Comparison between ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ positron emission tomography-computed tomography in the evaluation of Parkinson’s disease

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder (1-4). Pathologically, the hallmarks of brain degeneration in PD are the presence of protein inclusions called “Lewy bodies” and the loss of dopaminergic neurons in the substantia nigra (SN) (5). Clinically, PD manifests as bradykinesia, rigidity, and tremor due to the loss of dopaminergic neurons (6,7). Current diagnostic criteria are primarily based on clinical symptoms, which can overlap with those of other neurodegenerative disorders, making early diagnosis challenging (6,8). In addition, there is a lack of definitive tests or biomarkers, particularly for early-stage PD diagnosis (9). Molecular imaging techniques, such as positron emission tomography (PET), offer a promising approach to detecting early pathological changes in PD by targeting certain biomarkers (10).

Advancements in molecular nuclear medicine have led to the development of imaging agents that selectively bind to neurotransmitters, receptors, transporters, and other molecular targets, which hold promise for improving the management of PD (11). Before the appearance of clinical features, the diagnosis of abnormal changes through metabolic and functional imaging may offer a critical opportunity to initiate appropriate interventions as early as possible. This early intervention could potentially slow or even halt the progression to advanced stages of the disease.

Notably, two PET tracers, carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl) tropane (¹¹C-CFT) and fluorine-18-labeled fluoropropyl-(+)-dihydrotetrabenazine [¹⁸F-FP-(+)-DTBZ], have emerged as key tools for PD imaging studies (12-14). ¹¹C-CFT targets the presynaptic dopamine transporter (DAT), whereas ¹⁸F-FP-(+)-DTBZ binds to the vesicular monoamine transporter type 2 (VMAT2) (15,16). DATs are localized on dopaminergic axons in the striatum and regulate extracellular dopamine levels (16). VMAT2 is responsible for the vesicular packaging and storage of monoamine neurotransmitters in the synapses (17,18). Despite promising results from preclinical and initial human studies (19), widespread clinical adoption of these tracers (VMAT2) has been limited. The short half-life of ¹¹C poses a challenge for the practical application of CFT, whereas the longer half-life of ¹⁸F-FP-(+)-DTBZ a more feasible option for widespread clinical use.

Animal studies have demonstrated a strong correlation between the specific uptake of CFT and DTBZ and dopaminergic cell counts in the nigrostriatal pathway (20,21). However, it is essential to acknowledge that the pathophysiology of nigrostriatal injury in drug-induced animal models may differ from that in patients with PD (21). Therefore, the clinical utility of both ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in the diagnosis of PD, as well as their relative ability to detect early-stage disease, remains unclear. In this study, we aimed to directly compare ¹⁸F-FP-(+)-DTBZ with ¹¹C-CFT in healthy controls (HCs) and patients with idiopathic PD across different disease stages to assess the application value of these two tracers in clinical practice. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2536/rc).

Methods

Participants

This prospective study was conducted at The First Hospital of Jilin University and enrolled patients diagnosed with idiopathic PD as delineated by the UK Brain Bank criteria (22) and the Movement Disorder Society clinical diagnostic criteria (1). Patients were further classified into categories of mild PD (stages 1–1.5), moderate PD (stages 2–3), and advanced PD (stages 4–5) based on their modified Hoehn-Yahr (H-Y) scale scores. HCs were also recruited for comparison. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Prior to inclusion, all participants provided written informed consent following approval from the Ethics Committee of The First Hospital of Jilin University (No. AF-IRB-029-07).

A total of 52 participants were initially recruited for the study; however, 12 patients were subsequently excluded due to motion artifacts observed during PET/magnetic resonance (MR) scans. Ultimately, 40 cases were included in the final analysis, and their detailed demographic information is presented in Table 1. To ensure consistent baseline conditions, all participants refrained from taking dopamine agonists for at least 12 hours before undergoing both ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT PET/MR scans (23). The two scans were performed within 1 week of each other to minimize potential variations in disease progression or clinical status.

Radiopharmaceuticals

The radiopharmaceuticals used in the study, including the synthesis and labeling of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ, were meticulously prepared in accordance with established procedures documented in previous studies (24,25). Both tracers were produced under strict quality control measures to ensure high radiochemical purity and specific activity as required for clinical imaging applications.

PET/MR data acquisition

Participants received an intravenous injection of either ¹¹C-CFT or ¹⁸F-FP-(+)-DTBZ at a dose of 370±10 MBq (10±0.27 mCi). PET/MR scans were acquired with a hybrid PET/MR system (SIGNA PET/MR, GE HealthCare, Chicago, IL, USA) equipped with a 19-channel head-and-neck union coil. Imaging for ¹¹C-CFT began 60 minutes postinjection, whereas imaging for ¹⁸F-FP-(+)-DTBZ began 80 minutes postinjection to allow for optimal tracer uptake and binding (23). During the scans, participants were instructed to remain still to minimize motion artifacts. Simultaneous PET and MR data acquisition ensured accurate anatomical and functional co-registration, enhancing the precision of the image analysis.

The MR imaging (MRI) protocol included the following sequences: zero echo time (TE) for attenuation correction and anatomical reference and three-dimensional (3D) brain volume (BRAVO) T1-weighted imaging [repetition time (TR)/TE =8 ms/3 ms and voxel size =0.94×0.94×1.6 mm³] for high-resolution structural imaging. The total MRI scan time was approximately 20 minutes. Simultaneously, PET data were acquired in list mode to allow for dynamic reconstruction and precise temporal analysis. This combined PET/MR approach facilitated comprehensive anatomical, functional, and molecular imaging within a single session.

PET images were reconstructed on an Advanced Workstation 4.7 (GE HealthCare) with zero-echo-time images for MR-based attenuation correction via the vendor-provided method. The reconstruction parameters included 20-minute list-mode data, a 192 × 192 matrix, a 350-mm field of view (FOV), a 2.78-mm slice thickness, and 89 slices, with the ordered subsets expectation maximum reconstruction algorithm (OSEM; 6 iterations, 28 subsets, and a 4-mm post-filter) and time-of-flight (TOF) and point-spread-function (PSF) techniques being used to enhance image resolution and quantitative accuracy.

Image analysis

Region-of-interest (ROI) analyses were performed for six brain regions: the caudate body (CB), caudate head (CH), anterior putamen (APu), posterior putamen (PPu), nucleus accumbens (AN), and SN. Visual and semiquantitative analyses were performed by a senior nuclear medicine physician with expertise in PET/MR, who was blinded to clinical information. In cases of uncertainty, the findings were reviewed and resolved through consultation with a more senior physician. A positive finding was defined as reduced radiotracer uptake in at least one hemisphere of the putamen.

In this study, we used six subcortical ROIs in Montreal Neurological Institute (MNI) space derived from the TD Brodmann areas of WFU PickAtlas (https://www.nitrc.org/projects/wfu_pickatlas), the Atlas of Intrinsic Connectivity of Homotopic Area (AICHA), and the Harvard-Oxford subcortical atlas (26-30). Anatomical localization was optimized via a 3D T1-weighted MRI sequence. Mean standardized uptake value (SUV) measurements were obtained for the bilateral CB, CH, APu, PPu, AN, and SN, with the occipital lobe serving as the reference region (31,32). The putamen was subdivided into the anterior (APu) and posterior (PPu) compartments along the anteroposterior midline at its largest axial cross-section. For the occipital lobe reference, an ROI of approximately 1 cm³ was placed in the cuneus. Figure S1 shows the detailed localization of six subcortical ROIs in MNI space, as well as the corresponding PET/MRI and PET images.

The SUV ratio (SUVR) for the ROI was calculated with the occipital cortex serving as the reference region (31,32) according to the following formula: SUVR = ROI uptake/reference uptake. In the PD group, contralateral ROIs were defined as the brain regions opposite to the predominantly affected limbs and were analyzed separately from the ipsilateral ROIs. For the HC group, since the bilateral values were similar, the mean SUVR values from bilateral regions were calculated for comparison. The final SUVR values were used for the subsequent analysis.

Statistical analysis

All statistical analyses were conducted with R software version 4.3.1 (The R Foundation for Statistical Computing, Vienna, Austria), with P values ≤0.05 being considered statistically significant. One-way analysis of variance (ANOVA) tests were performed to assess significant SUVR differences in six brain regions (contralateral and ipsilateral) between the HC and PD groups. Nonparametric correlation analyses were conducted to evaluate the relationship between SUVR values derived from ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ across various brain regions. Subsequently, random forest models were applied to both the ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ PET SUVR datasets. The data were randomly divided into training and testing sets at an 8:2 ratio for model training and evaluation. To improve model stability, average receiver operating characteristic (ROC) curves were computed from the test datasets over 100 iterations. Additionally, the DeLong test was used to compare the ROC curves generated from the ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ datasets.

Results

Patient characteristics

A total of 12 HCs and 28 patients with PD (10 with mild PD, 11 with moderate PD, and 7 with advanced PD) were enrolled between July 2022 and August 2023. Table 1 presents the clinical data for the 28 patients with PD. Comparison of demographic characteristics between PD patients and HCs revealed no significant differences in age (P=0.81) or sex (P=0.71). However, significant differences were observed for motor symptom scores [Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III) scores; P=0.002] between PD patients with different H-Y stages.

Visual analysis of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ imaging

The study compared the in vivo distribution patterns of ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT in HCs and patients with PD. Figure 1 provides axial exemplars of these pathognomonic patterns across disease stages, demonstrating high intertracer concordance in capturing PD-associated dopaminergic degeneration. Both tracers exhibited comparable uptake profiles, with peak radioactivity localized in the caudate nucleus and putamen. Subsequent hierarchical uptake patterns demonstrated marginally higher accumulation in the SN and moderate uptake in the AN. Notably, ¹⁸F-FP-(+)-DTBZ imaging provided enhanced delineation of both AN and SN structures as compared to ¹¹C-CFT. Visual assessments confirmed that both tracers facilitated distinct anatomical differentiation of the caudate-putamen complex.

Figure 1 Representative cases of a healthy condition and of mild, moderate, and advanced PD as demonstrated by ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ PET imaging. ¹¹C-CFT, carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl) tropane; ¹⁸F-FP-(+)-DTBZ, fluorine-18-labeled fluoropropyl-(+)-dihydrotetrabenazine; PD, Parkinson’s disease; PET, positron emission tomography; SUVR, standardized uptake value ratio.

In patients with PD, marked reductions in radiotracer uptake were observed across multiple regions, including the caudate, APu, PPu, AN, and SN, with severity correlating to disease progression. Mild PD cases exhibited asymmetric bilateral uptake deficits in the caudate and putamen, predominantly contralateral to the clinically affected hemibody, which was particularly evident in the putamen. The spatiotemporal trajectory of uptake loss followed a characteristic pattern: PPu involvement preceded APu and caudate degeneration.

In patients with moderate-to-advanced PD, progressive bilateral reductions in tracer uptake were observed across both imaging modalities, with severity correlating to disease stage. The putamen exhibited marked bilateral signal attenuation (approaching complete loss in advanced PD), accompanied by significant caudate nucleus hypoaccumulation. Notably, this degenerative pattern displayed near-symmetrical interhemispheric distribution. Although residual tracer retention persisted in the SN and AN of moderate PD cases, these structures demonstrated progressive effacement in advanced PD, becoming radiologically indistinct on both ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT imaging.

Comparison of SUVR between HCs and patients with PD across disease stages

The results from the comparison of the SUVR between HCs and patients with PD across disease stages are summarized in Table 2 and Figure 2. Overall, in the HC group, higher SUVR values were observed with ¹⁸F-FP-(+)-DTBZ than with ¹¹C-CFT in all six regions. Patients with PD across all disease stages (mild, moderate, and advanced) exhibited lower SUVR values in the bilateral CH, CB, APu, PPu, AN, and SN than did HCs. Significant intergroup differences in SUVR were observed across PD stages and HCs for all regions with both tracers (P≤0.001–0.017) except for the ipsilateral SN under ¹¹C-CFT.

Figure 2 Comparison of regional SUVR values of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ between the PD groups and the HC group. The decreasing color intensity associated with the brain regions indicates the loss of dopaminergic neurons from the healthy to severe PD groups in these two types of images. In the healthy group, the APu, PPu, AN, and SN are highlighted in ¹⁸F-FP-(+)-DTBZ with red color, which indicates higher SUVR values with ¹⁸F-FP-(+)-DTBZ than with ¹¹C-CFT (all P values <0.05; see Table 2 for details). In the PD groups, ↓↓ and ↓↓↓ indicate a decrease in SUVR, which was statistically significant compared with that in the HC group (P<0.05 and P<0.01, respectively; see Table 2 for details). ¹¹C-CFT, carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl) tropane; ¹⁸F-FP-(+)-DTBZ; fluorine-18-labeled fluoropropyl-(+)-dihydrotetrabenazine; AN, nucleus accumbens; APu, anterior putamen; CB, caudate body; CH, caudate head; HC, healthy control; PD, Parkinson’s disease; PPu, posterior putamen; SN, substantia nigra; SUVR, standardized uptake value ratio.

Certain stage-specific reductions were observed. For patients with mild PD, significant SUVR reductions were detected in the contralateral CB (P<0.001), bilateral APu (P<0.001), and bilateral PPu (P<0.001) with both tracers. Additional reductions were observed in the ipsilateral CH (P<0.001), bilateral AN (P<0.001), and contralateral SN (P=0.02) with ¹¹C-CFT, whereas there was a distinct reduction in the ipsilateral CB (P<0.001) with ¹⁸F-FP-(+)-DTBZ. For patients with moderate PD, progressive SUVR decreases occurred bilaterally in the CB, CH, APu, PPu, and AN (P≤0.001–0.005) with both tracers. For patients with advanced PD, marked reductions extended to all studied regions (P≤0.001–0.017) except the ipsilateral SN, which remained unaffected under ¹¹C-CFT.

There was also evidence for tracer-specific patterns. Notably, ¹⁸F-FP-(+)-DTBZ demonstrated enhanced sensitivity in the detection of nigral degeneration, revealing significant bilateral SN reductions in moderate and advanced PD (P=0.003); these findings were not consistently observed with ¹¹C-CFT (Figure 2). This difference in performance between tracers highlights distinct binding properties and regional selectivity in dopaminergic terminal imaging.

Concordance of SUVR between ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ

The Spearman rank correlation analysis (Figure 3) demonstrated a strong positive correlation between ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT in brain regions. Notably, the correlation was robust in both sides of the PPu (contralateral: ρ=0.75, P<0.001; ipsilateral: ρ=0.82, P<0.001), APu (contralateral: ρ=0.75, P<0.001; ipsilateral: ρ=0.76, P<0.001), and contralateral CB (ρ=0.61, P<0.001). In other regions, significant, albeit weaker, correlations were observed, including in both sides of the CH (contralateral: ρ=0.56, P<0.001; ipsilateral: ρ=0.46, P<0.001), ipsilateral CB (ρ=0.40; P=0.01), contralateral SN (ρ=0.33; P=0.03), and ipsilateral AN (ρ=0.31; P=0.05). However, no significant correlation was found in the ipsilateral SN (P=0.07) or contralateral AN (P=0.37). These results indicate a high agreement between ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in terms of the SUVR in most regions.

Figure 3 Spearman rank correlation analysis of SUVR for ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in HCs and patients with PD with different stages. ¹¹C-CFT, carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl) tropane; ¹⁸F-FP-(+)-DTBZ; fluorine-18-labeled fluoropropyl-(+)-dihydrotetrabenazine; AN, nucleus accumbens; APu, anterior putamen; CB, caudate body; CH, caudate head; CI, confidence interval; contra, contralateral; HC, healthy control; ipsil, ipsilateral; PD, Parkinson’s disease; PPu, posterior putamen; SN, substantia nigra; SUVR, standardized uptake value ratio.

Diagnostic performance of both ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ

In the evaluation of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ for the diagnosis of PD, PET SUVR datasets were analyzed with a random forest model. ROC curves were generated, and the corresponding area under the curve (AUC) values were calculated (Figure 4). Both tracers demonstrated strong diagnostic performance (AUC >0.7) in identifying patients with PD and differentiating patients with PD across various Suzuki stages. The variable importance within the random forest models for ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ was visually represented. Both models identified the putamen as having the most significant impact on PD staging, with the CH also playing a critical role in this process (Figure S2). In addition, the DeLong test was employed to compare the ROC curves for differentiating between HCs and other conditions (P<0.001), mild PD and other conditions (P=0.02), moderate PD and other conditions (P=0.04), and advanced PD and other conditions (P=0.74). The results of the DeLong test indicated that CFT outperforms DTBZ significantly in distinguishing between HCs, individuals with mild PD, and those with moderate PD.

Figure 4 Random forest model analysis of SUVR and corresponding ROC curves for both ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in HCs and patients with PD with different stages. Random forest models were applied to both the ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ PET SUVR datasets. The data were randomly split into training and testing sets at an 8:2 ratio. To reduce the instability of the models, average ROC curves were derived from test datasets with 100 repetitions. ¹¹C-CFT, carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl) tropane; ¹⁸F-FP-(+)-DTBZ; fluorine-18-labeled fluoropropyl-(+)-dihydrotetrabenazine; AUC, area under the curve; HC, healthy control; PD, Parkinson’s disease; PET, positron emission tomography; ROC, receiver operating characteristic; SUVR, standardized uptake value ratio.

Discussion

Dopaminergic neurotransmission is primarily regulated by DAT and VMAT2, both of which serve as critical biomarkers in PD imaging (15,33). ¹¹C-CFT PET evaluates DAT function, whereas ¹⁸F-FP-(+)-DTBZ PET assesses VMAT2 density. However, their relative performance in PD diagnosis, particularly when used with hybrid PET/MR systems and superior anatomical resolution, remains underexplored. This study systematically compared these tracers when integrated into PET/MR in differentiating HCs and PD patients of different disease stages. ROIs included the CB, CH, APu, PPu, AN, and SN. In addition to the traditionally focused striatum area, we observed the uptake of these two radiotracers in small nuclei groups, including the AN and SN, with 3D-T1 MRI being used to assist in localization.

Visual analysis and comparison of SUVR in PD imaging

The comparison of ¹⁸F-FP-(+)-DTBZ (VMAT2-targeted) and ¹¹C-CFT (DAT-targeted) in PET imaging revealed both concordant and tracer-specific patterns in capturing dopaminergic degeneration across PD stages. These findings provide critical insights into the spatiotemporal dynamics of PD pathology and the distinct molecular mechanisms probed by each tracer.

Concordance in striatal degradation patterns

Both tracers demonstrated high agreement in detecting early and progressive dopaminergic loss in the striatum. This finding of a characteristic spatiotemporal trajectory—PPu involvement preceding APu and caudate nucleus degeneration—is consistent with previous studies (34). This pattern was evident in both visual assessments and SUVR quantification, reinforcing the utility of these tracers for tracking disease progression. The near-complete signal loss in the putamen of patients with advanced PD, observed under both modalities, underscores the severe nigrostriatal depletion characteristic of late-stage disease.

Tracer-specific advantages and regional selectivity

¹⁸F-FP-(+)-DTBZ PET imaging provided enhanced spatial resolution for visualizing extrastriatal brain structures. The superior delineation of the AN and SN by ¹⁸F-FP-(+)-DTBZ likely stems from its higher baseline SUVR values in these regions (HC SN:SUVR =1.811) compared to ¹¹C-CFT (HC SN:SUVR =1.421), which improve contrast-to-noise ratios. This aligns with autoradiographic evidence showing higher VMAT2 density (than DAT) in the SN pars compacta (SNc) and ventral tegmental area (35), enabling clearer visualization of small nuclei. Notably, ¹⁸F-FP-(+)-DTBZ detected significant bilateral SN reductions in patients with moderate PD (P=0.003), while this reduction was less pronounced with ¹¹C-CFT for patients at an early or intermediate disease stage. This suggests that VMAT2 imaging may better reflect later-stage nigral neuron loss, whereas DAT tracers capture early synaptic dysfunction.

Meanwhile, ¹¹C-CFT was more sensitive to early compensatory changes. In patients with mild PD, ¹¹C-CFT was associated with broader SUVR reductions, including in the ipsilateral CH (P<0.001), bilateral AN (P<0.001), and contralateral SN (P=0.02), as compared to ¹⁸F-FP-(+)-DTBZ. This aligns with the hypothesis that DAT downregulation occurs earlier in PD as a compensatory response to dopaminergic neuron loss, preceding VMAT2 decline. The significant contralateral SN reduction with ¹¹C-CFT in patients with mild PD (P=0.02) further supports its utility in detecting SNc-specific pathology, the hallmark of early PD, whereas ¹⁸F-FP-(+)-DTBZ was only associated with a slight decrease. This difference in loss between DAT and VMAT2, with larger deficits in DAT, aligns with previous work by Wilson et al. (36).

Differences in performance in the SN and AN

The lack of significant SUVR differences with ¹¹C-CFT in the ipsilateral SN with (P=0.26) contrasts with ¹⁸F-FP-(+)-DTBZ’s bilateral nigral sensitivity. This discrepancy may be attributed to a number of factors. The first is molecular target specificity: DAT is predominantly expressed in SNc neurons, which degenerate early, whereas VMAT2 is retained in surviving neurons and glial cells, enabling later detection. The second is partial-volume effects: The SN’s small size and ¹¹C-CFT’s lower spatial resolution may obscure ipsilateral changes, which may be exacerbated by incomplete partial volume correction. Similarly, the weaker correlations between tracers in the AN (ipsilateral AN: ρ=0.31, P=0.05) may arise from differences in regulation between DAT and VMAT2 in this region.

Correlation between ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT

The robust Spearman correlations between ¹⁸F-FP-(+)-DTBZ and ¹¹C-CFT SUVR values in key striatal regions (e.g., the bilateral PPu and APu and the contralateral CB; ρ=0.75–0.82; P<0.001) indicate a high degree of concordance in capturing dopaminergic terminal integrity across these regions. These findings align with the shared pathological basis of PD, in which progressive nigrostriatal degeneration drives parallel reductions in both DAT and VMAT2 density. The strong correlations in the PPu and APu—regions known to exhibit early and severe dopaminergic depletion in PD—suggest that either tracer could reliably monitor disease progression in these areas. This consistency reinforces their utility as complementary biomarkers for striatal degeneration. However, weaker correlations in regions such as the ipsilateral CB (ρ=0.40; P=0.01) and contralateral SN (ρ=0.33; P=0.03), along with nonsignificant correlations in the ipsilateral SN (P=0.37) and contralateral AN (P=0.05), highlight region-specific differences between the tracers. These discrepancies may arise from distinct molecular targets (DAT vs. VMAT2) and their differential expression patterns. For instance, the SNc, a primary site of PD pathology, exhibits higher DAT messenger RNA expression than it does VMAT2 expression in the ventral tegmental area (37). Microglial activation developing from the midbrain of patients with early-stage PD is vital in disease initiation and progression (38). This regional heterogeneity could explain why ¹¹C-CFT (a DAT ligand) showed significant reductions in the contralateral SN during early PD (Table 2), whereas scans with ¹⁸F-FP-(+)-DTBZ (a VMAT2 ligand) indicated delayed SN changes, primarily in the advanced stages. Similarly, the lack of correlation in the contralateral AN may reflect distinct compensatory mechanisms (20,39), with DAT downregulation in early PD potentially preceding VMAT2 loss, thus leading to differences in the SUVR. These findings can also be explained by methodological factors. The ipsilateral SN and AN are small structures prone to partial volume effects, which disproportionately affect SUVR quantification, especially for ¹⁸F-FP-(+)-DTBZ due to its higher baseline uptake. Without partial volume correction, spill-in or spill-out artifacts could artificially inflate or diminish SUVR values, masking true correlations. Furthermore, the moderate sample size of patients with PD (n=28) may limit statistical power in detecting weaker associations in regions with high intersubject variability (e.g., SN).

Diagnostic performance of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in PD

The diagnostic efficacy of ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ in PD was rigorously evaluated via machine learning-driven ROC analysis, revealing both shared and tracer-specific strengths. Both tracers demonstrated robust diagnostic performance across PD stages, with AUC values exceeding 0.7 for distinguishing PD patients from HCs and discerning disease severity. These findings underscore their utility as reliable biomarkers for PD diagnosis and staging. However, there were subtle differences in their performance, particularly in early-stage PD, which highlight the complementary roles of DAT and VMAT2 imaging in capturing distinct aspects of dopaminergic pathology. The DeLong test revealed that ¹¹C-CFT significantly outperformed ¹⁸F-FP-(+)-DTBZ in differentiating HCs from patients with PD (P<0.001) and distinguishing mild PD (P=0.02) and moderate PD (P=0.04) from other stages. This aligns with ¹¹C-CFT’s sensitivity to early synaptic DAT downregulation, a compensatory response to dopaminergic neuron loss that precedes VMAT2 decline. The putamen and CH emerged as the most influential regions in both random forest models, consistent with their early involvement in PD pathology. The putamen’s hierarchical importance likely reflects its role as the earliest site of dopaminergic depletion, whereas the involvement of the CH may relate to its connectivity with the prefrontal cortical regions affected in PD progression. In advanced PD, no significant difference was observed between the tracers (P=0.74), suggesting that widespread nigrostriatal degeneration at this stage reduces the difference between the performance of the tracers. Both tracers exhibited near-complete signal loss in the putamen and caudate, mirroring the severe neuronal depletion characteristic of late-stage PD. This convergence underscores the utility of both tracers in monitoring advanced disease but also their limited ability to resolve subtle pathological differences in patients with end-stage disease.

Mechanistic insights and clinical implications

The superior performance of ¹¹C-CFT in early PD may stem from its ability to detect functional DAT deficits before irreversible neuronal loss occurs. In contrast, ¹⁸F-FP-(+)-DTBZ’s reliance on VMAT2 density—a marker of surviving neurons—may render it less sensitive to early compensatory changes but more reflective of later neuronal attrition. This dichotomy suggests that combining both tracers could enhance diagnostic accuracy, with DAT imaging being used for early detection and VMAT2 imaging for tracking neuronal survival. Clinically, ¹¹C-CFT’s early-stage sensitivity could aid in identifying prodromal PD or patients eligible for neuroprotective trials, whereas ¹⁸F-FP-(+)-DTBZ’s anatomical resolution may better guide deep brain stimulation targeting.

In conclusion, ¹¹C-CFT and ¹⁸F-FP-(+)-DTBZ demonstrate high concordance in striatal and extrastriatal regions; however, their divergent performance in the SN underscores the need for tracer-specific interpretation. The superior sensitivity of ¹¹C-CFT in detecting early SNc degeneration may reflect its alignment with PD’s pathognomonic nigral pathology, whereas ¹⁸F-FP-(+)-DTBZ’s delayed signal decline could indicate VMAT2 preservation in surviving neurons. However, methodological limitations—particularly partial-volume effects and cohort size—suggest that caution against overgeneralization is warranted. Future work integrating longitudinal, multimodal, and partial volume-corrected data will be pivotal in translating these findings into clinically actionable tools for PD staging and therapeutic monitoring.

Limitations and future directions

Although this study has provided novel insights, the moderate sample size limited the statistical power for subgroup analyses (e.g., advanced PD). Additionally, partial-volume correction was not applied, which may disproportionately affect small regions such as the SN. In a similar study by Fu et al. (40), PET tracers targeting DAT (¹¹C-CFT and ¹¹C-MP) and VMAT2 [¹⁸F-FP-(+)-DTBZ and ¹¹C-DTBZ] demonstrated high consistency in capturing striatal dopaminergic degeneration in patients with PD, reflecting a shared pathological basis of nigrostriatal depletion. Both studies confirm the presence of strong correlations between these two tracer classes in key striatal regions (e.g., the APu, PPu, and SN), validating their utility as complementary biomarkers for tracking disease-related structural changes. However, our study extends these observations by revealing distinct clinical advantages for each tracer: ¹¹C-CFT demonstrates higher sensitivity in distinguishing early-stage PD (mild to moderate) and detecting the compensatory downregulation of the DAT, consistent with Fu et al.’s (40) findings that DAT-specific residual gradients may represent an early-stage response. In contrast, ¹⁸F-FP-(+)-DTBZ offers superior delineation of extrastriatal structures (AN and SN) and higher sensitivity for detecting late-stage bilateral nigral degeneration, corroborating Fu et al.’s (40) conclusion that VMAT2 tracers more directly reflect terminal neuronal integrity. Future studies should validate these findings in larger cohorts, integrate longitudinal data to track tracer dynamics across PD progression, and examine hybrid PET/MR biomarkers (e.g., neuromelanin-sensitive MRI) to correlate metabolic and structural changes.

Conclusions

This comparative PET/MRI study demonstrated that both ¹¹C-CFT (DAT) and ¹⁸F-FP-(+)-DTBZ (VMAT2) are highly effective and largely concordant biomarkers for evaluating nigrostriatal degeneration in PD. They reliably trace the characteristic spatiotemporal progression of pathology, from the posterior putamen to the anterior striatal and extrastriatal regions. However, ¹¹C-CFT exhibited superior diagnostic performance in early-stage PD, showing greater sensitivity to the initial compensatory downregulation of DAT, which makes it a powerful tool for the early diagnosis and differentiation of mild and moderate disease stages. Conversely, ¹⁸F-FP-(+)-DTBZ provided enhanced anatomical delineation of the SN and AN, potentially offering a more direct reflection of neuronal integrity in later stages. Future studies with larger cohorts and partial-volume correction are warranted to further validate these findings and clarify their longitudinal applications.

Acknowledgments

The authors would like to thank the patients and their families and physicians for their trust and contribution to this study, as well as Huawei Liu, Yifei Zhang, and Hong Li for their assistance in statistical analysis and manuscript revision.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2536/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2536/dss

Funding: This work was supported by the Scientific Research Project of the Education Department of Jilin Province (No. JJKH20231241KJ).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2536/coif). All authors report that this work was supported by the Scientific Research Project of the Education Department of Jilin Province (No. JJKH20231241KJ). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Prior to inclusion, all participants provided written informed consent following approval from the Ethics Committee of The First Hospital of Jilin University (No. AF-IRB-029-07).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones & J. Gray)