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. 2026 Aug 24;17(9):1948–1955. doi: 10.1021/acsmedchemlett.6c00226

Modified Reaction Conditions for the Radiosynthesis of 11C‑Labeled Asymmetrical Guanidines and the Automated Radiosynthesis of a [11C]mIBG Analog

Jason A Witek †, Avery C Allen †, Allen F Brooks †, Shelbie J Cingoranelli †, Jenelle Stauff †, Tanpreet Kaur †, Xia Shao †, Peter J H Scott †,§,¶,*, David M Raffel †,*
PMCID: PMC13573262  PMID: 42741634

Abstract

Radiolabeled guanidines such as 123/131I-labeled meta-iodobenzylguanidine (mIBG) have been widely used in nuclear medicine for imaging of cardiac sympathetic nerves, as well as imaging and treatment of neuroendocrine tumors. For a variety of reasons (e.g., low tumor uptake, suboptimal kinetics), there is a need for second generation guanidines, and the synthesis and evaluation of such radiopharmaceuticals is a long-standing focus of our group. However, to date, the generation of analogues has been limited to other monosubstituted guanidines, while both symmetrical and asymmetrical disubstituted analogues around the guanidine have been largely ignored because of their synthetic challenges. To address this limitation, herein we report general conditions for the synthesis of carbon-11 radiolabeled asymmetric guanidines and show proof-of-concept through the automated radiosynthesis and preclinical evaluation of a novel mIBG analogue.

Keywords: Carbon 11, radiochemistry, PET imaging, radiolabeled guanidines, cardiac PET

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For decades, guanidine-containing radiolabeled compounds (radiopharmaceuticals) have been utilized in nuclear medicine imaging and therapy. The best-known example used for the imaging of cardiac sympathetic nerves as well as the imaging and treatment of neuroendocrine tumors is 123/131I-labeled meta-iodobenzylguanidine (mIBG, Figure ). More recently, both carbon-11 and fluorine-18 radiolabeled guanidines such as [11C]­3F-PHPOG, [11C]­3Br-pHPG, [18F]­4F-mHPG, and [18F]­3F-pHPG have also been evaluated as potential positron emission tomography (PET) imaging agents (Figure ), ,− and there is considerable interest from our lab and others in development of additional guanidine-based radiopharmaceuticals for both PET imaging and radiotherapy. However, to date, the generation of analogues has been limited to other monosubstituted guanidines, while both symmetrical and asymmetrical disubstituted analogues around the guanidine have been largely ignored because of their synthetic challenges. The goal of the present work is to introduce methods for the radiosynthesis of asymmetrical guanidines and to radiolabel them with carbon-11 for PET imaging applications.

1.

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Representative examples of radiolabeled guanidines.

Our continued focus on developing new guanidine-based radiopharmaceuticals is to address issues with existing agents like mIBG, including optimization of the pharmacokinetics for quantification of norepinephrine transporter (NET) expression in cardiac imaging, and to improve uptake in neuroendocrine cancer for improved detection and treatment of NET-expressing tumors like pheochromocytoma, paraganglioma, and neuroblastoma. Despite many successes, the clinical utility of [131I]mIBG therapy in neuroblastoma is limited, with only approximately 30% of pediatric patients exhibiting a positive response. This modest efficacy is primarily attributed to insufficient expression of NET, the primary means by which mIBG enters the tumor and is retained (through reuptake due to the poor intratumoral retention of mIBG). The tumor microenvironment often exacerbates this issue; hypoxia and altered cellular energetics collapse the transmembrane sodium gradient, functionally downregulating the NET. As a 12-transmembrane protein, NET-mediated uptake is an ATP-dependent process sensitive to NaCl co-transport, pH, and oxygenation levels.

Furthermore, neuroblastoma cells frequently lack the mature storage vesicles found in healthy sympathetic tissues, leading to rapid tracer efflux. Moving from a benzylguanidine to a phenethylguanidine architecture offers a superior alternative by engaging vesicular monoamine transporter 2 (VMAT2). This enables vesicular trapping, providing a secondary retention mechanism that persists even when NET expression is compromised. However, a significant chemical hurdle remains: appending large halogens to the phenyl ring typically reduces the rate of VMAT2 uptake. In this work, we developed both a means to address the chemistry limitations for the formation of diverse 11C-labeled guanidines and a means to generate new mIBG analogues for screening as potential theranostic agents. Historically, generation of asymmetrical carbon-11-labeled guanidines has been difficult since there is always some of the first amine remaining in the reaction mixture, along with the radiolabeled intermediate. There is always a competing reaction to form the symmetric guanidine with two of the first amine versus reaction of the intermediate with the second amine to give an asymmetric amine. In this work, developing a method for radiolabeling the guanidine moiety itself makes it possible to prepare both symmetrical and asymmetrical analogs, enabling entirely new analogues to be readily produced and evaluated. This strategy allows the molecule to carry therapeutic payloads, such as iodine-131 or astatine-211, at alternate sites, such as the other side of the guanidine functional group in asymmetric analogues, allowing for investigations of new radiopharmaceuticals expected to have good NET and VMAT2 uptake.

The use of a carbon-11 synthon provides a facile platform for the rapid evaluation of libraries of radiolabeled guanidines to identify potent agents suitable as potential future theranostic agents for neuroendocrine tumors like neuroblastoma. Specifically, the use of [11C]­cyanogen bromide ([11C]­BrCN) in this work represents a means to produce numerous labeled guanidine analogues quickly and will facilitate the evaluation of second generation theranostics for NET expressing tumors going forward. Building on our group’s continued interest in the synthesis of radiolabeled guanidine compounds, we set out to identify and optimize reaction conditions allowing for consistent formation of carbon-11 labeled guanidines and then expand the scope to include disubstituted guanidines with different modifications around the guanidine core (Scheme ). , Herein, we report general conditions for the synthesis of carbon-11 radiolabeled asymmetric guanidines and the automated radiosynthesis of a novel mIBG analog, [11C]1 (Figure ).

1. Carbon-11 Guanidine: Current State of the Art.

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Full experimental details for syntheses and radiosyntheses as well as analytical data, including copies of nuclear magnetic resonance (NMR) spectra and radio-high-performance liquid chromatography (radio-HPLC) traces, are provided in the Supporting Information.

Synthesis of precursors and standards: HCl salts of asymmetric guanidine standards were obtained using previously reported synthetic methods. , The standard for 1 was synthesized using previously reported literature methods. , Additional details of reaction conditions and general reaction schemes can be found in the Supporting Information.

General Radiolabeling Conditions for Reaction Development: [11C]­Cyanogen bromide was generated from hydrogen [11C]­cyanide and sparged (∼150 mL/min) through a solution containing the first amine precursor (5 μL) dissolved in the desired solvent (H2O, DMSO, i-propanol, 3-pentanol or 2-octanol, 250 μL) as previously reported, , including in preliminary results from our group. The reaction mixture was then kept at room temperature or heated to 80 °C. The resulting [11C]­cyanamide intermediate was then treated with a second amine (15 μL, 100 or 200 μL in 250 μL of solvent) at the indicated temperature (100, 120, 130, or 140 °C) in an open or closed (under pressure) reaction vessel for the indicated time length (5, 8, or 10 min). The radiochemical conversion values of the reaction mixtures were obtained using analytical HPLC (Luna C18 150 mm × 4.6 mm; 60 mM NH4OAc aqueous solution 5–80% acetonitrile; 1.2 mL/min; UV 254 and rad).

Automated Radiosynthesis of [ 11 C]­1: 3-Iodopropene amine HCl (Amine A) (5 mg, 0.023 mmol) was dissolved in 0.1 M sodium borate pH 8.0 (250 μL) and then placed into the reactor of a GE TRACERLab FXM synthesis module. [11C]­Cyanogen bromide was prepared as previously described and bubbled into the reactor while being held at room temperature for 2 min. The resulting [11C]­cyanamide intermediate was then treated with 3-iodobenzyl amine (Amine B) (∼100 μL, 0.178 mmol amine in 50 μL i-PrOH) and heated at 130 °C for 8 min under pressure (∼250 kPa). The reaction mixture was then quenched with 100 mM NH4OAc, pH 4.5 (500 μL), and glacial acetic acid (200 μL, 3.48 mmol). The quenched solution was next purified by reverse phase HPLC (Synergi 4 μ Polar-RP 80Å; 250 mm × 10 mm) at a flow rate of 4 mL/min using 50% acetonitrile, 40 mM NH4OAc, pH 4.7, buffer. The product peak was collected (∼12 min, Figure ) and diluted with 30 mL of MQ H2O, followed by trapping on a C18 solid-phase extraction cartridge. The trapped product was washed with 5 mL of sterile H2O, eluted with 250 μL of EtOH, and then rinsed with 2.25 mL of saline into a sterile dose vial to give a formulated dose of [11C]1 (10% EtOH in saline, 2.5 mL, pH 5.5, 153.6 MBq (4.15 mCi, 0.14% radiochemical yield)).

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Representative semipreparative HPLC trace for purification of [11C]1 (t R ∼ 12 min).

HPLC analysis: The chemical and radiochemical purities of compounds were analyzed using a Shimadzu LC2010 HPLC equipped with a Bioscan/Eckert and Ziegler radioactivity detector and an ultraviolet (UV) detector. Representative analytical HPLC traces are provided in the Supporting Information.

General Reaction Methodology Development: Analytical HPLC Column: Luna C18 150 mm × 4.6 mm; mobile phase: 60 mM NH4OAc aqueous solution 5–80% acetonitrile; flow rate: 1.2 mL/min; UV: 254 nm and rad; oven temperature: 40 °C.

Automated Radiosynthesis of [ 11 C]­1: Analytical HPLC – Column: Synergi 4 μ Polar-RP 80Å 250 × 4.6 mm; mobile phase: 50% acetonitrile, 40 mM NH4OAc, pH: 4.7; flow rate: 2 mL/min; UV: 254 nm; oven temperature: 40 °C; Semi-Preparative HPLC – Column: Synergi 4 μ Polar-RP 80 Å 250 mm × 10 mm; 50% acetonitrile, 40 mM NH4OAc, pH 4.7; 4 mL/min; UV: 254 nm; column temperature: 25 °C.

At the onset of this project, two goals for improved reaction conditions were set: (1) consistent, cleaner formation of the [11C]­cyanamide intermediate en route to labeled guanidines and (2) reagent stoichiometry that favors asymmetric guanidine formation. Precursor amines were commercially available or synthesized using previously reported methods. , Standards were synthesized using reported procedures (see SI for full details). , Initially, the traditionally used conditions for generation of [11C]­cyanamide intermediate 2 that involve heating of a solution of borate/H2O and [11C]­cyanogen bromide at 80 °C were revisited. Unfortunately, it was found that the [11C]­cyanamide intermediate 2 was susceptible to hydrolysis in water, especially at elevated reaction temperatures, leading to decreased overall formation (Table , entries 1 and 2). In an attempt to minimize this breakdown of the reaction intermediate, DMSO was used as the reaction solvent at 80 °C. This resulted in slightly decreased formation of the [11C]­cyanamide intermediate 2 (Table , entry 3).

1. Optimization of Reaction Conditions to Generate [11C]­Cyanamide Intermediate 2 (RCC = Radiochemical Conversion).

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  Solvent Temperature Time (min) RCC (%)
1 borate/H2O 80 °C 5 45 ± 13 (n = 2)
2 borate/H2O room temperature 1 67 ± 1.6 (n = 2)
3 DMSO 80 °C 5 39 (n = 1)
4 i-propanol room temperature 1 94 ± 2.3 (n = 2)
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When revisiting the literature for inspiration, we found that, in 1996, Niwa and co-workers reported the synthesis of isomelamines and isocyanurate through trimerization of cyanamides. Closer inspection of the reported reaction conditions revealed that the initial cyanamides were generated at −5 °C. As noted above, generation of [11C]­cyanamide intermediate 2 in borate/H2O was attempted at room temperature to decrease preference for hydrolysis. While this did lead to increased formation of [11C]­cyanamide intermediate 2 (Table , entry 2), a significant amount of unwanted hydrolysis side product was still observed. Upon reflection, it became clear that the reaction solvent should facilitate both increased cyanamide formation and good conversion to the final guanidine product; therefore, it was postulated that a polar protic solvent could be necessary to aid in activation of [11C]­cyanamide intermediate 2 toward nucleophilic attack. As non-sterically hindered polar protic solvent such as water can easily react with the intermediate instead of the desired amine nucleophile, the use of i-propanol, a secondary alcohol was investigated. Gratifyingly, the increased steric bulk of i-propanol was found to minimize hydrolysis of [11C]­cyanamide intermediate 2 (Table , entry 4), while also having the hydrogen bonding activation required for good conversion of intermediate 2 to the final desired guanidine (see Table ).

2. Brief Amine Ratio Screen.

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  Amine A amount (μL) Amine B amount (μL) Symmetric Guanidine 3 (RCC, % n = 1) Asymmetric Guanidine 4 (RCC, % n = 1)
1 5 15 28 2
2 5 200 21 38
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After optimizing the generation of 2, the next task was to identify conditions favoring generation of asymmetric vs symmetric [11C]­guanidines. Our previous work describes methods to automate the formation of monosubstituted [11C]­guandines. Building on this, next changes in the amount of the first and second amines and how they affect the ratio of symmetric to desired asymmetric guanidine 4 were systematically explored. It was found that increasing the volume of amine B from 3× to 40× that of the volume of amine A was able to shift the reaction mixture to predominate formation of the [11C]­asymmetric guanidine 4 (Table , entry 1 vs entry 2). It should be noted that amine B was added dissolved in solvent or buffer to decrease total loss from dead volume and transfer.

With conditions for producing asymmetric guanidines identified, a series of symmetric and asymmetric [11C]­labeled guanidines 3–10 were next synthesized using the optimized reaction (Table ). Radiosynthesis of symmetric guanidine 3 mirrored trends observed during optimization of the production of cyanamide intermediate 2. It was found that use of DMSO as the reaction solvent decreased formation of the final guanidine product, but interestingly a fair amount of unreacted cyanamide intermediate 2 was also isolated (Table , entry 2). This supports the suspected important role that polar protic solvent plays in activating the intermediate cyanamide toward nucleophilic attack (vide supra). Interestingly, a small change in the reaction temperature from 130 to 140 °C caused a dramatic drop in the amount of final guanidine 3 isolated (Table , entry 3 vs entry 4). This may be due to an increased rate of solvent loss that does not leave sufficient reaction solution left to facilitate complete reaction.

3. Symmetric and Asymmetric [11C]­Guanidines (RCC = Radiochemical Conversion).

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During the course of this work, it was found that in several cases the replacement of i-propanol with 3-pentanol afforded higher RCC of the final asymmetric [11C]­guanidine (e.g. product 5, Table , entry 7 vs entry 8). It is suspected that this is due to decreased loss of solvent over the course of the reaction (reaction temperature 130 °C, bp 3-pentanol = 116 °C vs bp i-propanol = 82 °C). Surprisingly, it was found that switching to a secondary alcohol that had an even higher boiling point than 3-pentanol (2-octanol, bp = 179 °C) as the reaction solvent led to diminishing returns and, in fact, lower conversions (Table , entry 9 vs entry 10 and entry 11 vs entry 12). This may be caused by the decreased polarity of the solvent (2-octanol) slowing down the reaction of the amine nucleophile with the intermediate cyanamide. The developed general radiolabeling conditions gave good RCC (50–76%) of a variety of asymmetric [11C]­guanidines 3–10 with minimal to no formation of the unwanted symmetric guanidine side product (Table ).

Concurrent with optimization of labeling conditions, we also radiolabeled a compound with potentially interesting imaging properties. Combining our interest in developing cardiac imaging agents with medicinal chemistry structural design knowledge, radiopharmaceutical [11C]1 was proposed (Figure ). [11C]1 is an asymmetric guanidine compound that contains two distinct portions. The first is the m-iodobenzyl amine guanidine portion of the molecule that resembles known cardiac sympathetic nerve imaging agent and neuroendocrine theranostic [123/131I]mIBG (Figure A, blue fragment). The second portion of the molecule contains a 3-iodoprop-(2E)-enyl amine that is one of the key moieties in the DAT (dopamine transporter) radioligand [11C]­PE2I (Figure B, purple fragment). − It is an iodine-containing side chain demonstrated to be stable in vivo and offers a place to start in the development of new substituted guanidine analogues of mIBG for development of new theranostics.

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(A) The benzyl core from mIBG was combined with the established stable iodo-side chain from PE2I to provide the new analog [11C]1. (B) Scheme for synthesis demonstrates how two amines can be combined sequentially using [11C]­BrCN to yield substituted guanidines for evaluation as NET substrates. (C) PET image of rat cardiac uptake with the new agent.

The automated radiosynthesis of [11C]1 was carried out early in development using sodium borate as the reaction solvent (Figure B). [11C]­BrCN was prepared and sparged into the reactor containing 3-iodoprop-(2E)-enyl amine (Amine A). The resulting cyanamide was then treated with m-iodobenzyl amine, heated to 130 °C, and allowed to stir for 8 min at temperature in a sealed reaction vessel. The crude reaction mixture was cooled to 50 °C, diluted with HPLC mobile phase and purified by semipreparative HPLC using a Synergi 4 μ Polar-RP at 4 mL/min. The product peak (∼11.5–12.5 min) was collected for ∼60 s (see Figure and Supporting Information), diluted, and reformulated using a C18 Sep-Pak cartridge. [11C]1 was trapped on the cartridge and washed with water to remove residual HPLC mobile phase. The radioligand was then eluted using ethanol and diluted with saline to afford 153.6 MBq (4.15 mCi) of [11C]1 (10% EtOH/saline, 2.5 mL, pH 5.5, radiochemical purity 99%, 0.14% radiochemical yield).

Formulated [11C]1 was next evaluated for suitability in preclinical PET by imaging cardiac uptake in rodent heart. Heart-in-frame by dynamic small animal PET imaging was performed in a Sprague–Dawley rat after administration of [11C]1 (16.4 ± 3.3 MBq, 444 ± 0.09 μCi, n = 2) via tail vein injection. Following a dynamic 90 min scan, a region-of-interest (ROI) for the heart was defined and then used to generate a time–activity curve (See Supporting Information, Figure S1). Peak uptake in the heart occurred rapidly (∼50 kBq/cc within a few minutes of injection corresponding to an SUV of ∼0.9) and was followed by slow washout throughout the duration of the scan, comparable to related agents previously reported. This preliminary imaging data demonstrates that [11C]1 has uptake in the heart and slowly leaks out, which is characteristic of prior mIBG derivatives (SUV of 123I-MIBG in normal rat heart ∼1–1.75 depending on age). , Notably, however, in rats, cardiac uptake of radiolabeled mIBG relies heavily on non-neural, extraneuronal pathways mediated by organic cation transporter 3 (OCT3) in cardiomyocytes, distinguishing it from human uptake which predominantly reflects neuronal NET activity. It is unclear whether this is also the case for [ 11 C]­1, and this should be taken into consideration when comparing rodent SUV values.

In conclusion, further optimization of the traditional reaction conditions for the synthesis of [11C]­guanidines was carried out by tuning the amine precursor ratios and screening reaction temperatures and solvents with the goal of reliable radiolabeling of symmetric and asymmetric guanidines. The optimal radiolabeling conditions using secondary alcohols as a solvent gave good RCC for symmetric and asymmetric guanidines, and a proof-of-concept was demonstrated through the automated radiosynthesis of [11C]1. Initial preclinical evaluation of an asymmetric guanidine in rodents demonstrated that [11C]1 has uptake in the heart, supporting its promising structural design. Further evaluation of [11C]1 and other analogues containing variation of the mIBG portion will be explored in the future. The developed radiolabeling conditions offer a useful tool to quickly combine two different functional motifs to access new radiopharmaceuticals for PET imaging. This work will build on existing PET imaging agents like 3F-pHPG, pairing its high-resolution detection of metastasis with a theranostic agent containing iodine-131, bromine-77, or astatine-211. This opens the door for further research into improved agents, as any two amines of interest can quickly be prepared as asymmetric disubstituted guanidines for evaluation. The automation of disubstituted guanidines with [11C]­BrCN also provides new opportunities in the preparation of other functional groups and heterocycles of interest with [11C]­BrCN as a carbon-11 synthon for the preparation of new PET imaging agents.

Safety Statement: Since radioactivity is hazardous, work was conducted by trained personnel in a dedicated radiochemistry facility, according to all institutional, state, and federal rules and the As Low As Reasonably Achievable (ALARA) principles.

Supplementary Material

ml6c00226_si_001.pdf (4.7MB, pdf)

Glossary

Abbreviations:

DMSO

dimethyl sulfoxide

HPLC

high-performance liquid chromatography

i-PrOH

isopropanol

mIBG

meta-iodobenzylguanidine

NET

norepinephrine transporter

NMR

nuclear magnetic resonance

PET

positron emission tomography

RCC

radiochemical conversion

VMAT2

vesicular monoamine transporter 2

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00226.

  • Chemistry and radiochemistry details, NMR, mass spectrometry and HPLC analysis data, animal imaging information (PDF)

‡.

J.W. and A.C.A. contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding for this research was made possible by financial support from the Michigan Pioneer Fellow program at the University of Michigan Medical School.

Ethics Statement: Rodent imaging studies were performed at the University of Michigan, which is AAALAC certified, in accordance with the standards set by the Institutional Animal Care and Use Committee (IACUC) and all applicable federal, state, local and institutional laws or guidelines governing animal research.

The authors declare the following competing financial interest(s): DMR holds intellectual property on [18F]­4F-mHPG and [18F]­3F-pHPG (US7534418B2 and US10259781B2).

Published as part of ACS Medicinal Chemistry Letters special issue “Radiopharmaceuticals”.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml6c00226_si_001.pdf (4.7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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