Emerging Receptor and Theranostic Imaging in ACC

Functional Imaging and Theranostics

Emerging receptor and theranostic imaging in adrenocortical carcinoma (ACC) refers to functional imaging approaches that visualize adrenal cortical lineage, receptor expression, or tumor-associated stromal targets with the aim of improving lesion characterization and, in selected cases, enabling radionuclide therapy.¹² Within ACC care, these methods sit downstream from standard anatomic imaging and pathology and are most closely related to the broader field of functional imaging and theranostics rather than to routine first-line staging.

The most developed ACC-specific platform is adrenal-directed imaging based on CYP11B-associated steroidogenic enzymes, particularly metomidate-family tracers and newer agents such as IMAZA.³⁴⁵ These techniques may help establish that a lesion is of adrenocortical origin and may identify a subset of patients with advanced disease who have sufficient target uptake for paired diagnostic and therapeutic radiopharmaceutical strategies.⁶⁷ Other targets, including CXCR4 and fibroblast activation protein (FAP), expand the field beyond adrenal-specific biology but remain exploratory in ACC.⁸⁹

The evidence base is limited. Most reports consist of retrospective single-center series, early translational studies, case reports, or reviews, with little prospective comparative evidence against standard imaging or standard systemic treatment pathways.¹⁰⁶² As a result, receptor-based imaging in ACC remains adjunctive and often investigational. Positive uptake does not by itself establish malignancy, exclude competing diagnoses, or guarantee therapeutic benefit, and negative uptake does not reliably exclude ACC because tracer avidity may vary across lesions and across stages of disease.⁶⁷

These limitations define the current place of the field. Emerging receptor and theranostic imaging may contribute to problem-solving in indeterminate adrenal lesions, biologic characterization of advanced disease, and referral for specialized theranostic protocols, but it does not replace surgery, histopathology, or standard cross-sectional and metabolic imaging workflows.¹²

Diagnostic context and biologic rationale

ACC is a heterogeneous adrenal cortical malignancy in which no single imaging modality fully captures tissue lineage, disease extent, and treatment susceptibility. CT, MRI, and FDG PET remain central to staging and response assessment, but they do not directly identify whether a lesion retains adrenal steroidogenic machinery or another target suitable for radionuclide therapy.¹² Receptor and theranostic imaging addresses this gap by attempting to visualize biologic features that are less apparent on anatomic imaging alone.

The most reliable rationale currently supports adrenal cortex enzyme imaging. Metomidate-based tracers bind CYP11B-related steroidogenic enzymes and therefore tend to highlight adrenocortical tissue rather than non-cortical adrenal or extra-adrenal lesions.³¹ This lineage signal appears reasonably dependable for tissue characterization, but it is less dependable as a complete survey of metastatic disease because not all ACC deposits are tracer-avid.⁶ Clinically, this means a positive study may support adrenocortical origin, whereas a negative study should not be used to rule out ACC.

This biologic framework also explains why theranostics in ACC remains selective. Imaging can reveal whether a target is present, but target expression may be heterogeneous between primary and metastatic sites and may diminish in more dedifferentiated lesions.⁶⁷ The practical implication is that uptake-based selection is necessary but not sufficient for treatment planning.

Adrenal-specific CYP11B-targeted imaging

Metomidate-family tracers

The clearest established use of receptor imaging in ACC involves ^123I-iodometomidate SPECT and ^11C-metomidate PET. Across the available literature, these tracers show relatively high specificity for adrenocortical tissue and may help distinguish adrenocortical lesions from non-adrenocortical adrenal masses.³⁴ This is the most consistent diagnostic strength of the platform and represents its most plausible clinical niche.

However, accuracy for whole-body disease mapping is less consistent in advanced ACC. Retrospective data suggest low overall lesion sensitivity in metastatic disease, with incomplete detection and marked interlesional variability.⁶ Therefore, metomidate-based imaging may complement rather than replace standard staging studies, and its strongest value is in biologic characterization rather than comprehensive burden assessment.

IMAZA and related newer adrenal-directed agents

Newer adrenal-specific agents such as IMAZA were developed to improve on the pharmacologic and imaging properties of earlier iodometomidate compounds.⁵ Early translational and retrospective experience suggests that diagnostic IMAZA uptake can identify a subset of patients with advanced ACC who may proceed to ^131I-labeled therapy, with disease stabilization reported more often than major objective responses.⁷²

At present, this evidence supports feasibility more than established superiority. Reported benefit is derived from highly selected uptake-positive patients, and comparative outcome data remain sparse.⁵⁷ In practice, IMAZA-based theranostics may be considered a specialized investigational option where expertise and infrastructure are available, rather than a routine component of standard ACC management.

Exploratory non-adrenal targets

Beyond adrenal lineage imaging, newer targets attempt to broaden theranostic opportunities in refractory or metastatic ACC. This shift moves from identifying cortical origin to identifying potentially actionable tumor or stromal biology.

CXCR4-targeted PET has shown notable uptake in ACC within mixed-tumor cohorts, suggesting that some tumors may express this receptor strongly enough to justify consideration of CXCR4-directed theranostic approaches.⁸ The finding is biologically interesting, but its reliability for ACC-specific treatment selection is uncertain because outcome data in ACC are limited. The main implication at present is for research prioritization and possible trial screening rather than routine care.

FAP-targeted imaging is similarly early. Preliminary reports and reviews indicate that recurrent or metastatic ACC may be FAP-avid, and compounds with more favorable retention characteristics may have greater therapeutic potential than purely diagnostic tracers.⁹ These observations are hypothesis-generating rather than practice-defining, so FAP-based strategies currently remain best viewed as investigational.

Differential-diagnostic pitfalls

Functional uptake patterns in adrenal tumors are not always specific, and false diagnostic reassurance from a single tracer pattern is a recurring concern. Rare ACCs may demonstrate uptake on MIBG or somatostatin receptor imaging and thereby mimic pheochromocytoma or neuroendocrine neoplasia.¹¹ This illustrates that functional imaging findings must be interpreted alongside biochemical testing, morphology, and pathology.

The supporting evidence for this pitfall is limited and largely case-based, but the principle is clinically important.¹¹ A positive non-specific functional scan should not be treated as definitive evidence against ACC in a large, atypical, or clinically discordant adrenal mass.

Evidence for treatment selection and outcomes

Moving from diagnosis to therapy, the central theranostic question is whether diagnostic uptake predicts meaningful clinical benefit from radionuclide treatment. Available data suggest that only a minority of patients with advanced ACC have uptake patterns sufficient to justify treatment consideration, whether with iodometomidate- or IMAZA-based strategies.⁶⁷²

Among treated patients, reported outcomes generally consist of temporary disease stabilization, with partial responses and prolonged control described in a smaller number of highly selected cases.¹⁰⁵⁷ This suggests biologic activity, but the evidence is not reliable enough to define radionuclide therapy as comparable or superior to established systemic therapy, nor does it alter the central role of surgery in localized disease.¹⁰² The practical implication is that current theranostic treatment is best framed as a niche option for refractory, unresectable, or metastatic ACC in specialized centers.

Limitations and implementation barriers

The main limitations of this literature are small cohorts, retrospective design, selection bias, and substantial heterogeneity in tracer methods, disease stage, and prior treatments.¹⁰⁶² These features limit generalizability and make cross-study comparisons uncertain. Reported response rates and tolerability should therefore be interpreted cautiously.

Operational constraints are also substantial. Access to specialized tracers is limited, expertise is concentrated in referral centers, and theranostic use requires coordinated imaging, dosimetry, and treatment infrastructure.⁷² More broadly, technically demanding functional imaging in adrenal disease can be vulnerable to artifact and interpretive error, reinforcing that such tests should inform but not independently determine diagnosis or treatment strategy.¹²

Role in management and research

Taken together, emerging receptor and theranostic imaging has a limited but distinct role in ACC. It may help clarify adrenocortical origin in selected indeterminate lesions, identify target-positive disease in advanced ACC, and support enrollment in specialized radionuclide therapy pathways or clinical studies.¹²

The field’s main research priorities are better target validation, more reproducible whole-body performance, and prospective evidence linking diagnostic uptake to clinically meaningful outcomes. Current evidence suggests promise, especially for adrenal-specific CYP11B-directed platforms, but does not yet support routine incorporation of these methods into standard ACC care outside selective referral-center or research use.⁵⁸⁹

Included Articles

• PMID 18397978: This study evaluates 123I-iodometomidate SPECT as a molecular imaging method for adrenocortical tissue by targeting CYP11B enzymes. In a small human series, tracer uptake was seen in adrenocortical primary and metastatic tumors but not in a melanoma metastasis, suggesting utility for distinguishing adrenocortical from non-adrenocortical lesions.³

• PMID 22124841: This review describes metomidate-based adrenal imaging as a highly specific method for identifying adrenocortical tissue via CYP11B binding. In ACC, 11C-metomidate PET and 123I-iodometomidate SPECT can visualize primary and metastatic disease, complement anatomic imaging, and support early theranostic use of 131I-iodometomidate.¹

• PMID 22170726: In a monocentric case series of 11 patients with unresectable advanced ACC selected for high [123I]iodometomidate uptake, [131I]iodometomidate radionuclide therapy produced one partial response and five cases of stable disease, with median progression-free survival of 14 months among responders. The treatment targeted adrenocortical tissue specifically, was generally well tolerated, and supports prospective evaluation of metomidate-based theranostics in selected ACC.¹⁰

• PMID 23426614: [123I]iodometomidate SPECT/CT showed high specificity for adrenocortical tissue and differentiated adrenocortical from nonadrenocortical adrenal lesions with reported sensitivity of 89% and specificity of 85% on qualitative analysis. The study supports metomidate-based functional imaging as a noninvasive tool for characterizing indeterminate adrenal masses.⁴

• PMID 23609836: In metastatic ACC, 123I-iodometomidate SPECT/CT showed very high specificity but low overall lesion sensitivity, with uptake present in only a subset of primary and metastatic lesions. About one third of patients had sufficient tracer-positive disease burden to be considered potential candidates for 131I-iodometomidate targeted radionuclide therapy.⁶

• PMID 31469118: This case report shows that adrenocortical carcinoma can rarely demonstrate increased heterogeneous uptake on 123I-MIBG scintigraphy and somatostatin-receptor scintigraphy, mimicking pheochromocytoma. The authors emphasize that false-positive functional imaging can occur in large adrenal masses, so alternate adrenal lesions should remain in the differential despite suggestive scans.¹¹

• PMID 34215922: This preclinical and first-in-human study describes the CYP11B-targeted radiopharmaceutical IMAZA for adrenocortical tumors, showing greater metabolic stability, higher specific adrenocortical uptake, and improved imaging properties than iodometomidate. In one patient with rapidly progressive metastatic ACC, therapeutic 131I-IMAZA was associated with a 21-month progression-free interval.⁵

• PMID 34904171: This retrospective series describes an adrenal-specific theranostic strategy using diagnostic [123I]IMAZA SPECT/CT to identify uptake-positive advanced ACC for treatment with [131I]IMAZA. About 38.5% of screened patients had high lesion uptake, and treated refractory cases showed mainly disease stabilization with limited toxicity.⁷

• PMID 35241482: In a large bicentric cohort spanning multiple cancers, adrenocortical carcinoma was among the tumor types with the highest 68Ga-Pentixafor PET uptake and high image contrast, indicating notable CXCR4 expression. The study frames CXCR4 PET as a potential tool to identify patients for CXCR4-directed theranostic strategies.⁸

• PMID 38256859: This review summarizes theranostic radiopharmaceutical strategies in advanced ACC, highlighting adrenal cortex enzyme-targeted imaging and therapy with the [123/131I]IMAZA pair. It reports that uptake-based patient selection identifies only a subset of metastatic ACC cases, but selected patients may achieve disease control with generally favorable tolerability.²

• PMID 39501489: This review and illustrative case series examine FAP-targeted theranostic approaches in recurrent or metastatic ACC, comparing SA.FAPi, FAPi46, and FAP2286. All showed lesion uptake on FAP PET, but 177Lu-FAP2286 had the most favorable retention and dosimetry, suggesting greater therapeutic promise.⁹

• PMID 19244058: A 2009 Radiology letter and response debated the technical adequacy of proton MR spectroscopy for adrenal masses, emphasizing motion, artifact, and peak-assignment problems that may limit interpretability. While not ACC-specific, it supports cautious framing around technically challenging functional imaging in adrenal tumors.¹²

References

Footnotes

1. Metomidate-based imaging of adrenal masses.. Horm Cancer. 2011. PMID: 22124841. Local full text: 22124841.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

2. Radiopharmaceuticals for Treatment of Adrenocortical Carcinoma.. Pharmaceuticals (Basel). 2023. PMID: 38256859. Local full text: 38256859.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹

3. [123 I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes.. J Clin Endocrinol Metab. 2008. PMID: 18397978. Local full text: 18397978.md ↩ ↩² ↩³ ↩⁴

4. Functional characterization of adrenal lesions using [123I]IMTO-SPECT/CT.. J Clin Endocrinol Metab. 2013. PMID: 23426614. Local full text: 23426614.md ↩ ↩² ↩³

5. Novel CYP11B-ligand [123/131I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience.. Eur J Nucl Med Mol Imaging. 2021. PMID: 34215922. Local full text: 34215922.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

6. [¹²³I]Iodometomidate imaging in adrenocortical carcinoma.. J Clin Endocrinol Metab. 2013. PMID: 23609836. Local full text: 23609836.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹

7. Targeting 11-Beta Hydroxylase With [131I]IMAZA: A Novel Approach for the Treatment of Advanced Adrenocortical Carcinoma.. J Clin Endocrinol Metab. 2022. PMID: 34904171. Local full text: 34904171.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹

8. Imaging of C-X-C Motif Chemokine Receptor 4 Expression in 690 Patients with Solid or Hematologic Neoplasms Using 68Ga-Pentixafor PET.. J Nucl Med. 2022. PMID: 35241482. Local full text: 35241482.md ↩ ↩² ↩³ ↩⁴

9. Exploring the FAP-Targeted Therapeutics for Adrenocortical Carcinoma: Choosing the Right Track.. Clin Nucl Med. 2025. PMID: 39501489. Local full text: 39501489.md ↩ ↩² ↩³ ↩⁴

10. [131I]iodometomidate for targeted radionuclide therapy of advanced adrenocortical carcinoma.. J Clin Endocrinol Metab. 2012. PMID: 22170726. Local full text: 22170726.md ↩ ↩² ↩³ ↩⁴ ↩⁵

11. Adrenocortical carcinoma mimicking pheochromocytoma on iodine 123-labeled metaiodobenzylguanidine scintigraphy.. Pol Arch Intern Med. 2019. PMID: 31469118. Local full text: 31469118.md ↩ ↩² ↩³

12. Insufficient spectral quality to draw conclusions.. Radiology. 2009. PMID: 19244058. Local full text: 19244058.md ↩ ↩²