more readily observed when a heated reaction mixture is required for a deprotection reaction post labeling, it was investigated further for clarification. To a 3 ml reaction mixture during an experimental trial of the synthesis of 2 , 200 μl of 0.4 N HCl was added and the mixture was concentrated in vacuo to a residue.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Smith

Freeman²,

Stehouwer

et al. 2012

Bioorganic & Medicinal Chemistry

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Compounds 1–4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1–4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1–4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [125I]1 and [125I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [125I]1 and [125I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [18F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [18F]3 and [11C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Smith

Freeman²,

Stehouwer

et al. 2012

Bioorganic & Medicinal Chemistry

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“…Thus, rat brain has seven times more NAT binding sites than non-human primate brain. This has been pointed out as one of the potential reasons underlying the different imaging profile measured with 123 I-NKJ64 (a SPECT radiotracer candidate for imaging of NAT in brain) in rats compared to baboons (Tavares et al, 2011;Tavares et al, 2012a). It is worth noting that that the density of NATs in human locus coereleus is similar to the one measure in non-human primates (Ordway et al, 1997).…”

Section: Preclinical Studies To Evaluate Novel Radiotracer Candidatesmentioning

confidence: 99%

Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use

Shaw

Tamagnan²,

Tavares

2020

Front. Neurosci.

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The advent of preclinical research scanners for in vivo imaging of small animals has added confidence into the multi-step decision-making process of radiotracer discovery and development. Furthermore, it has expanded the utility of imaging techniques available to dissect clinical questions, fostering a cyclic interaction between the clinical and the preclinical worlds. Significant efforts from medicinal chemistry have also made available several high-affinity and selective compounds amenable for radiolabeling, that target different receptors, transporters and enzymes in vivo . This substantially increased the range of applications of molecular imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT). However, the process of developing novel radiotracers for in vivo imaging of the human brain is a multi-step process that has several inherent pitfalls and technical difficulties, which often hampers the successful translation of novel imaging agents from preclinical research into clinical use. In this paper, the process of radiotracer development and its relevance in brain research is discussed; as well as, its pitfalls, technical challenges and future promises. Examples of successful and unsuccessful translation of brain radiotracers will be presented.

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“…Our lead candidate, NKJ64, a stereoisomer of INER was found to have high affinity for the NAT in rat brain ( K i of 8.4 ± 1.7 nM) (Jobson et al,2009). Recently, we reported the radiosynthesis of 123 I‐NKJ64 (Tavares et al,2011b) and the evaluation of 123 I‐NKJ64 in rat brain tissue revealed a nanomolar affinity for NAT ( K D of 4.82 ± 0.87 nM in cortical homogenates) (Tavares et al,2011a). Additional evaluation of 123 I‐NKJ64 in rats showed: (1) the regional distribution of 123 I‐NKJ64 binding to be consistent with the known density of NAT in rodent brain; (2) a maximum uptake of 2.9% of the injected dose in brain; (3) a specific to non‐specific ratio (locus coeruleus:caudate putamen) of 2.8 at 30 min post‐intravenous injection; (4) a relatively fast washout from whole brain with an effective half‐life of 49 min (Tavares et al,2011a).…”

Section: Introductionmentioning

confidence: 99%

Iodine‐123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Tavares

Jobson

Dewar

et al. 2012

Synapse

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(2012) Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography. Synapse, 66 (11). pp. [923][924][925][926][927][928][929][930] Copyright © 2012 Wiley Periodicals, Inc A copy can be downloaded for personal non-commercial research or study, without prior permission or chargeThe content must not be changed in any way or reproduced in any format or medium without the formal permission of the copyright holder(s) When referring to this work, full bibliographic details must be given http://eprints.gla.ac.uk/68100 may lack affinity and selectivity for NAT in baboon brain and 123 I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo.

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Development of the radiosynthesis of high-specific-activity 123I-NKJ64

Cited by 3 publications

References 32 publications

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use

Iodine‐123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

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